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Impact Of DNA mutations on blood cell production uncovered

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Impact Of DNA mutations on blood cell production uncovered

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This article goes over the mutation in the blood and how to better understand it

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Researchers have uncovered how genetic mutations hijack the production of blood cells in different periods of life, and how these changes relate to the development of age-related diseases, including blood cancer.

The new study, published in Nature, represents the first time that the lifelong impact of genetic mutations on cell growth dynamics has been explored. The work was carried out by scientists at the Wellcome Sanger Institute, the Cambridge Stem Cell Institute, EMBL's European Bioinformatics Institute (EMBL-EBI), and collaborators.

Why do cells exhibit DNA mutations?

All human cells acquire genetic changes in their DNA throughout life, known as somatic mutations. A specific subset of these mutations drives cells to multiply. This is common in blood stem cells, and results in the growth of populations of cells with identical mutations known as 'clones'. This process, termed 'clonal haematopoiesis', becomes ubiquitous with age and is a risk factor for developing blood cancer and other age-related conditions.

Tracking cells and patients

"For the first time we have been able to use genomic analysis to understand the past, present, and future of mutant clones in our blood," said Moritz Gerstung, co-senior author of the study, from EMBL's European Bioinformatics Institute and the German Cancer Research Centre (DKFZ). "These data show that the dynamics of blood clones are surprisingly predictable over a period of years, but also highlight that they change over a lifetime in ways we don't understand yet."

To understand how and when clonal haematopoiesis develops, how it is influenced by ageing, and how it relates to disease, the researchers tracked nearly 700 blood cell clones from 385 individuals aged over 55. Participants donated regular blood samples for up to 16 years.

DNA sequencing of blood samples showed that over 90% of clones expanded at a stable exponential rate over the period studied. The rate of growth was primarily influenced by the nature of the mutated gene in each clone.

Using the past to predict future mutations

"Our findings reveal how acquired genetic DNA changes hijack blood formation during our lifetimes, with normal blood stem cells competing against cells with pre-leukaemia mutations," said Margarete Fabre, PhD student at the Wellcome Sanger Institute and the University of Cambridge. "Understanding why some mutations prevail in youth and others in old age could help us find ways to maintain the health and diversity of our blood cells."

"Our work shows that mutations not only grow at different rates but also appear at different times during adult life, and that there is a good association between higher growth rates and progression to myeloid cancers," concluded Jose Guilherme Coelho Peres de Almeida, previously a PhD student at EMBL-EBI, now a Postdoc at the Champalimaud Centre for the Unknown. "This provides not only insights into the fundamental biology of somatic evolution but can also be helpful in the clinic."

This is a short version of a press release published on the Wellcome Sanger Institute website.

Funding

This research was funded by the Leukaemia and Lymphoma Society, Rising Tide Foundation for Clinical Cancer Research, Wellcome Trust and Cancer Research UK.

Patients were part of the SardiNIA longitudinal cohort study supported by the National Institute of Health and the European Union's Horizon 2020 Research and Innovation Programme.

Source article(s)

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Impact of DNA mutations on blood cell production uncovered | EMBL

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Researchers have uncovered how genetic mutations hijack the production of blood cells in different periods of life, and how these changes relate to the development of age-related diseases, including blood cancer. The new study, published in Nature , represents the first time that the lifelong impact of genetic mutations on cell growth dynamics has been explored.

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The heredity is the result of discrete units of inheritance, and every single gene was independent in its actions in an individual's genome.

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Mendelian inheritance, the principles of heredity formulated by Austrian-born botanist, teacher, and Augustinian prelate Gregor Mendel in 1865. These principles compose what is known as the system of particulate inheritance by units, or genes. The later discovery of chromosomes as the carriers of genetic units supported Mendel's two basic laws, known as the law of segregation and the law of independent assortment.

In modern terms, the first of Mendel's laws states that genes are transferred as separate and distinct units from one generation to the next. The two members ( alleles) of a gene pair, one on each of paired chromosomes, separate during the formation of sex cells by a parent organism. One-half of the sex cells will have one form of the gene, one-half the other form; the offspring that result from these sex cells will reflect those proportions.

A modern formulation of the second law, the law of independent assortment, is that the alleles of a gene pair located on one pair of chromosomes are inherited independently of the alleles of a gene pair located on another chromosome pair and that the sex cells containing various assortments of these genes fuse at random with the sex cells produced by the other parent.

Mendel also developed the law of dominance, in which one allele exerts greater influence than the other on the same inherited character. Mendel developed the concept of dominance from his experiments with plants, based on the supposition that each plant carried two trait units, one of which dominated the other. For example, if a pea plant with the alleles T and t ( T = tallness, t = shortness) is equal in height to a T T individual, the T allele (and the trait of tallness) is completely dominant. If the T t individual is shorter than the T T but still taller than the t t individual, T is partially or incompletely dominant-i.e., it has a greater influence than t but does not completely mask the presence of t, which is recessive.

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Mendelian inheritance | Gregor Mendel, Genes, & Genetics

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Mendelian inheritance, principles of heredity formulated by Austrian-born botanist, teacher, and Augustinian prelate Gregor Mendel in 1865. These principles form what is known as the system of particulate inheritance by units, or genes. Mendel's laws include the law of segregation and the law of independent assortment.

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Harvard study identifies inherited mutations precancerous blood condition. 

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Harvard study identifies inherited mutations precancerous blood condition. 

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10% of 65 year olds have this condition where they have abnormal white blood cells which may become cancerous.

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A new study led by researchers at Harvard Medical School and the Harvard T.H. Chan School of Public Health has identified some of the first known inherited genetic variants that significantly raise a person's likelihood of developing clonal hematopoiesis, an age-related white blood cell condition linked with higher risk of certain blood cancers and cardiovascular disease.

The findings, published online July 11 in , should help illuminate several questions about clonal hematopoiesis: how it arises, why it occurs in more than 10 percent of people over 65 and how the genome we inherit influences the mutations we acquire later in life.
Get more HMS news here
The condition, uncovered in a series of studies over the past 10 years, is marked by the accumulation of genetically abnormal white blood cells, which may become cancerous or contribute to inflammation in atherosclerotic plaques.

"Clonal hematopoiesis is increasingly appreciated to be an important biomarker of risk for future illness, but we haven't known what brings it about," said the study's co-senior author, Steven McCarroll, the Dorothy and Milton Flier Professor of Biomedical Science and Genetics at HMS and director of genetics at the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard.

"These findings reveal specific sequences of genetic events-some inherited, others acquired-that give rise to these abnormal blood cells," he said.

The study also reaches the surprising conclusion that inherited genetic variants and acquired mutations are more connected than previously understood.

Acquired mutations are believed to occur randomly over time, appearing spontaneously or after exposure to damaging agents such as ultraviolet light. However, the team found examples where inherited variants led to the appearance of specific acquired mutations later in life or gave cells with such mutations a growth advantage over other cells.

"Conceptually one of the most intriguing things to come out of this work is the blurring of that distinction between genetic inheritance and acquired mutations," said McCarroll. "Inherited alleles turn out to have powerful influences on what was previously thought to be a more capricious process."
Out of proportion
Normally, each of the body's 10,000 to 20,000 hematopoietic, or blood-forming, stem cells contributes roughly the same number of mature blood cells to the body's total. The result: a pool of hundreds of billions of blood cells with many different parents.

Clonal hematopoiesis occurs when a single stem cell acquires mutations that cause it to produce far more than its share of new cells, including white blood cells. Over many years, the mutants out-compete normal blood cells, either proliferating more rapidly or surviving longer. Instead of the typical 1/10,000th, or 0.0001 percent, of a person's total white cell count, the progeny of a single mutated stem cell might make up 2 percent, or 20 percent, or more than 90 percent of a person's white blood cells. These genetically dominant blood cells are called clones.

Previous research from McCarroll's lab and others showed that only some clones cause trouble. For example, only about 10 percent of people with clonal hematopoiesis go on to develop blood cancer. Even so, that risk is 10 times higher than that in the general U.S. population.

The team set out to learn which parts of the genome tend to be mutated in clones, which mutations are most harmful, and how clones arise and expand their numbers.

To do so, co-first authors Po-Ru Loh, assistant professor of medicine at HMS and Brigham and Women's Hospital, and Giulio Genovese, senior computational biologist in the McCarroll lab, developed a mathematical approach that let them identify clones early on, when they accounted for as little as 1 percent of a person's white blood cells. Previous methods lacked the precision to detect clones unless they had expanded to at least 15 to 20 percent of white blood cells.

Armed with their new technique, Loh and Genovese analyzed DNA from the blood of 151,000 people who'd donated samples to the UK Biobank.
Not so random after all
The increased level of sensitivity allowed the team to find clones in more than 8,000 participants, many of whom had acquired similar mutations.

To the researchers' surprise, participants with similar acquired mutations often shared a rare, inherited variant nearby. Further investigation confirmed that this was far from a coincidence; the inherited variants had powerful effects on whether people acquired those other mutations later in life.

"When Giulio suggested searching for influences of inherited genetic variants, I never expected to turn up anything interesting," said Loh. "When I first saw the results, the associations were so strong I wondered if they were a bug in the code."

The researchers were then able to figure out the specific ways that the inherited variants made people vulnerable to developing clones.

The inherited variants and acquired mutations typically appeared in the same part of the genome. Some inherited variants made certain spots on chromosomes more vulnerable to future mutation. Others created easy ways for future mutations to increase the rate at which cells proliferate.

In some cases, an inherited variant inactivated one copy of a gene that normally protects against cancer. Later on, an acquired mutation inactivated the other copy.

"These are examples of what cancer geneticists call the two-hit model, where the inherited allele is the first hit and then the subsequent acquired mutation is the second hit," said McCarroll. "It's still not cancer, but having many, many white blood cells with that combination of mutations almost certainly puts one in a more vulnerable place."

Another inherited variant inactivated one copy of a gene that promotes cell growth. This flummoxed the researchers at first, since the variant appeared to protect against aggressive cell growth or cancer. But many of the people who inherited this variant later acquired a mutation that replaced the inactivated gene with the full-strength copy inherited from the other parent. Cells with the acquired mutation then out-competed other cells.

The variants the team uncovered are rare, and inheriting one doesn't guarantee that a person will develop clonal hematopoiesis. However, certain variants did make acquiring clones with a specific mutation much more likely-conferring up to a 50 percent chance, compared to the normal risk of well under 1 percent.

The researchers even found instances where multiple family members who inherited the same variant went on to develop clones with the same mutation.

The authors believe their findings are likely not a fluke.

"I think it's safe to predict that these are early examples of a phenomenon we'll see again and again," said McCarroll.
The demographics of clones
Some acquired mutations were more common in women, others in men. Although clones in general are much more common in older people, two acquired mutations appeared across all ages, suggesting they arise from developmental rather than age-related processes.

The discoveries invite further efforts to understand the nature and consequences of each mutation.

"Although it's been possible to say that, on average, clones might increase the risk of blood cancer tenfold, that doesn't mean every specific clone does," said McCarroll. "A key direction is to go from talking generically about clones to knowing each clone's history and risk profile based on its specific mutations and frequency in the blood."

As information builds, researchers will be able to better assess the risk of each clone and try to develop environmental or medical interventions might slow the growth of clones and avert disease, McCarroll said.
Funding and affiliations
Alkes Price, professor of statistical genetics at the Harvard T.H. Chan School of Public Health, is co-senior author of the study. Loh was a postdoctoral researcher in the Price lab before joining the HMS faculty.

McCarroll is an institute member of the Broad Institute; Alkes and Loh are associate members. Additional study authors are based at Harvard University, the University of Oxford, Massachusetts General Hospital, Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine.

This study was supported by the National Institutes of Health (grants R01HG006399, R01GM105857, R01MH101244, R01HG006855, R01HD081256, R21HG009513, P30CA008748, UM1HG008900 and fellowship F32HG007805), a Burroughs Wellcome Fund Career Award at the Scientific Interface, the Next Generation Fund at the Broad Institute of MIT and Harvard, the Stanley Center for Psychiatric Research, the Fannie and John Hertz Foundation, the U.S. Department of Defense (Breast Cancer Research Breakthrough Awards W81XWH-16-1-0315 and W81XW-H-16-1-0316), the Elsa U. Pardee Foundation and the Simons Foundation (SFARI awards 346042 and 385027).

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A new study led by researchers at Harvard Medical School and the Harvard T.H. Chan School of Public Health has identified some of the first known inherited genetic variants that significantly raise a person's likelihood of developing clonal hematopoiesis, an age-related white blood cell condition linked with higher risk of certain blood cancers and cardiovascular disease.

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Why do some people get ADHD, while others do not? And how early in life or in the womb is the seed of ADHD sown?

Researchers from Aarhus University have come closer to answering this question in a large study, which has just been published in the journal Nature Genetics.

Together with national and international partners, the researchers have studied more than six million genetic variants in 38,691 people with ADHD and 186,843 people without ADHD. By this means it has been possible to identify 27 genetic risk variants for the common neurodevelopmental disorder.
Risk genes are expressed in the brain and neurons
The study is ground-breaking, inter alia because it finds more than twice as many risk variants as previous studies have identified.

The term "genetic variants" means specific variations in the DNA code -- in this case, variants which are observed more frequently in people with ADHD than in people without the diagnosis. Variants in DNA affect, for example, the degree to which a gene is expressed and subsequently the amount of protein that is encoded by the gene.

By linking the genetic variants -- i.e. the variations in DNA -- to specific genes, the researchers have gained new knowledge about which tissues and cell types are particularly affected in individuals with ADHD. The study is based on data from the Danish iPSYCH cohort, deCODE Genetics in Iceland and the Psychiatric Genomics Consortium.

Subsequently, the researchers combined the results with existing data on gene expression in different tissues, cell types and brain development stages, and they discovered that genes involved in ADHD have a particularly high level of expression in a wide range of brain tissues and early in brain development -- in fact already at the embryonic stage.

"This emphasises that ADHD should be seen as a brain developmental disorder, and that this is most likely influenced by genes that have a major impact on the brain's early development," says Professor Ditte Demontis of the Department of Biomedicine at Aarhus University, who is first author of the study.

In addition, the researchers found that the genetics that increase the risk of ADHD particularly affect genes that are expressed in neurons, especially dopaminergic neurons.

"This is interesting because dopamine plays a role in relation to the reward response in the brain, and because a frequently used form of ADHD medicine works by increasing the concentration of dopamine in different brain regions. Our results indicate that the imbalance in dopamine in the brains of people with ADHD is partly attributable to genetic risk factors," says Ditte Demontis.
Associated with reduced concentration capacity and short-term memory
ADHD is influenced by many common genetic variants, each of which increases the risk slightly, says the professor.

In fact, with the help of advanced statistical models, the researchers have estimated that there are around 7,300 common genetic variants that increase the risk of ADHD. It is particularly interesting that the vast majority of these variants -- 84-98 percent -- also have an influence on other mental disorders, e.g. autism, depression and schizophrenia.

It has previously been shown that risk variants for ADHD can affect a person's cognitive abilities.

To investigate this further, the researchers analysed data from an independent dataset, consisting of 4,973 people who had undergone extensive neuro-cognitive tests. By using information from the new study about which variants increase the risk of ADHD, they found in the independent data set that an increased load of ADHD risk variants in the genome of an individual is associated with reduced reading and mathematical abilities, reduced attention and reduced short-term memory.

"The results increase our knowledge of the biological mechanisms underlying ADHD, and they point to specific genes, tissues and cell types involved in ADHD. This knowledge can be used as a starting point for further studies of the disease mechanisms and identification of new drug targets," explains Ditte Demontis.

And the study must be followed up, she emphasises.

"We have only mapped a small fraction of the common variants that influence ADHD -- just 27 of the 7,300 that potentially exist. So there is a need for larger genetic studies," she says.
International cross-disciplinary collaboration is the way forward
Large international collaborations are crucial to identifying the genetic causes of psychiatric diseases and neurodevelopmental disorders, because to do so requires studies of tens or hundreds of thousands of people with these conditions. Just as in the current ADHD study, there are often 100 or more researchers involved, with different areas of expertise, such as genetics, psychiatry, psychology, epidemiology, molecular biology, statistics, bioinformatics and computer science.

"In order to understand more of the genetic and biological mechanisms, it is important to have even larger studies, involving more people with ADHD," says Professor Anders Børglum of the Department of Biomedicine, Aarhus University, who is the last author of the study and one of the research directors of the Danish iPSYCH project.

"But it is also important to undertake studies that focus on identifying how the genetic risk variants perturb biological processes in the brain cells (the neurons), and their way of joining up and communicating with each other in the brain. For the latter, both brain cells and early developmental stages of the brain, so-called mini-brains or brain organoids, are currently being examined" he says.

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attention deficit disorder; mental health research; genes; diseases and conditions; mental health; add and adhd; disorders and syndromes; learning disorders

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Researchers link 27 genetic variants to ADHD

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Why do some people get ADHD, while others do not? And how early in life or in the womb is the seed of ADHD sown? Researchers from Aarhus University have come closer to answering this question in a large study, which has just been published in the journal Nature Genetics.

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-Keely keeton

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Gregor Mendel, the Moravian monk, was indeed "decades ahead of his time and truly deserves the title of 'founder of genetics.'" So concludes an international team of scientists as the 200th birthday of Mendel approaches on 20 July.

The team, from KeyGene in the Netherlands and the John Innes Centre in the UK, draw on newly-discovered historical information to conclude that, when his proposals are viewed in the light of what was known of cells in the mid-19th century, Mendel was decades ahead of his time.

"Uncovering hidden details about Mendel has helped to build a picture of the scientific and intellectual environment in which he worked. At the outset Mendel knew nothing about Genetics and had to deduce it all for himself. How he went about this is highly instructive," said Dr Noel Ellis from the John Innes Centre, one of the contributors to the study.

The new information shows that Mendel began his work with the practical objectives of a plant breeder, before he became interested in the underlying biological processes that condition the heritable differences between organisms. It also shows that Mendel recognised the importance of understanding the formation of reproductive cells and the process of fertilisation.
A small but rich inheritance
Mendel's work and ideas have been studied by many, even though material describing his work is limited. Where Darwin left thousands of letters, for Mendel only a few are known.

Mendel's work started to receive significant recognition 34 years after its publication and 16 years after his death. No notes relating to this work have been found. All that was left was a pair of scientific papers, one of which is the famous 'Experiments on Plant Hybrids' published in German in 1866. This paper remains the basis of what children at school learn about genetics today.
Newspaper articles from Mendel's time have been digitised
Thanks to modern technology, the authors were able to extract valuable information from 19th-century newspaper articles, proceedings, and yearbooks that have recently been digitised. These show how advanced the ideas and work of Mendel were as he used cell biological theory to come to conclusions on how traits of plants are transmitted from parents to their offspring.
Mendel's Elemente: what we know as genes
Mendel noted that pea plants must maintain and transmit the 'code' for the appearance of a trait, we now call these coding instructions genes, Mendel called them 'Elemente.'

For many traits, two different Elemente or 'Elements' are present, for example to code for flower colour in peas, one which conditions purple and an alternative for white flower colour.

Mendel proposed that in the male and female parts of the flower, reproductive cells are formed that only contain one type of Element, and these single Elements are transmitted to a daughter plant, one from the male and another from the female.

We now know that only half of the number of chromosomes is transmitted to egg cells in the female flower parts and pollen in the male flower parts, thanks to the division that occurs during meiosis at the formation of gametes.

Two centuries on from his birth this remarkable scientific life is still offering up new insights.

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botany; genetics; mating and breeding; new species; fossils; origin of life; early climate; ancient dna

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Proof Mendel discovered the laws of inheritance decades ahead of his time

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Gregor Mendel, the Moravian monk, was indeed "decades ahead of his time and truly deserves the title of 'founder of genetics.'" So concludes an international team of scientists as the 200th birthday of Mendel approaches on 20 July.

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Translational medicine will soon be able to be at your side.

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Translational medicine will soon be able to be at your side.

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-Ace Farley

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This week (November 7-8, 2013) the Library of Congress will celebrate the life of Gregor Johann Mendel, the discovery of DNA structure, and the discoveries in biology that are critically necessary for the advancement of clinical and translational medicine.

Gregor Johann Mendel, a Silesian friar known as the father of genetics initiated experimental studies on the laws of inheritance using a variety of plants including peas. His discovery of the laws, now known as Mendelian inheritance, was a scientific breakthrough that was initially overlooked. Mendel presented his results in a paper, Versuche über Pflanzenhybriden [ Experiments on Plant Hybridization] at two meetings of the Natural History Society of Brno in Moravia on February 8 and March 8, 1865. After Mendel's presentations, the key element of inheritance, Deoxyribonucleic acid (DNA), was first isolated by FriedrichMiescher, a Swiss physician at the University of Tübingen in 1869.

The relationship between DNA and inheritance was not uncovered until the 20 th century. The rediscovery of Mendel's results was followed by a chromosomal theory of inheritance and by an understanding of how complex traits involved multiple Mendelian determinants. By the middle of the 20 th century, DNA was thought to be the repository of genetic information and the molecule became a focus of intense study. It was 60 years ago that James Watson and Francis Crick published their monumental paper Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid in Nature, v. 4356, April 25, 1953: 787-788 claiming their discovery of the structure of DNA and indicating how the structure of DNA could facilitate the storage and inheritance of genetic information.

The Library's Science, Technology, and Business Division is sponsoring a panel discussion and lecture/book signing for the 60 th anniversary of the discovery of DNA structure.

On November 7th, a panel will discuss "Translational Medicine: Advancing from Bench to Bedside." The panel is moderated by Orla Smith, the Managing Editor of the Science Translational Medicine and includes two prominent Nobel laureates: Dr. James Watson, an author of the paper published in Nature 60 years ago and Dr. Carol Greider, a recent Nobel laureate in Physiology or Medicine based on her co-discovery that telomeres are protected from progressive shortening by the enzyme called telomerase. Carol Greider is the Daniel Nathans Professor and Director of Molecular Biology and Genetics at Johns Hopkins University. The discussion starts at 11:30 a.m. in the Montpelier Room on the sixth floor of the James Madison Building, 101 Independence Ave. S.E., Washington, D.C.

On November 8th, the Division will sponsor Jan Klein, Director Emeritus of the Max Planck Society for the Advancement of Science and current Frances R. and Helen M. Pentz Visiting Professor of Science in the Department of Biology at Pennsylvania State University for a talk on his biography of Gregor Johann Mendel, Solitude of a humble genius-Gregor Johann Mendel. A native of the Czech Republic- the region where Mendel also called home- Klein is an internationally known immuno-geneticist and has done extensive research on Mendel's work using the scientist's original papers and notes. Klein's presentation is accompanied with illustrations by coauthor and nature illustrator, Norman Klein. This event will start at 11:30 a.m. in the Montpelier Room on the sixth floor of the James Madison Building, 101 Independence Ave. S.E.,Washington,D.C.

These programs are free and open to the public. Tickets are not required, but space is limited and early arrival is advised. Also, these events will be recorded and later broadcast on the Library's webcast and YouTube pages in the coming months.

To learn more about topics related to the lectures you might find the following reference guides of interest:

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Mendel to DNA Structure to Translational Medicine

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This post is about two Library events to mark the 60th anniversary of the discovery of DNA structure- Translational Medicine: Advancing from Bench to Bedside panel discussion with Nobel Laureates Dr. James Watson and Dr. Carol Greider and a lecture/book signing of Solitude of a Humble Genius-Gregor Johann Mendel with author Jan Klein.

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Four ways inheritance is more complex than Mendel knew

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This year marks the 150th anniversary of Gregor Mendel’s publication that--after sitting ignored for a few decades--helped launch the field of modern genetics. Today, we know that inheritance is far more complex than what Mendel saw in his pea plants. Now scientists who track progress in genetics re…

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Certain mental illnesses can be traced to chromosomes 3 and 10 

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Certain mental illnesses can be traced to chromosomes 3 and 10 

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https://www.nih.gov/news-events/nih-research-matters/common-genetic-factors-found-5-mental-disorders

-Finnley Oxford

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The initial sequencing results and analysis of the human genome were published in February 2001, and the data now available, although preliminary, are of critical importance, given the amount of information potentially held in the DNA sequence regarding evolution, human development, physiology and normal and abnormal brain functions.

In this context, the book Genetics of Mental Disorders appears particularly timely, in that it represents a valuable guide to understanding the main issues implicated in the study and treatment of psychiatric disorders from a genetic perspective.

The volume provides a clear and solid basis for an understanding of the genetics of complex traits, from the basic principles of the classical mendelian laws, through the bases of molecular strategies to detect genetic susceptibility, to the non-mendelian patterns of inheritance in psychiatric disorders. Overall, the book has a clinical flavour and constantly refers to the practical clinical applications of information derived from psychiatric genetic studies. Thus, it will be particularly appealing to readers who are not experts in the genetics of complex traits but who want to learn more about this rapidly expanding field. The basic concepts are easily accessible, especially given the concise but substantial glossary, where the meaning of technical terms such as "imprinting," "linkage," "linkage disequilibrium," "phenocopy" and "penetrance" are clearly and effectively explained.

The first 2 chapters introduce the epidemiological bases of psychiatric genetics and the complex factors involved in the study of the heritable nature of psychiatric disorders (including the problem of clinical heterogeneity of psychiatric phenotypes and the complex interaction between genetic and environmental factors in determining their expression). Particularly valuable in this introductory overview is the fact that epidemiological data and information about the complex interactions between genes and environment are addressed from a clinical perspective, with frequent reference to the importance and utility of this information for clinical practice.

The concepts of clinical and etiologic heterogeneity, as well as genetic, biological and clinical dimensions, are clearly discussed in chapter 3. The chapter is enriched with a description of the different approaches suitable for addressing and understanding these issues in both the clinical and the research settings, and it includes a good review of studies on the genetics of schizophrenia, bipolar disorder and attention deficit hyperactivity disorder.

The heterogeneity of the clinical and neurobiological correlates of mental disorders is of particular relevance in psychiatric genetics. In most of the genetic studies on psychiatric disorders performed to date, the phenotype has been defined as the clinical diagnosis. However, the diagnosis, even though structured and validated, is often heterogenous and covers patients with different clinical characteristics, outcomes, biological characteristics and responses to medication. Thus, the definition of more homogenous subphenotypes is likely to be a valid and innovative alternative strategy to deal with the complexity of any psychiatric phenotype. As an example, the consideration of traits that display quantitative variations within a given diagnostic category, instead of (or together with) the diagnosis, has been recognized as a good strategy to take into account the heterogeneity of psychiatric diseases and the complex influence of genetic factors in determining them.

According to a logical sequence, the chapter on causal and clinical heterogeneity in psychiatric disorders is followed by an overview of the available mathematical models to study the mode of inheritance of a given disease. Strategies applicable to both mendelian and non-mendelian diseases are reviewed, together with models of oligogenic and polygenic inheritance, the study of the heritability of quantitative traits, and the genetic concepts of liability and penetrance. Again, the most valuable quality of this section is its simple, clear descriptions of complex mathematical models, with frequent reference to the clinical utility of the information provided. The reader will find suggestions regarding how to use this information in the clinical setting, together with a solid background to help in answering the most common questions asked by patients and their relatives. This aspect makes the section particularly suitable for readers who are not geneticists, although researchers with some expertise in the field will miss more specific information about epistasis and the new population-based approaches to the study of models of gene-gene interaction.

The human genome shows variability across individuals that may underlie variations in biological function, susceptibility to illness or response to medication. There appear to be 30 000 to 40 000 protein-coding genes in the human genome and more than 1.4 million single-nucleotide polymorphisms. The authors review the basic concepts of the various analytical strategies for molecular genetic data, such as linkage analysis, case-control and family-based association designs. The most widely used and validated family-based association design is now the Transmission Disequilibrium Test (TDT), which the authors discuss extensively. The investigation of an association between a given gene and a given disease by means of the TDT has been considered a particularly useful strategy in identifying genes that may contribute to disease susceptibility, especially when the genes are assumed to be of small effect, as in psychiatric disorders. The TDT has been extended recently to the analysis of quantitative traits and thus appears to hold promise for the study of the genetic basis of clinically relevant phenotypes related to dimensions of psychiatric disorders (e.g., age at onset and severity of symptoms).

The chapter on the clinical application of psychiatric genetics covers the instruments used in clinical interviews for genetic purposes, several aspects of genetic counselling and the implications of genetic assessment for the diagnosis and treatment of psychiatric conditions. As an example, the importance of obtaining a good family history for clarifying the diagnosis of probands in families with atypical phenotypes is discussed, together with "clinical tips" to obtain the most reliable information from interviews and case reports.

The last chapter gives an insightful overview of the future of psychiatric genetics, including a careful discussion of the ethical issues implicated by the extensive use of genetic testing.

Perhaps the most promising application of the new genetic knowledge and the new genetic strategies for decoding the information carried by the human genome is the development of new therapeutic strategies and accurate prediction techniques for complications or adverse events during the course of a given medication treatment of illness. This line of research is called pharmacogenetics. Its main goal consists of identifying the genetic factors responsible for variability in response to medication, which is a critical, but still unsolved, problem in psychiatric care. Armed with information about the genetic makeup of individual patients, we will be able to design new therapeutic compounds that relate directly to specific genetic information and to accurately predict response to medication for each patient. This will lead to a dramatic improvement in the long-term outcome of psychiatric diseases that are often chronically disabling and difficult to treat.

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The initial sequencing results and analysis of the human genome were published in February 2001, and the data now available, although preliminary, are of critical importance, given the amount of information potentially held in the DNA sequence regarding evolution, human development, physiology and normal and abnormal brain functions.

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-Ariana Cuellar

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A small mutation can make Zika virus even more dangerous: How outbreaks could happen, even in areas with prior immunity

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Researchers have found that Zika virus can mutate to become more infective -- and potentially break through pre-existing immunity.

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https://www.sciencedaily.com/releases/2006/07/060721202359.htm

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How Purple Corn And RNA Break Genetic Laws

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A newly cloned gene in corn will help explain how unusual interactions between a parent's genes can have lasting effects in future generations. The finding has implications for breeding better crop plants and unraveling complex genetic diseases. The new research indicates that an additional molecule, DNA's little cousin RNA, is needed for the intriguing gene interactions known as paramutation.

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Blue-eyed humans have a single, common ancestor

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New research shows that people with blue eyes have a single, common ancestor. Scientists have tracked down a genetic mutation which took place 6,000-10,000 years ago and is the cause of the eye color of all blue-eyed humans alive on the planet today.

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Over 20% of adults have migraines. This tends to run through families and genetics.

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The nauseating, often debilitating, headaches affect 15-20 percent of adults in developed countries, yet they remain stubbornly hard to explain. Scientists know that migraines tend to run in families but aren't sure exactly how.

A new study published May 3 in the journal Neuron shows why some families are susceptible to migraines and how genetics may influence the type of migraine they get.

"For a long time, we have been wondering why common disease (like migraines) aggregates in families," said Aarno Palotie of the Institute for Molecular Medicine in Finland and the Broad Institute of MIT and Harvard in Cambridge, Mass.

Previous migraine research identified two ways migraines might run in families. Linkage studies, which track sections of chromosomes passed down from parent to child, identified three genes (CACNA1A, ATP1A2 and SCN1A) associated to hemiplegic migraine, a severe form of migraine that induces stroke-like symptoms. These genes fall under a Mendelian inheritance model, meaning the two copies of a gene a child inherits from his or her parents determine a trait or disease. Sickle cell anemia could be thought of as Mendelian.

Another way migraines could run in families involves polygenic inheritance. If a trait is polygenic, that means that a group of genes collectively influence that characteristic. Like being dealt a bad hand in a card game, each common genetic variant may have only a small individual effect, but the collection of common variants builds up to influence the trait -- or disease risk -- a person inherits. Height is an example of a polygenic trait.

Palotie and his colleagues set out to find out whether a few, powerful Mendelian genes or a polygenic accumulation of common variants -- or a combination of both -- influenced how migraines are inherited in families.

First, the researchers developed a polygenic risk score to estimate the genetic burden of common variants. To do this, they gathered data from a previous genome-wide association study, which is a type of study that compares genomes of individuals and flags loci (locations on chromosomes) that differ in people with a disease. In all, hundreds (possibly even thousands) of loci linked to migraines were incorporated into the polygenic risk score.

Next, the researchers tested the influence of the polygenic risk score and the three known Mendelian migraine-linked genes within a large family study of migraine sufferers in Finland. The study included medical history and genetic data of 1,589 families (made up of 8,319 individuals) of known migraine sufferers. The family migraine cohort was compared against other large cohorts as a control, such as the FINRISK study that had 14,470 people total, including 1,101 people with migraine.

Result after result showed that the polygenic common variants were driving migraine risk more than the three Mendelian genes. If a person's migraines started at an earlier age, if a person experienced more severe migraines, or if migraines ran in a person's family, the data showed that it's more likely that person had a greater genetic burden of common polygenic variants to blame.

"The strength of the common variants in these families surprised us," said Palotie.

On the other hand, the three rare but powerful Mendelian genes linked to migraine didn't seem to influence migraine risk as much as the researchers expected. Out of the large family study, researchers identified 45 families with hemiplegic migraine and sequenced their genes. Migraines in only four out of 45 families were driven by the rare Mendelian genes -- more cases were driven by common variants.

"This really shows, in a very big sample set, that common variants are very important factors in aggregation of migraines in the family," said Palotie.

Palotie believes more genome sequencing and larger studies will help researchers find both more common variants linked to migraines and more Mendelian variants.

"This is of special interest for drug development," said Palotie. Even if Mendelian variants don't drive the majority of migraine cases, scientists can research how these genes impact biological pathways responsible for migraine symptoms and potentially develop drugs to target those pathways.

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headache research; genes; cold and flu; teen health; headaches; disorders and syndromes; parkinson's; huntington's disease

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New light on genetic foundation of migraines

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The nauseating, often debilitating, headaches affect 15-20 percent of adults in developed countries, yet they remain stubbornly hard to explain. Scientists know that migraines tend to run in families but aren't sure exactly how. A new study shows why some families are susceptible to migraines and how genetics may influence the type of migraine they get.

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scientists are rediscovering the work of mendel and are finding new species due to genetic mutations.

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Chromosomes, Mutation, and the Birth of Modern Genetics: Thomas Hunt Morgan - Understanding Evolution

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In 1900 several scientists across Europe came to the same realization about heredity that Mendel had some 40 years before. But they arrived at the discovery from a very different direction. Chromosomes contain genetic material Nineteenth century cell biologists discovered that animal and plant cells had a central compartment known as the nucleus.

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In cells, UV-emitting nail polish dryers damage DNA and cause mutations

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In cells, UV-emitting nail polish dryers damage DNA and cause mutations

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The ultraviolet nail polish drying devices used to cure gel manicures may pose more of a public health concern than previously thought. Researchers at the University of California San Diego studied these ultraviolet (UV) light-emitting devices, and found that their use leads to cell death and cancer-causing mutations in human cells.

The devices are a common fixture in nail salons, and generally use a particular spectrum of UV light (340-395nm) to cure the chemicals used in gel manicures. While tanning beds use a different spectrum of UV light (280-400nm) that studies have conclusively proven to be carcinogenic, the spectrum used in the nail dryers has not been well studied.

"If you look at the way these devices are presented, they are marketed as safe, with nothing to be concerned about," said Ludmil Alexandrov, a professor of bioengineering as well as cellular and molecular medicine at UC San Diego, and corresponding author of the study published January 17 in Nature Communications. "But to the best of our knowledge, no one has actually studied these devices and how they affect human cells at the molecular and cellular levels until now."

Using three different cell lines -- adult human skin keratinocytes, human foreskin fibroblasts, and mouse embryonic fibroblasts -- the researchers found that the use of these UV emitting devices for just one 20-minute session led to between 20 and 30 percent cell death, while three consecutive 20-minute exposures caused between 65 and 70 percent of the exposed cells to die.

Exposure to the UV light also caused mitochondrial and DNA damage in the remaining cells and resulted in mutations with patterns that can be observed in skin cancer in humans.

"We saw multiple things: first, we saw that DNA gets damaged," said Alexandrov. " We also saw that some of the DNA damage does not get repaired over time, and it does lead to mutations after every exposure with a UV-nail polish dryer. Lastly, we saw that exposure may cause mitochondrial dysfunction, which may also result in additional mutations. We looked at patients with skin cancers, and we see the exact same patterns of mutations in these patients that were seen in the irradiated cells."

The researchers caution that, while the results show the harmful effects of the repeated use of these devices on human cells, a long-term epidemiological study would be required before stating conclusively that using these machines leads to an increased risk of skin cancers. However, the results of the study were clear: the chronic use of these nail polish drying machines is damaging to human cells.

Maria Zhivagui, a postdoctoral scholar in the Alexandrov Lab and first author of the study, used to be a fan of gel manicures herself, but has sworn off the technique after seeing the results.

"When I was doing my PhD, I started hearing about gel manicures, which last longer than normal polish. I was interested in trying out gel nail polish, particularly in the setting of working in an experimental lab where I frequently put gloves on and off, to maintain a presentable appearance," said Zhivagui. "So I started using gel manicures periodically for several years. Once I saw the effect of radiation emitted by the gel polish drying device on cell death and that it actually mutates cells even after just one 20-minute session, I was surprised. I found this to be very alarming, and decided to stop using it."
Studying their effect on human cells
The idea to study these particular devices came to Alexandrov in a dentist's office, of all places. As he waited to be seen, he read a magazine article about a young beauty pageant contestant who was diagnosed with a rare form of skin cancer on her finger.

"I thought that was odd, so we began looking into it, and noticed a number of reports in medical journals saying that people who get gel manicures very frequently -- like pageant contestants and estheticians -- are reporting cases of very rare cancers in the fingers, suggesting that this may be something that causes this type of cancer," said Alexandrov. "And what we saw was that there was zero molecular understanding of what these devices were doing to human cells."

To conduct the study, Zhivagui exposed the three cell types to two different conditions: acute exposure and chronic exposure to the UV light device. Under acute exposure, Petri dishes containing one of the cell types were placed in one of these UV curing machines for a 20-minute session. They were then taken out for an hour to repair or return to their steady state, and then given one more 20-minute exposure. Under chronic exposure, the cells were placed under the machine for 20 minutes a day for three days.

Cell death, damage and DNA mutations were seen under both conditions, with an elevation of reactive oxygen species molecules- known to cause DNA damage and mutations- and mitochondrial dysfunction in the cells. Genomic profiling revealed higher levels of somatic mutations in the irradiated cells, with patterns of mutations ubiquitously present in melanoma patients.
Is the risk worth the reward?
This data in human cells, coupled with a number of prior reports of cancers in people who get gel manicures very frequently, paint a picture of a purely cosmetic procedure that is riskier than previously believed. But is getting a gel manicure once a year really cause for concern, or should only those who get this done on a very regular basis be worried? Further studies are needed to quantify any increased risk of cancer and at what frequency of use, but with plenty of alternatives to this cosmetic procedure, the risk may not be worth it to some consumers.

"Our experimental results and the prior evidence strongly suggest that radiation emitted by UV-nail polish dryers may cause cancers of the hand and that UV-nail polish dryers, similar to tanning beds, may increase the risk of early-onset skin cancer," they write. "Nevertheless, future large-scale epidemiological studies are warranted to accurately quantify the risk for skin cancer of the hand in people regularly using UV-nail polish dryers. It is likely that such studies will take at least a decade to complete and to subsequently inform the general public. "

Though other consumer products use UV light in the same spectrum -- including the tool used to cure dental fillings and some hair removal treatments -- the researchers note that the regularity of use, plus the entirely cosmetic nature of nail dryers, sets them apart.

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cosmetics; skin cancer; lymphoma; cancer; optics; biochemistry; technology; graphene

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In cells, UV-emitting nail polish dryers damage DNA and cause mutations

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The ultraviolet nail polish drying devices used to cure gel manicures may pose more of a public health concern than previously thought. Researchers studied these ultraviolet (UV) light-emitting devices, and found that their use leads to cell death and cancer-causing mutations in human cells.

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Rare genetic conditions fine new ways to reach out

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Rare genetic conditions fine new ways to reach out

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Shortly after Milo Lorentzen was born, nurses whisked him away to the neonatal intensive care unit for low blood sugar and jaundice. An exam then found a cluster of irregularities, including a cleft palate and a hole in his heart.

The staff called in a geneticist, who issued a misdiagnosis - the first frustrating episode in what would become years of testing, as Karen Park and Peter Lorentzen searched for a way to help their son.

Five years later, Park and Lorentzen know Milo's significant developmental delays likely stem from a mutation in a gene called KDM1A. He didn't inherit that mutation from his parents; it's new in Milo, though it could be passed along to any children he might one day have. And because a mutation in that gene is so rare, little is known about it.

If KDM1A is indeed the culprit, Milo has what's known as a Mendelian disorder - a rare condition caused by a genetic mutation, typically in a single gene. There are some 7,000 to 8,000 Mendelian conditions known, but researchers have found the specific genetic cause for only half. The rest are categorized as Mendelian because they are transmitted from parents to children in ways suggesting they are caused by mutations in single genes.

In some cases - and researchers say Milo's appears to be one of them - a new mutation reveals a condition that's never been identified before. There is no treatment for his condition.

Families who have a child with an illness that's likely genetically based, but never before described in the scientific literature, are lost in an information desert. They can be isolated by research protocols that keep scientific findings quiet until they are published, and by health privacy laws that prevent, for example, a genetics lab from connecting two families who have the same mutation.

The journey of Milo Lorentzen reveals what Dr. Christian Schaaf, a geneticist and assistant professor at Baylor College of Medicine, says are two major inadequacies in genetic medicine - the absence of support for families whose kids are ill but don't yet have a diagnosis, and the lack of a clearinghouse where families and researchers can find one another.

"We all worry about the correct diagnosis, and therapy, and management of the disease," Schaaf says, "but we don't think enough about the isolation these families feel, about the stress and anxiety that comes with these disorders."

Recently, however, new and cheaper techniques in genetic testing and efforts to connect families to each other and to researchers offer promise of a future less desolate.

"There are lots of researchers who might be interested in families with genetic conditions if they knew they existed," says Dr. Michael Bamshad, a pediatrician and research geneticist with the University of Washington Center for Mendelian Genomics.

Bamshad is also cofounder of MyGene2, a grant-funded, not-for-profit website where families, researchers, and clinicians can connect and share information about rare genetic conditions at no cost. The site was a first-round winner in a recent National Institutes of Health competition to make scientific information broadly available.
'You're The Other-Other'
When your child has an undiagnosed genetic disorder, one of life's hallmarks is a frustrating series of tests yielding no answers.

"The first several years of his life was test after test," says Karen Park, Milo's mother. "X-rays, MRIs, blood tests, skin biopsies."

Milo had a range of symptoms: low muscle tone and a body that lacked strength, making him slow to lift his head or push up off his stomach; delays in mimicking people and expressing himself. To his doctors, these symptoms suggested many possibilities.

"It takes forever; it's very slow," Park says of all the testing. "And when things keep coming back negative, you feel like: My child is getting tortured; I'm not getting any insight out of this; I just feel like giving up."

Many rare disorders affect at least enough families to constitute what Park calls a tribe -- enough affected people to spin offparent groups, coping tips, research tools and fundraising walks.

But Milo's parents were on their own.

So far, researchers I spoke with know of only two other children in the world who have a genetic mutation similar to Milo's. In fact, KDM1A is known to be resistant to evolutionary change - a mutation in it is so rare that researchers hardly ever see it in any animal species.

"You're the 'other-other' and not just the 'other,'" Park says.

Bo Bigelow, whose daughter Tess is one of only 10 people in the world known to have a mutation in a gene called USP7, went five years before he knew there was anyone else with a similar mutation.

"These days there are ribbons and awareness weeks for so many diseases," Bigelow says, "but when yours is ultra-rare, you feel completely isolated. You feel like you're never going to hear another person say, 'Us, too!' And being connected to other families changes all that."
Pinpointing The Problem
In 2013, Milo's parents had his genes sequenced with a relatively new technique called exome sequencing, which streamlines the process by focusing only on the parts of the genome that code for proteins, rather than looking at an individual's total DNA. It was then that they learned about Milo's gene mutation.

Still, mutations in KD1MA are so rare that just spotting it didn't give Milo's parents a diagnosis.

Why not?

"We don't know what most of our genes do," explains Barry Starr, a geneticist and director of Stanford at the Tech, a collaboration between Stanford University's department of genetics and the Tech Museum of Innovation in San Jose, Calif.

Genes issue instructions to make proteins that run the functions of a cell. But figuring out what any single gene mutation does is complicated.

You need to know how the mutation affects the proteins, and how the proteins relate to the disease. You also want to know whether the mutation has appeared in other family members who have experienced symptoms.

"You're playing all these games like a detective story," says Starr, "trying to solve a mystery."

One way to get a diagnosis is by looking at previous research.

Bamshad once found a mutation in a gene called MYLPF in a boy who had no muscles in his foot. Bamshad next found a mouse study in which researchers had made a deliberate mutation inMYLPF, resulting in a complete lack of skeletal muscle in the rodent. That was enough evidence to conclude the MYLPF gene was involved in the boy's condition.

But sometimes there is no previously published research to search.

Bigelow says geneticists who told him of Tess' mutation didn't know what this mutation in the USP7 gene did.
Easing The Isolation
Last August, Bigelow put out a beacon to other families who might have the same mutation: a website and social media posts. Remarkably, it took less than a day for a response. Researchers are now examining his daughter's case, and at their request Bigelow has used his website to find two more families with the same mutation.

But it can be a lot slower for families and researchers to search through hundreds of websites and Facebook pages for common ground.

Now Bigelow and Milo Lorentzen's parents are registered on MyGene2, where roughly 130 families are seeking information on mutations in more than 100 genes.

Bamshad envisions expanding that to tens of thousands of families.

"Our major goal is gene discovery and facilitating clinical diagnosis," he says. "Very quickly, we could identify hundreds of Mendelian conditions and help thousands of families get a diagnosis for rare diseases."

The main stumbling block is money to pay for outreach, Bamshad says. Tens of thousands of exome sequences are siloed at individual labs and clinics around the country. Because of federal privacy laws, the only people who can share those are the families who commissioned the sequencing.

"We see lots of families on Facebook who are searching for a diagnosis," says geneticist Jessica Chong, MyGene2 cofounder. "It would take time to go search for them and message each one of them to say, 'We can help you.' "

Dr. Christian Schaaf, who's working with Tess Bigelow's mutation, says it has typically taken 15 to 20 years from the time a disease gene has been discovered until the first patients enter clinical trials. He's hoping new sequencing tools and social outreach can shrink that to seven or eight years.

Milo's parents hope that new research will give them more answers. They found a U.S. lab that has agreed to grow cell lines from Milo's and his father's DNA, and another lab in Europe is looking to run studies using the gene-editing tool CRISPR.

If the labs can replicate Milo's mutation and study its effects, perhaps Karen Park and Peter Lorentzen will learn more about how the mutation led to their son's disorder. From there, will some lab be willing to look at developing a treatment? They don't know.

"It's all us flying blind and making it up as we go along," says Park.

This story was produced by KQED's blog Future of You.

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Families Isolated By Rare Genetic Conditions Find New Ways To Reach Out

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Shortly after Milo Lorentzen was born, nurses whisked him away to the neonatal intensive care unit for low blood sugar and jaundice. An exam then found a cluster of irregularities, including a cleft palate and a hole in his heart.

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Blue-eyed humans have a single, common ancestor

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New research shows that people with blue eyes have a single, common ancestor. Scientists have tracked down a genetic mutation which took place 6,000-10,000 years ago and is the cause of the eye color of all blue-eyed humans alive on the planet today.

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Brody English

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When the man known as "father of genetics" turns 200, how do you celebrate?

By digging up his body and sequencing his DNA, of course.

That's what a team of scientists in the Czech Republic did this year to celebrate Gregor Mendel, a scientist and friar whose experiments in the mid-1800s laid the groundwork for modern genetics.

Mendel lived and worked in Brno, the second-largest city in the Czech Republic. With 2022 marking the bicentennial of Mendel's birth, local researchers there - where Mendel remains something of a hometown hero - searched for ways to remember the man and honor the moment. Possibilities included a festival, a scientific conference, and a statue.

Astronomer Jiří Dušek, director of the Brno Observatory and Planetarium, wondered whether the founder of genetics had ever been subjected to any genetic testing.

"So that was the beginning," says Šárka Pospíšilová, a geneticist who is also the vice rector for research at Masaryk University in Brno.

A 'crazy' idea becomes reality

At first, she says the idea of analyzing Mendel's genes seemed "crazy."

Still, Pospíšilová went around to different specialists at the university to ask what might be possible.

"I asked the anthropologists who had experiences with analysis of remains of various historical persons," she recalls. She consulted with archaeologists as well.

Exhuming Mendel from his grave in Brno and running genetic tests on his remains turned out to be a doable project - so long as they could get permission from the Augustinians. That's the religious order that Mendel belonged to, and with which he remains: The Augustinian tomb in the city's central cemetery was thought to contain Mendel's body.

Local religious leaders consulted with Augustinians in Prague, their bishop, and finally Augustinians in Rome. Eventually, permission was granted.

He had an extraordinarily large brain 🧠 and was 168 cm tall.🚶‍♂️We are talking about the founder of genetics, Gregor Johann Mendel. His remains are currently being studied by scientists from Masaryk University. pic.twitter.com/2TZEUNbrPQ
- BrnoNewsCTV (@BrnoNewsCTV) November 4, 2021

A giant in genetics

Filip Pardy, a molecular biologist on the research team, felt that a heavy sense of responsibility came with being part of this effort.

"Gregor Mendel is a person that is taught at the first course of genetics at the university," says Pardy. "Everybody feels that he's very important, especially here in Brno. He's kind of a role model ... who stood at the beginning of everything we do."

Mendel was ahead of his time in the way he used math to study patterns of inheritance in pea plants when looking at things like flower color and plant height, says Pardy.

"He analyzed a set of about 25,000 plants to actually get his numbers right and to create the formulas," says Pardy. "And so in this regard he was also kind of a visionary and one step ahead."

Mendel's plant experiments were known and respected during his lifetime, but his fame really took off after 1900, when geneticists rediscovered his work and realized its implications.

"No one at the time, including Mendel, I think, suspected that his work would be so groundbreaking in terms of being a major scientific theory," says Daniel Fairbanks, a plant geneticist and author of a book called Gregor Mendel: His Life and Legacy.

Mendel's genes offer clues about his life

The excavation of Mendel's tomb revealed five coffins, stacked one on top of the other. That was a bit of a surprise, given that the tomb's marker had the names of only four Augustinian brothers.

Mendel's coffin seemed to be the metal one at the bottom. It was lined with some newspapers that were dated shortly before he died, which seemed pretty conclusive. Still, Pardy says they wanted even better evidence that this coffin held Mendel's remains.

"We actually came up with this idea of going through his personal possessions because we knew we needed some reference material to actually confirm his identity," says Pardy.

Curators at local museums let them swab items like Mendel's microscopes, his eyeglasses, written records of his meteorological measurements, and a cigarette case. The team also carefully searched inside Mendel's favorite books and, in a book about astronomy, found a hair.

By looking at DNA from all that, and comparing it to DNA in the skeleton, they felt certain that they'd found Mendel's body.

Sequencing his DNA revealed genetic variants linked to diabetes, heart problems, and kidney disease. The variant that most intrigued Fairbanks was in a gene that has been associated with epilepsy and neurological issues.

"He suffered throughout his life from some sort of a psychological or neurological disorder that caused him to have very severe nervous breakdowns," says Fairbanks. "That may well have been an inherited condition - and that was a fascinating discovery that these scientists made."

What would Mendel do?

Fairbanks has thought about how Mendel would feel about being disturbed in his grave to satisfy the curiosity of today's scientists.

"I tend to think, from what I know about him, that he very well may have been happy about this," says Fairbanks. "But of course we can't directly ask him."

Pospíšilová leans toward that theory, too.

"We believe that he would be happy. We know he was very enthusiastic for all kinds of research," she says - noting that just before he died, Mendel requested that an extensive autopsy be done.

"He wasn't against research on his own body," she says.

Even though Mendel knew nothing about DNA or the role that it played in the inheritance patterns he so closely observed, she says, in all likelihood "he wouldn't mind being part of research, even after his death."

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Why scientists dug up the father of genetics, Gregor Mendel, and analyzed his DNA

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When the man known as "father of genetics" turns 200, how do you celebrate? By digging up his body and sequencing his DNA, of course. That's what a team of scientists in the Czech Republic did this year to celebrate Gregor Mendel, a scientist and friar whose experiments in the mid-1800s laid the groundwork for modern genetics.

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Emma VanDorn

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Given the dazzling array of dog breeds, from dachshunds to mastiffs, from poodles to bloodhounds, it's easy to forget that most of that diversity arose only in the last few centuries or so, thanks to human tinkering. People have bred dogs for their looks, but the lion's share of breeding efforts have taken aim at eliciting particular behaviors, according to the University of Pennsylvania's James A. Serpell.

"If you look at the evolution of the dog, selection has been primarily for behaviors: hunting behaviors, guarding behaviors, or giving companionship to humans," he says.

In a new study, Serpell and colleagues Evan L. MacLean of the University of Arizona, Noah Snyder-Mackler of the University of Washington, and Bridgett M. vonHoldt of Princeton University offer strong evidence to support what scientists have long suspected: that some of the behaviors that help characterize breeds -- a drive to chase, for example, or aggression toward strangers -- are associated with distinct genetic differences between them. Their findings were published in the Proceedings of the Royal Society B.

"Dogs present a good model for understanding what portion of the variation in their behavior is attributable to differences in genetics, and how much to their environment and experiences," says Snyder-Mackler, who earned his undergraduate and doctoral degrees from Penn.

What seems obvious -- that genes can influence an individual's behaviors -- has not always been easy to support with evidence, in large part because behaviors are complex traits. Tendencies such as aggression, anxiety, or a compulsion to chase anything that moves are governed by many genes, not just one.

But dog breeds, being highly inbred, have allowed researchers to make progress in this area. Serpell and his colleagues recognized that, if a dog breed is associated with a particular behavior that distinguishes it from other breeds, it might be easier to detect the genetic variants contributing to that behavior if you compared that breed's genome to a host of others.

It helped that Serpell was in possession of a treasure-trove of behavior data from C-BARQ, short for Canine Behavioral Assessment and Research Questionnaire, a survey that more than 50,000 dog owners have filled out about their pets. C-BARQ returns a result on 14 behavioral "factors" about each dog surveyed, giving a measure of traits such as stranger-directed aggression, excitability, energy level, and predatory chasing drive.

For this study, the researchers pulled 14,020 of those entries that included information about pure-bred dogs. To look for associations with genetics, they borrowed data from two earlier studies, together representing 5,697 dogs, for which 172,000 points in the genome had been sequenced.

They found that about half of the variation in the 14 measured behaviors across breeds could be attributed to genetics -- a greater proportion that previous studies have found.

"This was based on breed-average behaviors," notes MacLean, "because we didn't have behavioral and genetic information from the same animals."

What stood out to the researchers was that the traits with the highest rates of heritability -- in other words, those that seemed to be most influenced by genetic factors rather than environmental ones -- were behaviors such as trainability, predatory chasing, stranger-directed aggression, and attention seeking. For these traits, genetics explained 60 to 70 percent of variation across breeds.

"These are exactly the types of traits that have been selected for in particular breeds of dogs," says Serpell. "So for trainability, you're thinking of breeds like border collies that have to respond to human signals to accomplish complicated tasks; for chasing behavior you can think of something like a greyhound, which is innately predisposed to chase anything that runs; and for stranger-directed aggression you might focus on some of the guard dog breeds that are highly protective and tend to respond in a hostile way to unfamiliar people."

Taking advantage of their vast pool of genomic data, the researchers looked for genetic variants associated with breed differences in the 14 C-BARQ traits. They found 131 variants tightly linked to these behaviors. Some were located in genes that have been implicated in influencing behavior, including in humans. But many were unknown and provide fodder for future study.

"This gives us an encouraging start and places to look," says MacLean. "We have ongoing projects where we've obtained genetic and behavioral data from the same individuals, so we'll be able to dive deeper into some of these traits and variants to see if the patterns we found here hold up."

If these genetic differences influence behavior, a good assumption would be that they somehow affect the brain. So, as a final step, the team looked to see where the genes in which key variants appeared were expressed in the body. Their analysis showed the genes were much more likely to be expressed in the brain than in other tissues in the body.

Of note, however, is that the researchers' results also leave plenty of room for individual differences and an animal's environment in influencing behavior.

"It's important to keep in mind that we looked at breed averages for behavior," says Snyder-Mackler. "We're not at a point yet where we can look at an individual's genome and predict behavior. Environment and training still has a very, very strong effect."

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dogs; behavioral science; evolutionary biology; genetics; animal learning and intelligence; biology; veterinary medicine; biochemistry research

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Genes play a role in dog breed differences in behavior

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Border collies are highly trainable, greyhounds love to chase, and German shepherds make good guard dogs. While the environment plays a role, traits like these are highly heritable, according to a study of 101 dog breeds. The work identifies 131 genetic variants associated with breed differences in behavior.

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Introduction
The role of twin and family-based studies
Genome-wide association studies (GWAS)
The relationship between age, genetics, and hypertension
Genetic base of hypertension
The future of genetic investigations in the context of hypertension
References
Further reading

Hypertension is a major modifiable risk factor for renal, cerebrovascular, and cardiovascular disease. The pathophysiology of hypertension, also known as high blood pressure, is complex, whereby both genetic and environmental factors interact with several physiological pathways and mechanisms to produce an observable phenotype.

Image Credit: Chompoo Suriyo/Shutterstock

Epidemiological studies have improved our understanding of the environmental factors that influence hypertension, particularly the role of diet and exercise; however, the role of genetics in the context of hypertension has been a challenge to determine.

Studies of blood pressure data systematically acquired across three generations of the Framingham Heart Study (the first and long-term, ongoing cardiovascular cohort study of residents of the city of Framingham, Massachusetts) have revealed that higher blood pressure in both grandparents and parents is associated with the risk of the same condition appearing in the third generation.

This is particularly true when a family history of hypertension is documented to have been developed before the age of 55; this represents the strongest risk factor via potential in the subsequent generation. This effect occurs independently of a range of measured environmental factors known to influence the risk of hypertension - including sodium intake, alcohol intake, and level of physical activity.

The role of twin and family-based studies

Twin and family-based studies have shown that blood pressure is a heritable characteristic; between 30 and 50% of the variance in this parameter has been linked to heritability. Rare disorders outside of hypertension have also demonstrated a demonstrable role of Mendelian genetics.

However, when observing the distribution of blood pressure, a Gaussian distribution can be seen, which suggests that the mutations are unlikely to play a major role and that the multiple genetic effects (which are quantifiably small) either contribute to or enhance an individual susceptibility to hypertension.

Following advances in genomics, a more widespread opinion is that hypertension is a complex trait with a polygenic (controlled or influenced by several genes) basis. Moreover, environmental influences are also likely to influence epigenetic changes, which can be transmitted across generations.

Image Credit: chayanuphol/Shutterstock

Genome-wide association studies (GWAS)

GWAS have been used to determine common genetic variants. The Wellcome Trust Case Control Consortium (WTCCC) was one of the first to embark upon this. bringing together over 50 research groups from the UK to explore complex human diseases of major public health importance- hypertension being amongst coronary artery disease, Crohn's disease, rheumatoid arthritis, types I and II diabetes, and bipolar disorder. Since then, more recent studies have been conducted, bringing the total number of variants associated with the risk of hypertension to 280. Moreover, these variants are associated with other diseases, such as coronary artery disease, a disease causally associated with the risk of high blood pressure.

The relationship between age, genetics, and hypertension

The premature onset of a condition is considered a genetically driven outcome rather than a result of environmental and lifestyle factors. Studies have shown that early-onset hypertension, occurring before the age of 55 years, is a great predictor of the risk of hypertension in subsequent generations. After the age of 55, systolic blood pressure is typically known to increase. In contrast, diastolic blood pressure is decreased - however, once over 55, this process is generally due to vascular aging, which is caused by stiffening of the arteries.

While family history does not provide information on this specific role of environmental or genetic effects that affect the risk of developing hypertension, to determine this, a more thorough investigation of the genome, as well as environmental exposure, is needed to identify the pathophysiological factors affecting the risk and their size.

Image Credit: Adheamir/Shutterstock

Genetic base of hypertension

By determining the known variants associated with an increased risk of hypertension and quantifying this using a genetic risk score, information related to individual susceptibility can be determined. Moreover, this could inform understanding of the pathways responsible for hypertension.

By understanding this, more effective prevention of hypertension and associated cardiovascular disease could occur based on the following:

1. The identification of at-risk subjects before developing hypertension

2. Implementing targeted and aggressive lifestyle interventions

3. Providing more rational and targeted selections of drugs that are likely to be both safe and effective for an individual patient

These principles are associated with precision medicine, an approach based on identifying high-risk patients before symptoms show, with distinct mechanisms of disease, as well as an understanding of their likelihood of responding to particular treatments.

Both hypertension and heart disease are prevalent and have a sizable impact on life expectancy; if precision medicine initiatives are applied to them, this may lead to marked improvements in public health outcomes.

The future of genetic investigations in the context of hypertension

As precision medicine becomes popularised, early identification of patients at risk of hypertension in the preclinical phases of the disease could be possible. In addition, modifying the factors likely involved in the development of hypertension promises to determine both non-responders and toxic responders among patients before prescribing the medication. This way, only patients who are responders and not predisposed to toxicity are prescribed the appropriate medication.

References

Mahmood SS, Levy D, Vasan RS, et al. (2014) The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective. Lancet. doi:10.1016/S0140-6736(13)61752-3.

Patel RS, Masi S, Taddei S. (2017) Understanding the role of genetics in hypertension. Eur Heart J. doi:10.1093/eurheartj/ehx273.

Magavern EF, Warren HR, Ng FL, et al. (2021) An Academic Clinician's Road Map to Hypertension Genomics: Recent Advances and Future Directions MMXX. Hypertension. doi:10.1161/HYPERTENSIONAHA.120.14535.

Eales JM, Jiang X, Xu X, et al. (2021) Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney. Nat Genet. doi:10.1038/s41588-021-00835-w.

Further Reading

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Hypertension is a major modifiable risk factor for renal, cerebrovascular, and cardiovascular disease. The pathophysiology of hypertension, also known as high blood pressure, is complex, whereby both genetic and environmental factors interact with several physiological pathways and mechanisms to produce an observable phenotype. This article explores the genetics of hypertension.

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Genetic study ties higher alcohol consumption to increased stroke and PAD risk. 

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Genetic study ties higher alcohol consumption to increased stroke and PAD risk. 

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Higher alcohol consumption was shown to be associated with an increased risk of having a stroke or developing peripheral artery disease, according to new research published today in Circulation: Genomic and Precision Medicine, an American Heart Association journal.

While observational studies have consistently shown that heavy alcohol consumption is associated with an increased risk of certain cardiovascular diseases, they often use self-reported data and are unable to determine cause. Researchers in this study used a different technique called Mendelian randomization that identifies genetic variants with a known association to potential risk factors to determine the potential degree of disease risk.

"Since genetic variants are determined at conception and cannot be affected by subsequent environmental factors, this technique allows us to better determine whether a risk factor -- in this case, heavy alcohol consumption -- is the cause of a disease, or if it is simply associated," said Susanna Larsson, Ph.D., senior researcher and associate professor of cardiovascular and nutritional epidemiology at Karolinska Institutet in Stockholm, Sweden. "To our knowledge, this is the first Mendelian randomization study on alcohol consumption and several cardiovascular diseases."

Researchers analyzed the genetic data from several large-scale consortia and the UK Biobank, which follows the health and well-being of 500,000 United Kingdom residents. Results indicate that with higher alcohol consumption:

a three-fold increase of peripheral artery disease, a narrowing of arteries that results in reduced blood flow, usually to the legs;

a 27% increase in stroke incidence; and

some evidence for a positive association of coronary artery disease, atrial fibrillation and aortic aneurysm.

"Higher alcohol consumption is a known cause of death and disability, yet it was previously unclear if alcohol consumption is also a cause of cardiovascular disease. Considering that many people consume alcohol regularly, it is important to disentangle any risks or benefits," Larsson said.

Researchers noted that this study suggested the mechanism by which higher consumption was associated with the risk of stroke and PAD may be blood pressure.

According to a statement on dietary health, the American Heart Association believes that alcohol intake can be a component of a healthy diet if consumed in moderation (no more than one alcoholic drink per day for women and 2 alcohol drinks per day for men) and only by nonpregnant women and adults when there is no risk to existing health conditions, medication-alcohol interaction, or personal safety and work situations. One drink is equivalent to 12 ounces of beer (5% alcohol); 5 ounces of wine (12% alcohol); or 1.5 ounces of 80-proof distilled spirits (40% alcohol).

The study has some limitations. According to Dr. Larsson, the prevalence of heavy drinking in the UK Biobank was low, and it is unlikely that the burden of increased risk of cardiovascular disease is restricted to heavy drinkers alone. Also, the exact amount and frequency of alcohol consumed could not be quantified for this study. The researchers said the causal role of alcohol consumption on cardiovascular diseases other than stroke and peripheral artery disease requires further research.

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heart disease; stroke prevention; diseases and conditions; cholesterol; alcoholism; addiction; stroke; caregiving

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Genetic study ties higher alcohol consumption to increased stroke and PAD risk

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Higher alcohol consumption was shown to be associated with an increased risk of having a stroke or developing peripheral artery disease, according to new research published today in Circulation: Genomic and Precision Medicine, an American Heart Association journal.

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Plants Defy Mendel's inheritance Laws, May Prompt Textbook Changes

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Plants Defy Mendel's inheritance Laws, May Prompt Textbook Changes

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WEST LAFAYETTE, Ind. - Contrary to inheritance laws the scientific world has accepted for more than 100 years, some plants revert to normal traits carried by their grandparents, bypassing genetic abnormalities carried by both parents.

March 23, 2005

Katarina's post

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WEST LAFAYETTE, Ind. - Contrary to inheritance laws the scientific world has accepted for more than 100 years, some plants revert to normal traits carried by their grandparents, bypassing genetic abnormalities carried by both parents.

These mutant parent plants apparently have hidden templates containing genetic information from the preceding generation that can be transferred to their offspring, even though the traits aren't evident in the parents, according to Purdue University researchers. This discovery flies in the face of the scientific laws of inheritance first described by Gregor Mendel in the mid-1800s and still taught in classrooms around the world today.

"This means that inheritance can happen more flexibly than we thought in the past," said Robert Pruitt, a Purdue Department of Botany and Plant Pathology molecular geneticist. "While Mendel's laws that we learned in high school still are fundamentally correct, they're not absolute.

"If the inheritance mechanism we found in the research plant Arabidopsis exists in animals, too, it's possible that it will be an avenue for gene therapy to treat or cure diseases in both plants and animals."

The study is published in the March 24 issue of the journal Nature.

Pruitt and collaborator Susan Lolle found that Arabidopsis in which each parent plant had two copies of a mutant gene could produce progeny that didn't show the parents' deformity, but rather were normal like the grandparents. Under Mendelian laws, the offspring should have shown the same mutation.

The first clue that the classic inheritance rules didn't always apply was the discovery of normal flowers on some offspring of mutant plants. In the deformed parents, the flowers were fused into tight balls. But in the grandparents and 10 percent of the grandchildren, the buds become 1-millimeter-long, bright white flowers that fully opened and radiated out from the center of a cluster.

"If you take this mutant Arabidopsis, which has two copies of the altered gene, let it seed and then plant the seeds, 90 percent of the offspring will look like the parent, but 10 percent will look like the normal grandparents," Pruitt said. "Our genetic training tells us that's just not possible. This challenges everything we believe.

"We've done a lot of experiments, described in this paper, that show none of the simple explanations account for this skipping of generations by an inherited trait."

The scientists kept the plants in isolation so they couldn't accidentally crossbreed with plants that didn't have the mutated gene, called hothead, that causes organ fusion like that seen in the flowers. The researchers used molecular markers - bits of DNA that help identify and locate genes in organisms - to determine whether a plant carried normal or mutant copies of the genes.

"It seems that these hothead-containing plants keep a cryptic copy of everything that was in the previous generation, even though it doesn't show up in the DNA, it's not in the chromosome," Pruitt said. "Some other type of gene sequence information that we don't really understand yet is modifying the inherited traits."

Although the hothead gene tipped the researchers off to this unconventional inheritance cycle, Pruitt believes that this particular DNA sequence is just a trigger for the phenomenon. He suspects that a number of other genes and the proteins they produce are involved in activating this process.

"We need to understand more about the molecular mechanics of how this process works," Pruitt said. "Then we will know exactly what role this gene plays."

Pruitt's team already knows that animals don't have hothead genes, either normal or mutated, so the scientists must investigate which genes might affect this novel inheritance in both plants and animals.

"There are probably a lot of other triggers yet to be discovered, and this mechanism for inheritance may require a different trigger to make it work in animals," he said.

Once scientists understand more about the mechanism, they then may be able to manipulate it to modify genes already in plants and animals in order to correct mutations that cause diseases and abnormal growth.

Though further research is required to learn how this form of inheritance happens and how it can help improve plants or animals through gene therapy, Pruitt said the discovery has opened an important new line of thinking.

The other researchers involved with this study were Jennifer Victor, a former Purdue graduate student now at Butler University; and Jessica Young, a botany and plant pathology laboratory technician. Lolle, a Purdue research scientist, is currently at the National Science Foundation.

The National Science Foundation provided funding for this research.

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endangered plants; life sciences; botany; genetics; nature; biotechnology and bioengineering; pests and parasites; seeds

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Plants Defy Mendel's Inheritance Laws, May Prompt Textbook Changes

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WEST LAFAYETTE, Ind. - Contrary to inheritance laws the scientific world has accepted for more than 100 years, some plants revert to normal traits carried by their grandparents, bypassing genetic abnormalities carried by both parents.

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How Purple Corn And RNA Break Genetic Laws

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A newly cloned gene in corn will help explain how unusual interactions between a parent's genes can have lasting effects in future generations. The finding has implications for breeding better crop plants and unraveling complex genetic diseases. The new research indicates that an additional molecule, DNA's little cousin RNA, is needed for the intriguing gene interactions known as paramutation.

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New genetic disorder named for Children’s Hospital of Philadelphia team

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Three scientists at Children’s Hospital of Philadelphia who identified and studied a genetic disease have been recognized by having their names attached to the disorder. An authoritative reference site for genetic diseases, Online Mendelian Inheritance in Man (OMIM) now designates this condition as…

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Gregor Mendel, the Moravian monk, was indeed "decades ahead of his time and truly deserves the title of 'founder of genetics.'" So concludes an international team of scientists as the 200th birthday of Mendel approaches on 20 July.

The team, from KeyGene in the Netherlands and the John Innes Centre in the UK, draw on newly-discovered historical information to conclude that, when his proposals are viewed in the light of what was known of cells in the mid-19th century, Mendel was decades ahead of his time.

"Uncovering hidden details about Mendel has helped to build a picture of the scientific and intellectual environment in which he worked. At the outset Mendel knew nothing about Genetics and had to deduce it all for himself. How he went about this is highly instructive," said Dr Noel Ellis from the John Innes Centre, one of the contributors to the study.

The new information shows that Mendel began his work with the practical objectives of a plant breeder, before he became interested in the underlying biological processes that condition the heritable differences between organisms. It also shows that Mendel recognised the importance of understanding the formation of reproductive cells and the process of fertilisation.
A small but rich inheritance
Mendel's work and ideas have been studied by many, even though material describing his work is limited. Where Darwin left thousands of letters, for Mendel only a few are known.

Mendel's work started to receive significant recognition 34 years after its publication and 16 years after his death. No notes relating to this work have been found. All that was left was a pair of scientific papers, one of which is the famous 'Experiments on Plant Hybrids' published in German in 1866. This paper remains the basis of what children at school learn about genetics today.
Newspaper articles from Mendel's time have been digitised
Thanks to modern technology, the authors were able to extract valuable information from 19th-century newspaper articles, proceedings, and yearbooks that have recently been digitised. These show how advanced the ideas and work of Mendel were as he used cell biological theory to come to conclusions on how traits of plants are transmitted from parents to their offspring.
Mendel's Elemente: what we know as genes
Mendel noted that pea plants must maintain and transmit the 'code' for the appearance of a trait, we now call these coding instructions genes, Mendel called them 'Elemente.'

For many traits, two different Elemente or 'Elements' are present, for example to code for flower colour in peas, one which conditions purple and an alternative for white flower colour.

Mendel proposed that in the male and female parts of the flower, reproductive cells are formed that only contain one type of Element, and these single Elements are transmitted to a daughter plant, one from the male and another from the female.

We now know that only half of the number of chromosomes is transmitted to egg cells in the female flower parts and pollen in the male flower parts, thanks to the division that occurs during meiosis at the formation of gametes.

Two centuries on from his birth this remarkable scientific life is still offering up new insights.

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botany; genetics; mating and breeding; new species; fossils; origin of life; early climate; ancient dna

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Proof Mendel discovered the laws of inheritance decades ahead of his time

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Gregor Mendel, the Moravian monk, was indeed "decades ahead of his time and truly deserves the title of 'founder of genetics.'" So concludes an international team of scientists as the 200th birthday of Mendel approaches on 20 July.

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Genetic Variants linked to congenital urinary track obstructions. 

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Genetic Variants linked to congenital urinary track obstructions. 

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The discovery may help scientists better understand what causes a rare condition called posterior urethral valves (PUV), which affects 1 in 4,000 males and leads to blockages in the urethra and a build up of urine in the bladder which can then damage the kidneys. About one-third of individuals with this condition develop kidney failure before age 30. Affected individuals often undergo surgery to remove the blockages, but most continue to have urinary tract problems even after surgery. Therefore, new insights about the condition's cause are required to better understand how the urinary tract develops in health and disease and potentially inform new treatment approaches in the future.

"PUV does not follow a Mendelian pattern of inheritance, where each parent contributes one of two possible alleles for a trait, and scientists have not identified a single gene cause," explains lead author Dr Melanie Chan, who conducted the study as a Clinical Research Fellow at the UCL Department of Renal Medicine, London, UK. "This suggests that the genetic basis of this condition is more complex."

To identify the genetic causes, Chan and colleagues analysed the genomes of 132 unrelated males with PUV and 23,727 individuals without the condition who had been recruited to the UK's 100,000 Genomes Project. They included individuals with diverse genetic ancestry, including people of South Asian, African and European descent. They found two genetic variants associated with the risk of PUV. One was a common genetic variant located on chromosome 12q24.21 and the other was a rare genetic variant on chromosome 6p21.1. They confirmed the link between these two genetic differences and the disease in a separate group of individuals of European descent that included 395 males with PUV and 4,152 individuals without the condition.

The team then mapped the variation on 12q24.21 to a gene called TBX5, which contributes to turning other genes on or off. They also mapped the 6p21.1 variation to a gene called PTK7, which plays an essential role in cell development. When they looked at cells from developing human embryos, they found that the proteins encoded by the genes are active in the developing urinary tract. This discovery suggests that alterations in these proteins may interfere with normal urethra development.

Finally, they showed that structural changes in chromosomes, including flipped sections of DNA or other changes that alter the regulation of gene expression, were also linked to PUV.

"Our study is the first to identify rare and common genetic variation strongly associated with PUV, as well as structural variations in chromosomes that may contribute to the disease," says Dr Chan. "It provides new insights on what causes this poorly understood disorder."

The authors add that the small number of individuals included in this genetic analysis reduces its statistical power to detect very rare genetic variations linked with PUV. Additionally, they say more studies are needed to verify how exactly these genetic changes cause PUV.

But senior author Professor Daniel Gale, the St Peter's Chair of Nephrology at the UCL Department of Renal Medicine, says the study demonstrates the importance of including people with diverse genetic backgrounds in genome-wide studies of rare conditions. Too often, he noted, genetic studies may consist of only European populations, making them less likely to identify genetic variants that might be important in other groups.

"Increasing diversity in genetic studies is both scientifically and ethically beneficial," Professor Gale says. "It increases the power of studies to find and verify rare genetic variants and allows detection of genetic variants disproportionately affecting individuals with Asian, African, or other non-European ancestries. It also helps to ensure that people across the world benefit more equally from treatment advances driven by genetic discoveries."

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personalized medicine; genes; gene therapy; human biology; diseases and conditions; kidney disease; down syndrome; urology

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Genetic variants linked to congenital urinary tract obstruction in males: A genome-wide study of individuals of diverse ancestry has identified two potential genetic contributors to a rare condition called posterior urethral valves.

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The discovery may help scientists better understand what causes a rare condition called posterior urethral valves (PUV), which affects 1 in 4,000 males and leads to blockages in the urethra and a build up of urine in the bladder which can then damage the kidneys.

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Flip-flopping Gene Expression Can Be Advantageous -- ScienceDaily

Halee Dodson

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Mendelian Diseases and Cancer

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Researchers in the Rabadan Lab have found that comorbidity between Mendelian diseases and cancer may result from shared genetic factors.

Genetic diseases can arise in a variety of ways. Mendelian disorders, for example, occur when specific mutations in single genes - called germline mutations - are inherited from either of one's two parents. Well-known examples of Mendelian diseases include cystic fibrosis, sickle cell disease, and Duchenne muscular dystrophy. Other genetic diseases, including cancer, result from somatic mutations, which occur in individual cells during a person's lifetime. Because the genetic origins of Mendelian diseases and cancer are so different, they are typically understood to be distinct phenomena. However, scientists in the Columbia University Department of Systems Biology have found evidence that there might be interesting genetic connections between them.

In a paper just published in Nature Communications, postdoctoral research scientist Rachel Melamed and colleagues in the laboratory of Associate Professor Raul Rabadan report on a new method that uses knowledge about Mendelian diseases to suggest mutations involved in cancer. The study takes advantage of an enormous collection of electronic health records representing over 110 million patients, a substantial percentage of US residents. The authors show that clinical co-occurrence of Mendelian diseases and cancer, known as comorbidity, can be tied to genetic changes that play roles in both diseases. The paper also identifies several specific relationships between Mendelian diseases and the cancers melanoma and glioblastoma.

The article grew from Dr. Melamed's PhD thesis, completed earlier this year, which built on a previous collaboration between the Rabadan Lab and that of Andrey Rzhetsky (University of Chicago). In that earlier work, the investigators mined a huge collection of electronic health records to determine the extent to which genes responsible for Mendelian diseases also raised a patient's risk of developing other complex diseases. In her thesis, Melamed ran with this idea in the context of cancer genomics, hypothesizing that comorbidity between a Mendelian disorder and cancer might result from overlap between the genes responsible for each disease.

To ascertain whether this is true, she and her colleagues first analyzed data from the same collection of electronic health records used in the earlier study, looking for patients who both had a Mendelian disorder and developed cancer. They then investigated whether the genes responsible for the Mendelian disorders were related to genes frequently mutated across more than 5000 tumors represented in The Cancer Genome Atlas (TCGA). Using multiple measures of genetic similarity - including shared genes, shared molecular pathways, and gene-protein interactions - they showed that there is greater than expected similarity between the genes involved in Mendelian disease and the somatic alterations involved in the comorbid cancers seen in those patients.

The authors also discovered several specific connections between Mendelian disorders and cancer. For example, they found that genes associated with melanoma are also found in oculocutaneous albinism, a disorder that affects the pigmentation of the skin, hair, and eyes. In addition, investigations of Diamond-Blackfan anemia, a blood disorder, and holoprosencephaly, a disorder in cranial development, identified genetic connections with glioblastoma, the most aggressive form of brain cancer.

"Comorbidity between Mendelian disease and cancer may be due to germline mutations that provide a fertile ground for the growth of certain aberrant cells."

Summarizing the implications of these discoveries, the authors write, "[T]his suggests that comorbidity between Mendelian disease and cancer may be due to germline mutations that provide a fertile ground for the growth of certain aberrant cells." They also write that some Mendelian diseases predispose patients to multiple types of cancer, a finding that is in line with a growing body of evidence that many tumor mutations have "pan-cancer" effects.

The Rabadan Lab's method is interesting not only because it provides a clearer picture of the genetic basis of comorbidities, but also because the cancer-associated genes it identifies are likely to be present in some tumors even in the absence of comorbid Mendelian disease. It therefore complements other methods for identifying cancer genes, as the role of cancer genes in a Mendelian disease can provide clues to their functions in the cancer. In the future, the authors predict, drugs targeting mutations shared between Mendelian disease patients and cancer patients could be repurposed based on the comorbidity between the diseases.
- Chris Williams
Related publication

Melamed RD, Emmett KJ, Madubata C, Rzhetsky A, Rabadan R. Genetic similarity between cancers and comorbid Mendelian diseases identifies candidate driver genes. Nat Commun. 2015 Apr 30.

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Connections Found between Mendelian Diseases and Cancer

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Researchers in the Rabadan Lab have found that comorbidity between Mendelian diseases and cancer may result from shared genetic factors. Genetic diseases can arise in a variety of ways. Mendelian disorders, for example, occur when specific mutations in single genes - called germline mutations - are inherited from either of one's two parents.

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https://www.sciencedaily.com/releases/2023/01/230126124330.htm

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Scientists have created an AI system capable of generating artificial enzymes from scratch. In laboratory tests, some of these enzymes worked as well as those found in nature, even when their artificially generated amino acid sequences diverged significantly from any known natural protein.

The experiment demonstrates that natural language processing, although it was developed to read and write language text, can learn at least some of the underlying principles of biology. Salesforce Research developed the AI program, called ProGen, which uses next-token prediction to assemble amino acid sequences into artificial proteins.

Scientists said the new technology could become more powerful than directed evolution, the Nobel-prize winning protein design technology, and it will energize the 50-year-old field of protein engineering by speeding the development of new proteins that can be used for almost anything from therapeutics to degrading plastic.

"The artificial designs perform much better than designs that were inspired by the evolutionary process," said James Fraser, PhD, professor of bioengineering and therapeutic sciences at the UCSF School of Pharmacy, and an author of the work, which was published Jan. 26, in Nature Biotechnology.

"The language model is learning aspects of evolution, but it's different than the normal evolutionary process," Fraser said. "We now have the ability to tune the generation of these properties for specific effects. For example, an enzyme that's incredibly thermostable or likes acidic environments or won't interact with other proteins."

To create the model, scientists simply fed the amino acid sequences of 280 million different proteins of all kinds into the machine learning model and let it digest the information for a couple of weeks. Then, they fine-tuned the model by priming it with 56,000 sequences from five lysozyme families, along with some contextual information about these proteins.

The model quickly generated a million sequences, and the research team selected 100 to test, based on how closely they resembled the sequences of natural proteins, as well how naturalistic the AI proteins' underlying amino acid "grammar" and "semantics" were.

Out of this first batch of a 100 proteins, which were screened in vitro by Tierra Biosciences, the team made five artificial proteins to test in cells and compared their activity to an enzyme found in the whites of chicken eggs, known as hen egg white lysozyme (HEWL). Similar lysozymes are found in human tears, saliva and milk, where they defend against bacteria and fungi.

Two of the artificial enzymes were able to break down the cell walls of bacteria with activity comparable to HEWL, yet their sequences were only about 18% identical to one another. The two sequences were about 90% and 70% identical to any known protein.

Just one mutation in a natural protein can make it stop working, but in a different round of screening, the team found that the AI-generated enzymes showed activity even when as little as 31.4% of their sequence resembled any known natural protein.

The AI was even able to learn how the enzymes should be shaped, simply from studying the raw sequence data. Measured with X-ray crystallography, the atomic structures of the artificial proteins looked just as they should, although the sequences were like nothing seen before.

Salesforce Research developed ProGen in 2020, based on a kind of natural language programming their researchers originally developed to generate English language text.

They knew from their previous work that the AI system could teach itself grammar and the meaning of words, along with other underlying rules that make writing well-composed.

"When you train sequence-based models with lots of data, they are really powerful in learning structure and rules," said Nikhil Naik, PhD, Director of AI Research at Salesforce Research, and the senior author of the paper. "They learn what words can co-occur, and also compositionality."

With proteins, the design choices were almost limitless. Lysozymes are small as proteins go, with up to about 300 amino acids. But with 20 possible amino acids, there are an enormous number (20 ³⁰⁰) of possible combinations. That's greater than taking all the humans who lived throughout time, multiplied by the number of grains of sand on Earth, multiplied by the number of atoms in the universe.

Given the limitless possibilities, it's remarkable that the model can so easily generate working enzymes.

"The capability to generate functional proteins from scratch out-of-the-box demonstrates we are entering into a new era of protein design," said Ali Madani, PhD, founder of Profluent Bio, former research scientist at Salesforce Research, and the paper's first author. "This is a versatile new tool available to protein engineers, and we're looking forward to seeing the therapeutic applications."

Further information: https://github.com/salesforce/progen

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human biology; dietary supplements and minerals; nutrition; cell biology; molecular biology; biology; artificial intelligence; computer modeling; mathematical modeling

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AI technology generates original proteins from scratch: Natural language model jumpstarts protein design with creation of active enzymes

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Scientists have created an AI system capable of generating artificial enzymes from scratch. In laboratory tests, some of these enzymes worked as well as those found in nature, even when their artificially generated amino acid sequences diverged significantly from any known natural protein.

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New genetic disorder named for Children’s Hospital of Philadelphia team

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Three scientists at Children’s Hospital of Philadelphia who identified and studied a genetic disease have been recognized by having their names attached to the disorder. An authoritative reference site for genetic diseases, Online Mendelian Inheritance in Man (OMIM) now designates this condition as…

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New Light on Genetic Foundation of Migraines

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New Light on Genetic Foundation of Migraines

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The nauseating, often debilitating, headaches affect 15-20 percent of adults in developed countries, yet they remain stubbornly hard to explain. Scientists know that migraines tend to run in families but aren't sure exactly how.

A new study published May 3 in the journal Neuron shows why some families are susceptible to migraines and how genetics may influence the type of migraine they get.

"For a long time, we have been wondering why common disease (like migraines) aggregates in families," said Aarno Palotie of the Institute for Molecular Medicine in Finland and the Broad Institute of MIT and Harvard in Cambridge, Mass.

Previous migraine research identified two ways migraines might run in families. Linkage studies, which track sections of chromosomes passed down from parent to child, identified three genes (CACNA1A, ATP1A2 and SCN1A) associated to hemiplegic migraine, a severe form of migraine that induces stroke-like symptoms. These genes fall under a Mendelian inheritance model, meaning the two copies of a gene a child inherits from his or her parents determine a trait or disease. Sickle cell anemia could be thought of as Mendelian.

Another way migraines could run in families involves polygenic inheritance. If a trait is polygenic, that means that a group of genes collectively influence that characteristic. Like being dealt a bad hand in a card game, each common genetic variant may have only a small individual effect, but the collection of common variants builds up to influence the trait -- or disease risk -- a person inherits. Height is an example of a polygenic trait.

Palotie and his colleagues set out to find out whether a few, powerful Mendelian genes or a polygenic accumulation of common variants -- or a combination of both -- influenced how migraines are inherited in families.

First, the researchers developed a polygenic risk score to estimate the genetic burden of common variants. To do this, they gathered data from a previous genome-wide association study, which is a type of study that compares genomes of individuals and flags loci (locations on chromosomes) that differ in people with a disease. In all, hundreds (possibly even thousands) of loci linked to migraines were incorporated into the polygenic risk score.

Next, the researchers tested the influence of the polygenic risk score and the three known Mendelian migraine-linked genes within a large family study of migraine sufferers in Finland. The study included medical history and genetic data of 1,589 families (made up of 8,319 individuals) of known migraine sufferers. The family migraine cohort was compared against other large cohorts as a control, such as the FINRISK study that had 14,470 people total, including 1,101 people with migraine.

Result after result showed that the polygenic common variants were driving migraine risk more than the three Mendelian genes. If a person's migraines started at an earlier age, if a person experienced more severe migraines, or if migraines ran in a person's family, the data showed that it's more likely that person had a greater genetic burden of common polygenic variants to blame.

"The strength of the common variants in these families surprised us," said Palotie.

On the other hand, the three rare but powerful Mendelian genes linked to migraine didn't seem to influence migraine risk as much as the researchers expected. Out of the large family study, researchers identified 45 families with hemiplegic migraine and sequenced their genes. Migraines in only four out of 45 families were driven by the rare Mendelian genes -- more cases were driven by common variants.

"This really shows, in a very big sample set, that common variants are very important factors in aggregation of migraines in the family," said Palotie.

Palotie believes more genome sequencing and larger studies will help researchers find both more common variants linked to migraines and more Mendelian variants.

"This is of special interest for drug development," said Palotie. Even if Mendelian variants don't drive the majority of migraine cases, scientists can research how these genes impact biological pathways responsible for migraine symptoms and potentially develop drugs to target those pathways.

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headache research; genes; cold and flu; teen health; headaches; disorders and syndromes; parkinson's; huntington's disease

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New light on genetic foundation of migraines

# data[].attributes.attachment_link.description
The nauseating, often debilitating, headaches affect 15-20 percent of adults in developed countries, yet they remain stubbornly hard to explain. Scientists know that migraines tend to run in families but aren't sure exactly how. A new study shows why some families are susceptible to migraines and how genetics may influence the type of migraine they get.

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Mendelian Genetics | Biological Principles

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Gregor Mendel is famous for discovering “particulate inheritance” or the idea that hereditary elements are passed on in discrete units rather than “blended” together at each new generation. Today we call those discrete units genes.

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https://www.sciencedaily.com/releases/2017/03/170327143509.htm

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New genetic disorder named for Children’s Hospital of Philadelphia team

# data[].attributes.attachment_link.description
Three scientists at Children’s Hospital of Philadelphia who identified and studied a genetic disease have been recognized by having their names attached to the disorder. An authoritative reference site for genetic diseases, Online Mendelian Inheritance in Man (OMIM) now designates this condition as…

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Researchers have developed a new, inexpensive technology that could save lives and money by routinely screening women for breast cancer without exposure to radiation. The system uses harmless microwaves and artificial intelligence (AI) software to detect even small, early-stage tumors within minutes.

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Researchers have developed a new, inexpensive technology that could save lives and money by routinely screening women for breast cancer without exposure to radiation.

The system, developed by researchers at the University of Waterloo, uses harmless microwaves and artificial intelligence (AI) software to detect even small, early-stage tumors within minutes.

"Our top priorities were to make this detection-based modality fast and inexpensive," said Omar Ramahi, a professor of electrical and computer engineering at Waterloo. "We have incredibly encouraging results and we believe that is because of its simplicity."

A prototype device -- the culmination of 15 years of work on the use of microwaves for tumor detection, not imaging -- cost less than $5,000 to build.

It consists of a small sensor in an adjustable box about 15 centimetres square that is situated under an opening in a padded examination table.

Patients lie face-down on the table so that one breast at a time is positioned in the box. The sensor emits microwaves that bounce back and are then processed by AI software on a laptop computer.

By comparing the tissue composition of one breast with the other, the system is sensitive enough to detect anomalies less than one centimeter in diameter.

Ramahi said a negative result could quickly rule out cancer, while a positive result would trigger referral for more expensive tests using mammography or magnetic resonance imaging (MRI).

"If women were screened regularly with this, potential problems would be caught much sooner -- in the early stages of cancer," he said. "Our system can complement existing technology, reserving much more expensive options for when they're really needed.

"We need a mixture, a combination of technologies. When our device sent up a red flag, it would mean more investigation was warranted."

In addition to reducing patient wait times and enabling earlier diagnosis, Ramahi said, the device would eliminate radiation exposure, improve patient comfort and work on particularly dense breasts, a problem with mammograms.

It would also save health-care systems enormous amounts of money and, because of its low cost and ease of use, dramatically increase access to screening in the developing world.

Researchers have applied for a patent and started a company, Wave Intelligence Inc. of Waterloo, to commercialize the system and hope to begin trials on patients within six months. Three rounds of preliminary testing included the use of artificial human torsos known as phantoms.

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breast cancer; cancer; medical devices; medical imaging; medical technology; technology; detectors; engineering

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New tech takes radiation out of cancer screening

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Researchers have developed a new, inexpensive technology that could save lives and money by routinely screening women for breast cancer without exposure to radiation. The system uses harmless microwaves and artificial intelligence (AI) software to detect even small, early-stage tumors within minutes.

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https://jmhg.springeropen.com/articles/10.1186/s43042-022-00339-0

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Egyptian Journal of Medical Human Genetics 23, Article number: 124 (2022) Cite this article

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Abstract

Background

July 20th, 2022, marks the 200th anniversary of the "Father of Genetics," Gregor Mendel's birth. His experiments with pea plants established the fundamental principles of genetic inheritance.

Main text

In this article, a succinct review of literature is hereby done to answer two key questions: (1) How Mendel's principles of genetic inheritance helped us understand Mendelian disorders? and (2) How the study of Mendelian disorders can help us understand complex diseases?

Conclusion

This literature review concludes that continued effort to understand the genetic basis of Mendelian disorders will improve our understanding and treatment strategies for complex diseases.

Background

The field of medical genetics has expanded to the point that we not only know the genetic underpinnings of many human diseases, but we are also able to cure some diseases, including sickle cell anemia, by editing the molecular lesions with gene therapies [ 1]. An appropriate evaluation of scientific literature from the historical perspective can trace these advancements back to the discovery of Gregor Mendel in 1865 which established the fundamental principles of genetic inheritance [ 2]. July 20th, 2022, marks the 200th anniversary of the "Father of Genetics," Gregor Mendel's birth. Commemorating Mendel's 200th Birth Anniversary, a review of literature was carried out to find the answer for two key questions: (1) How Mendel's principles of genetic inheritance helped us understand Mendelian disorders? and (2) How the study of Mendelian disorders can help us understand complex diseases? Findings from the literature review is succinctly presented in this article.

Mendelian theory of inheritance: birth of "genetics"

Inquisitive minds have wondered why living things tend to look like their parents and why some families are affected by certain diseases. However, there was a lack of understanding of the causal mechanisms. The early popular views included the "blending" of parental traits in their offspring [ 3]. An alternative theory proposed by Mendel based on the results of his experiments on pea plants challenged the existing theories. Using data from large-scale experiments on pea plants followed by a pioneering systematic mathematical analysis, Mendel was able to find a pattern for the transmission of contrasting trait pairs through generations. His experiments lead to the conclusion that each trait is determined by pairs of "antagonistic elements", one dominates over the other in their manifestation, and rather than blending, they "segregate" among the progeny, and thus, are "particulate" in nature [ 4]. The Mendelian theory of inheritance also suggests that the assortment of one trait is independent of that of another trait. These particulate units of inheritance are now known as "genes", and the antagonistic elements resulting from the variations in DNA sequences of a gene are called "alleles". Unfortunately, Mendel's work was not widely accepted during his lifetime. However, the rediscovery of Mendel's work through independent experiments by Correns, de Vries, and Tschermak in 1900 ultimately established the principles of genetic inheritance and hailed Mendel as the "Father of Genetics".

Mendelism relevant for both Mendelian and complex genetic disorders in humans

In humans, disease traits following Mendelian inheritance patterns are called "Mendelian disorders" and are commonly caused by variants in a single gene ("monogenic"). In contrast, diseases caused by the combined action of variants in many genes and their interactions with the environment, tend to show an apparent departure from Mendelian expectations and are considered as "complex" [ 5, 6, 7, 8]. Mendel's laws of inheritance, however, are applicable to complex traits since the inheritance of each of the genes involved in these diseases follows Mendel's laws [ 9]. Thus, Mendel's theories remain instrumental in revealing casual mechanisms for both monogenic and complex diseases.

Mendel's principles of genetic inheritance helped us identify genes for Mendelian disorders

Early understanding of the genetic underpinnings of human diseases came from studying their inheritance patterns in families (pedigree analysis). These analyses together with knowledge of the location of the genes on chromosomes helped in finding the dominant and recessive nature of alleles of disease genes and differences in their inheritance patterns. Further advancements in our understanding of the molecular basis of genetic variants, as well as the technological capabilities to create genetic maps for chromosomes, eventually led to the localization and identification of disease genes. Computational methods, including linkage analysis, use naturally occurring DNA variations as markers to trace inheritance patterns in families to identify the location of disease genes on the chromosomes [ 10]. Furthermore, positional molecular cloning approaches have been successful in identifying genes responsible for Mendelian diseases [ 10]. Most Mendelian diseases are caused primarily by a single high-penetrance mutation in a family. These mutations affect the coding or other functional regions of a gene and have a low frequency within a population. Indicating major success, the Online Mendelian Inheritance of Man (OMIM), a catalog of human genetic diseases, now includes over 6000 Mendelian phenotypes with a known molecular basis [ 11].

The study of Mendelian disorders can help us understand complex diseases

Linkage analysis approaches remain largely unsuccessful for finding genetic underpinnings for common diseases that do not conform to Mendelian inheritance patterns and suggests a different genetic architecture for these complex diseases [ 7]. Genome-wide association studies (GWAS) suggest that complex diseases are associated with many high-frequency variants with low-effect sizes on disease susceptibility, which together explain a small fraction of disease heritability. These common variants are mostly located in the non-coding regulatory regions of the genome [ 5]. Despite differences in genetic architecture, current evidence suggests that complex and Mendelian traits might not be as biologically distinct as previously thought. For example, common and rare monogenic obesity are shown to have shared genetic and biological underpinnings, pointing to an important role of the brain in controlling body weight [ 12]. Several recent analyses of GWAS found significant enrichment of Mendelian disorder genes in GWAS gene sets for phenotypically matched complex traits. Genes affected by Mendelian disease-causing mutations are also dysregulated by noncoding variants in complex traits [ 13, 14, 15]. These findings support a shared genetic basis between complex and Mendelian forms of the disease.

Conclusion

The fundamental principles of genetic inheritance discovered by Gregor Mendel paved the path toward understanding human genetic diseases. In the bigger picture, Mendelian diseases arising from single genes and complex diseases caused by many genetic variants are two extremes in the continuum of the genetic architecture of human diseases [ 6, 16]. Thus, continued effort to understand the genetic basis of Mendelian disorders will improve our understanding and treatment strategies for complex diseases.

Availability of data and materials

All data included in this manuscript are from published literature and databases.

Abbreviations

DNA:

Deoxyribonucleic acid

GWAS:

Genome-wide association studies

OMIM:

Online Mendelian inheritance of man

References

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Acknowledgments

SSD acknowledges availability of library resources at Coy C. Carpenter Library, Wake Forest School of Medicine, Winston-Salem, NC. SSD also acknowledges critical help in research from Dr SK Das (Associate Professor, Department of Internal Medicine, Wake Forest School of Medicine).

Author information

Authors and Affiliations

The School of Biotechnology at Atkins, Atkins Academic and Technology High School, 3605 Old Greensboro Road, Winston-Salem, NC, 27101, USA

Sreejon Sundar Das

Contributions

SSD completed literature review, wrote, and edited the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Sreejon Sundar Das.

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Das, S.S. Mendel paved the path toward understanding genetic diseases. Egypt J Med Hum Genet 23, 124 (2022). https://doi.org/10.1186/s43042-022-00339-0
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Keywords

Mendelism

Monogenic disease

Complex disease

# data[].attributes.attachment_link.title
Mendel paved the path toward understanding genetic diseases - Egyptian Journal of Medical Human Genetics

# data[].attributes.attachment_link.description
Background July 20th, 2022, marks the 200th anniversary of the "Father of Genetics," Gregor Mendel's birth. His experiments with pea plants established the fundamental principles of genetic inheritance. Main text In this article, a succinct review of literature is hereby done to answer two key questions: (1) How Mendel's principles of genetic inheritance helped us understand Mendelian disorders?

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Geneticist solves long-standing finch beak mystery: Bridgett vonHoldt found a single genetic key that unlocked beak size in a central African finch species

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Biologist have compared the genes of large-beaked Cameroonian finches to those of their smaller-beaked counterparts, found the answer to a 20-year old mystery: 300,000 base pairs, apparently inherited as a unit, always varied between them, and right in the middle of that genetic sequence was the wel…

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Gregor Mendel and the Principles of Inheritance | Learn Science at Scitable

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By experimenting with pea plant breeding, Gregor Mendel developed three principles of inheritance that described the transmission of genetic traits before anyone knew exactly what genes were. Mendel’s insight provided a great expansion of the understanding of genetic inheritance, and led to the development of new experimental methods.

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Gregor Mendel, the Moravian monk, was indeed "decades ahead of his time and truly deserves the title of 'founder of genetics.'" So concludes an international team of scientists as the 200th birthday of Mendel approaches on 20 July.

The team, from KeyGene in the Netherlands and the John Innes Centre in the UK, draw on newly-discovered historical information to conclude that, when his proposals are viewed in the light of what was known of cells in the mid-19th century, Mendel was decades ahead of his time.

"Uncovering hidden details about Mendel has helped to build a picture of the scientific and intellectual environment in which he worked. At the outset Mendel knew nothing about Genetics and had to deduce it all for himself. How he went about this is highly instructive," said Dr Noel Ellis from the John Innes Centre, one of the contributors to the study.

The new information shows that Mendel began his work with the practical objectives of a plant breeder, before he became interested in the underlying biological processes that condition the heritable differences between organisms. It also shows that Mendel recognised the importance of understanding the formation of reproductive cells and the process of fertilisation.
A small but rich inheritance
Mendel's work and ideas have been studied by many, even though material describing his work is limited. Where Darwin left thousands of letters, for Mendel only a few are known.

Mendel's work started to receive significant recognition 34 years after its publication and 16 years after his death. No notes relating to this work have been found. All that was left was a pair of scientific papers, one of which is the famous 'Experiments on Plant Hybrids' published in German in 1866. This paper remains the basis of what children at school learn about genetics today.
Newspaper articles from Mendel's time have been digitised
Thanks to modern technology, the authors were able to extract valuable information from 19th-century newspaper articles, proceedings, and yearbooks that have recently been digitised. These show how advanced the ideas and work of Mendel were as he used cell biological theory to come to conclusions on how traits of plants are transmitted from parents to their offspring.
Mendel's Elemente: what we know as genes
Mendel noted that pea plants must maintain and transmit the 'code' for the appearance of a trait, we now call these coding instructions genes, Mendel called them 'Elemente.'

For many traits, two different Elemente or 'Elements' are present, for example to code for flower colour in peas, one which conditions purple and an alternative for white flower colour.

Mendel proposed that in the male and female parts of the flower, reproductive cells are formed that only contain one type of Element, and these single Elements are transmitted to a daughter plant, one from the male and another from the female.

We now know that only half of the number of chromosomes is transmitted to egg cells in the female flower parts and pollen in the male flower parts, thanks to the division that occurs during meiosis at the formation of gametes.

Two centuries on from his birth this remarkable scientific life is still offering up new insights.

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botany; genetics; mating and breeding; new species; fossils; origin of life; early climate; ancient dna

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Proof Mendel discovered the laws of inheritance decades ahead of his time

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Gregor Mendel, the Moravian monk, was indeed "decades ahead of his time and truly deserves the title of 'founder of genetics.'" So concludes an international team of scientists as the 200th birthday of Mendel approaches on 20 July.

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Four ways inheritance is more complex than Mendel knew

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This year marks the 150th anniversary of Gregor Mendel’s publication that--after sitting ignored for a few decades--helped launch the field of modern genetics. Today, we know that inheritance is far more complex than what Mendel saw in his pea plants. Now scientists who track progress in genetics re…