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Sickle Cell Disease Association of America Inc.

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What is Sickle Cell Disease (SCD)? - Sickle Cell Disease Association of America Inc.

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Sickle cell disease is an inherited blood disorder that affects red blood cells. People with sickle cell disease have red blood cells that contain mostly hemoglobin S, an abnormal type of hemoglobin. Sometimes these red blood cells become sickle-shaped (crescent shaped) and have difficulty passing t…

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Source

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(with subtitles in Spanish!)

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How this disease changes the shape of your cells - Amber M. Yates

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Introduction

Everyone has two copies of the haemoglobin gene in every cell in their body (apart from eggs and sperm). They get one from their mother and one from their father. When eggs and sperm are made, only one of the two genes goes into each egg or sperm cell. This is so that when the egg and sperm come together to make a new baby this new person has two genes in every cell in their body as well. The genes the baby gets will therefore depend on the genes carried in its parents.

Sickle Cell Anaemia is called a recessive condition because you must have two copies of the sickle haemoglobin gene to have the disorder. Sickle haemoglobin is often shortened to S or HbS. If you have only one copy of the sickle haemoglobin along with one copy of the more usual haemoglobin (A or HbA) you are said to have Sickle Cell Trait. This is not an illness but means that you "carry" the gene and can pass it on to you children. If your partner also has Sickle Cell Trait or Sickle Cell Anaemia your children could get Sickle Cell Anaemia.

If you know the types of haemoglobin you and your partner have, you will know the different possible combinations of genes that your baby could inherit. Only when both parents are HbAA and/or HbSS will all your children inherit the same combination of genes so you can be sure whether your child will be affected or not.

Could my Children get Sickle Cell Anaemia?

You may find the following diagrams useful to help you understand how sickle haemoglobin is inherited. In all the following diagrams you will get the same possibilities if the genes in the mother and father are swapped over.

The lines coming in to each baby show that one gene has come from the mother and one gene has come from the father. In these diagrams the presence of the usual haemoglobin gene is shown by pink and the presence of the sickle haemoglobin gene is shown by blue.

The diagrams show the following combinations of parents and the types of children they can have:

Sickle Cell Trait and Unaffected

Sickle Cell Trait and Sickle Cell Trait

Sickle Cell Trait and Sickle Cell Anaemia

Sickle Cell Anaemia and Unaffected

If one parent has sickle cell trait (HbAS) and the other does not carry the sickle haemoglobin at all (HbAA) then none of the children will have sickle cell anaemia. There is a one in two (50%) chance that any given child will get one copy of the HbS gene and therefore have the sickle cell trait. It is equally likely that any given child will get two HbA genes and be completely unaffected.

It is possible to test an unborn baby for the type of haemoglobin it has. Go to the Prenatal Testing page for more details.

If both parents have sickle cell trait (HbAS) there is a one in four (25%) chance that any given child could be born with sickle cell anaemia. There is also a one in four chance that any given child could be completely unaffected. There is a one in two (50%) chance that any given child will get the sickle cell trait.

It is possible to test an unborn baby for the type of haemoglobin it has. Go to the Prenatal Testing page for more details.

If one parent has sickle cell trait (HbAS) and the other has sickle cell anaemia (HbSS) there is a one in two(50%) chance that any given child will get sickle cell trait and a one in two chance that any given child will get sickle cell anaemia. No children will be completely unaffected.

It is possible to test an unborn baby for the type of haemoglobin it has. Go to the Prenatal Testing page for more details.

If one parent has sickle cell anaemia (HbSS) and the other is completely unaffected (HbAA) then all the children will have sickle cell trait. None will have sickle cell anaemia. The parent who has sickle cell anaemia (HbSS) can only pass the sickle haemoglobin gene to each of their children.

It is possible to test an unborn baby for the type of haemoglobin it has. Go to the Prenatal Testing page for more details.

Understanding Chance

To help you to think about chance it can be useful to use things that we are all used to. When a woman has a baby there is a one in two (50%) chance that the baby will be a girl and a one in two (50%) chance that the baby will be a boy. Although over the whole population there are almost exactly equal numbers of men and women, within any family there may be all girls, all boys or a mixture of both.

The one in two chance applies to each pregnancy afresh. The one in two chance just tells you that nature will choose one out of two different possibilities. If the chance is one in four, there are four different possibilities and the outcome will be one of these. This is very important in understanding what sort of children you will have if you carry the sickle haemoglobin gene.

For example, if there is a one in four chance that you will have a baby with sickle cell anaemia, and if you go on to have a number of children, it is still possible that all your children could have sickle cell anaemia or that none will have sickle cell anaemia.

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Inheritance of Sickle Cell Anaemia " Sickle Cell Society

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Introduction Everyone has two copies of the haemoglobin gene in every cell in their body (apart from eggs and sperm). They get one from their mother and one from their father. When eggs and sperm are made, only one of the two genes goes into each egg or sperm cell.

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Centers for Disease Control and Prevention

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Sickle cell disease (SCD) affects millions of people throughout the world and is particularly common among those whose ancestors came from sub-Saharan Africa; Spanish-speaking regions in the Western Hemisphere (South America, the Caribbean, and Central America); Saudi Arabia; India; and Mediterranean countries such as Turkey, Greece, and Italy.

Sickle cell disease occurs more often among people from parts of the world where malaria is or was common. It is believed that people who carry the sickle cell trait are less likely to have severe forms of malaria.

In the United States

The exact number of people living with SCD in the U.S. is unknown. Working with partners, the CDC supports projects to learn about the number of people living with SCD to better understand how the disease impacts their health.

It is estimated that:

SCD affects approximately 100,000 Americans.

SCD occurs among about 1 out of every 365 Black or African-American births.

SCD occurs among about 1 out of every 16,300 Hispanic-American births.

About 1 in 13 Black or African-American babies is born with sickle cell trait (SCT).

Comprehensive Care

People with SCD have less access to comprehensive team care than people with genetic disorders such as hemophilia and cystic fibrosis. [Read articleExternal ]

Mortality

Sickle cell-related death among Black or African-American children younger than 4 years of age fell by 42% from 1999 through 2002. This drop coincided with the introduction in 2000 of a vaccine that protects against invasive pneumococcal disease.
[Read summaryExternal ]

Relative to the rate for the period 1983 through 1986, the SCD mortality rate for the period 1999 through 2002 decreased by:

68% at age 0 through 3 years;

39% at age 4 through 9 years; and

24% at age 10 through 14 years.
[Read summaryExternal ]

Mortality Among Children with Sickle Cell Disease Identified by Newborn Screening During 1990-1994 - California, Illinois, and New York:

Among the children with Hb SS disease, 1% died as a result of SCD-related causes during the first 3 years of life.

In California and Illinois, by the end of 1995, the cumulative mortality rate was 1.5 per 100 Black or African-American children with SCD. The equivalent cumulative mortality rate for all Black or African-American infants born during this period in California and Illinois was 2.0 per 100 Black or African-American newborns.
[Read article]

Economic Costs

During 2005, medical expenditures for children with SCD averaged $11,702 for children with Medicaid coverage and $14,772 for children with employer-sponsored insurance. About 40% of both groups had at least one hospital stay.
[Read summaryExternal ]

SCD is a major public health concern. From 1989 through 1993, an average of 75,000 hospitalizations due to SCD occurred in the United States, costing approximately $475 million.
[Read summaryExternal ]

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Data & Statistics on Sickle Cell Disease | CDC

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Sickle cell disease (SCD) affects millions of people throughout the world and is particularly common among those whose ancestors came from sub-Saharan Africa; Spanish-speaking regions in the Western Hemisphere (South America, the Caribbean, and Central America); Saudi Arabia; India; and Mediterranean countries such as Turkey, Greece, and Italy.

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Sickle cell disease usually requires lifelong treatment.
Children and adults with sickle cell disease are supported by a team of different healthcare professionals working together at a specialist sickle cell centre.

Your healthcare team will help you learn more about sickle cell disease, and work with you to come up with an individual care plan that takes into account all your needs and health concerns.

Preventing painful episodes

The main thing you can do to reduce your chances of experiencing a painful episode (sickle cell crisis) is to try avoiding possible triggers.

You may be advised to:

drink plenty of fluids to avoid dehydration

wear warm clothing to stop you getting cold

avoid sudden temperature changes, such as swimming in cold water

Get more advice about living with sickle cell disease

Medicine for sickle cell pain

If you continue to have episodes of pain, a medicine called hydroxycarbamide (hydroxyurea) may be recommended. You usually take it as a capsule once a day.

Hydroxycarbamide can lower the amount of other blood cells, such as white blood cells and platelets (clotting cells), so you'll usually have regular blood tests to monitor your health.

If you have regular episodes of pain, you may also be able to have a medicine called crizanlizumab. Crizanlizumab can be taken on its own or alongside hydroxycarbamide. You will usually be given crizanlizumab by injection into a vein every 4 weeks.

Find out more about crizanlizumab from the National Institute for Health and Care Excellence (NICE).

Self-help for treating a sickle cell crisis

If you have a sickle cell crisis, you can usually manage it at home.

The following things can help:

take over-the-counter painkillers, such as paracetamol or ibuprofen (do not give aspirin to children under 16 unless a doctor has prescribed it) - if the pain is more severe, your GP may prescribe stronger painkillers

have plenty to drink

use a warm towel or a wrapped heated pad to gently massage the affected body part - many pharmacies sell heat pads that you can use for this purpose

distractions to take your mind off the pain - for example, children might like to read a story, watch a film or play their favourite computer game

Contact your GP if these measures do not work or the pain is particularly severe. If this is not possible, go to your local A&E.

You may need treatment with very strong painkillers, such as morphine, in hospital for a few days.

Preventing infections if you have sickle cell disease

People with sickle cell disease are more vulnerable to infections.

Most people need to take a daily dose of antibiotics, usually penicillin, often for the rest of their life.

Long-term use of antibiotics will not pose any serious risks to your health.

Children with sickle cell disease should also have all the routine vaccinations, and possibly also additional vaccinations like the annual flu vaccine and the hepatitis B vaccine.

Treatments for sickle cell-related anaemia

Anaemia often causes few symptoms and may not require specific treatment.

But dietary supplements like folic acid, which helps stimulate the production of red blood cells, may sometimes be required to help improve anaemia if your child has a restricted diet, such as a vegetarian or vegan diet.

Anaemia caused by sickle cell disease is not the same as the more common iron deficiency anaemia.

Do not take iron supplements to treat it without seeking medical advice, as they could be dangerous.

If anaemia is particularly severe or persistent, treatment with blood transfusions or hydroxycarbamide may be necessary.

Stem cell or bone marrow transplants

Stem cell or bone marrow transplants are the only cure for sickle cell disease, but they're not done very often because of the significant risks involved.

Stem cells are special cells produced by bone marrow, a spongy tissue found in the centre of some bones. They can turn into different types of blood cells.

For a stem cell transplant, stem cells from a healthy donor are given through a drip into a vein.

These cells then start to produce healthy red blood cells to replace the sickle cells.

A stem cell transplant is an intensive treatment that carries a number of risks.

The main risk is graft versus host disease, a life-threatening problem where the transplanted cells start to attack the other cells in your body.

Stem cell transplants are generally only considered in children with sickle cell disease who have severe symptoms that have not responded to other treatments, when the long-term benefits of a transplant are thought to outweigh the possible risks.

Treating other problems

Sickle cell disease can also cause a number of other problems that may need to be treated.

For example:

a short course of hormonal medicine may be prescribed to trigger puberty in children with delayed puberty

gallstones may be treated with gallbladder removal surgery

bone and joint pain can be treated with painkillers, although more severe cases may require surgery

persistent and painful erections (priapism) may require medication to stimulate blood flow or using a needle to drain blood from the penis - read more about treatments for priapism

leg ulcers can be treated by cleaning the ulcer and dressing it with a bandage

people at increased risk of having a stroke, or those who have had a stroke, may need regular blood transfusions or treatment with hydroxycarbamide

acute chest syndrome, a serious lung condition, usually requires emergency treatment with antibiotics, blood transfusions, oxygen and fluids given into a vein - hydroxycarbamide may be needed to prevent further episodes

People who need a lot of blood transfusions may also need to take medicine called chelation therapy. This reduces the amount of iron in their blood to safe levels.

A helpful leaflet about sickle cell disease

The NHS Sickle Cell and Thalassaemia Screening Programme has a helpful parents' guide to managing sickle cell disease (PDF, 3.57Mb).

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Sickle cell disease usually requires lifelong treatment. Children and adults with sickle cell disease are supported by a team of different healthcare professionals working together at a specialist sickle cell centre. Your healthcare team will help you learn more about sickle cell disease, and work with you to come up with an individual care plan that takes into account all your needs and health concerns.

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ARTICLE: MedLine Plus Sickle Cell Disease

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ARTICLE: MedLine Plus Sickle Cell Disease

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What is sickle cell disease (SCD)?

Sickle cell disease (SCD) is a group of inherited red blood cell disorders. If you have SCD, there is a problem with your hemoglobin. Hemoglobin is a protein in red blood cells that carries oxygen throughout the body. With SCD, the hemoglobin forms into stiff rods within the red blood cells. This changes the shape of the red blood cells. The cells are supposed to be disc-shaped, but this changes them into a crescent, or sickle, shape.

The sickle-shaped cells are not flexible and cannot change shape easily. Many of them burst apart as they move through your blood vessels. The sickle cells usually only last 10 to 20 days, instead of the normal 90 to 120 days. Your body may have trouble making enough new cells to replace the ones that you lost. Because of this, you may not have enough red blood cells. This is a condition called anemia, and it can make you feel tired.

The sickle-shaped cells can also stick to vessel walls, causing a blockage that slows or stops the flow of blood. When this happens, oxygen can't reach nearby tissues. The lack of oxygen can cause attacks of sudden, severe pain, called pain crises. These attacks can occur without warning. If you get one, you might need to go to the hospital for treatment.

What causes sickle cell disease (SCD)?

The cause of SCD is a defective gene, called a sickle cell gene. People with the disease are born with two sickle cell genes, one from each parent.

If you are born with one sickle cell gene, it's called sickle cell trait. People with sickle cell trait are generally healthy, but they can pass the defective gene on to their children.

Who is at risk for sickle cell disease (SCD)?

In the United States, most of the people with SCD are African Americans:

About 1 in 13 African American babies is born with sickle cell trait

About 1 in every 365 black children is born with sickle cell disease

SCD also affects some people who come from Hispanic, southern European, Middle Eastern, or Asian Indian backgrounds.

What are the symptoms of sickle cell disease (SCD)?

People with SCD start to have signs of the disease during the first year of life, usually around 5 months of age. Early symptoms of SCD may include:

Painful swelling of the hands and feet

Fatigue or fussiness from anemia

A yellowish color of the skin (jaundice) or the whites of the eyes (icterus)

The effects of SCD vary from person to person and can change over time. Most of the signs and symptoms of SCD are related to complications of the disease. They may include severe pain, anemia, organ damage, and infections.

How is sickle cell disease (SCD) diagnosed?

A blood test can show if you have SCD or sickle cell trait. All states now test newborns as part of their screening programs, so treatment can begin early.

People who are thinking about having children can have the test to find out how likely it is that their children will have SCD.

Doctors can also diagnose SCD before a baby is born. That test uses a sample of amniotic fluid (the liquid in the sac surrounding the baby) or tissue taken from the placenta (the organ that brings oxygen and nutrients to the baby).

What are the treatments for sickle cell disease (SCD)?

The only cure for SCD is bone marrow or stem cell transplantation. Because these transplants are risky and can have serious side effects, they are usually only used in children with severe SCD. For the transplant to work, the bone marrow must be a close match. Usually, the best donor is a brother or sister.

There are treatments that can help relieve symptoms, lessen complications, and prolong life:

Antibiotics to try to prevent infections in younger children

Pain relievers for acute or chronic pain

Hydroxyurea, a medicine that has been shown to reduce or prevent several SCD complications. It increases the amount of fetal hemoglobin in the blood. This medicine is not right for everyone; talk to your health care provider about whether you should take it. This medicine is not safe during pregnancy.

Childhood vaccinations to prevent infections

Blood transfusions for severe anemia. If you have had some serious complications, such as a stroke, you may have transfusions to prevent more complications.

There are other treatments for specific complications.

To stay as healthy as possible, make sure that you get regular medical care, live a healthy lifestyle, and avoid situations that may set off a pain crisis.

NIH: National Heart, Lung, and Blood Institute

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Sickle Cell Disease | Sickle Cell Anemia | MedlinePlus

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Sickle cell disease (SCD) is a group of inherited red blood cell disorders. If you have SCD, there is a problem with your hemoglobin. Hemoglobin is a protein in red blood cells that carries oxygen throughout the body. With SCD, the hemoglobin forms into stiff rods within the red blood cells.

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CHALLENGING READ: The Heterozygote Advantage

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CHALLENGING READ: The Heterozygote Advantage

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Heterozygote Advantage

Heterotic balance (heterozygous advantage) polymorphisms develop when the fitness of heterozygotes is higher than the fitness of both homozygotes in a given population. A classic case of balanced polymorphism in human populations is sickle cell anemia. A mutation in the hemoglobin gene (β S) leads to an alteration in the hemoglobin protein such that the homozygote (β Sβ S) genotype is effectively lethal because individuals die of anemia due to the characteristic sickling of red blood cells (see Fig. 1a). Normally, this would lead to the elimination of the β S allele from the population. However, in regions where malaria is prevalent, the incidence of mortality from malaria (caused by Plasmodium falciparum) is relatively higher in normal homozygote (β Aβ A) individuals than in heterozygous individuals (β Aβ S). Of the three genotypes, β Aβ S has the highest fitness by being partly protected from both anemia and malaria. The loss of β S alleles due to anemia is compensated (at equilibrium) by the loss of β A alleles from malaria, and thus both alleles are maintained in a state of balanced polymorphism. Such polymorphisms are found in many parts of the world where there is a high incidence of malaria, such as Africa, the Middle East, and India, and many of these regions have fairly high (5-6%) frequencies of the sickle cell allele (see Fig. 1b). Eradication of malaria would lead to the reduction of the β S allele from human populations, as appears to be the trend in African-American populations in the United States. Thus, the heterozygote advantage is a powerful mechanism in maintaining genetic polymorphisms, even for deleterious alleles; many debilitating human diseases (eg, Tay-Sachs, Gaucher, and Niemann-Pick diseases in Ashkenazi Jews) and some of the highly polymorphic blood group and enzyme genes (eg, the ABO blood groups and glucose-6-phosphate dehydrogenase) are suspected of being cases of present or past selectively maintained balanced polymorphisms.

Another example of an overdominant molecular polymorphism is the alcohol dehydrogenase (Adh) gene in natural populations of Drosophila melanogaster. This gene segregates two protein electrophoretic alleles, Adh-F (Fast) and Adh-S (Slow), which show north-south (latitudinal) clinical variation in populations from different continents. DNA sequencing reveals that the Adh-F allele is of recent origin, and a lysine residue in the Adh-S allele has been replaced by a threonine residue in the Adh-F allele. The ADH-F protein shows more enzymatic activity and is produced in larger quantities. DNA sequencing studies of representative samples of these two alleles have shown many silent site polymorphisms and a higher level of nucleotide variation at sites near the amino acid-altering mutation than elsewhere on the protein. The latter observation is expected, because linked polymorphic nucleotide sites cannot segregate freely, and a nucleotide site under balancing selection within the gene, through linkage, will affect levels of the polymorphism at the tightly linked sites. Together, these observations support that Adh polymorphism is maintained by heterozygote advantage.

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URL: https://www.sciencedirect.com/science/article/pii/B9780128096338061240

39.2 Heterozygous Advantage and Homozygous Disadvantage

The notion of heterozygous advantage with respect to infectious disease is typified by the example of sickle-cell disease and malaria . It is important to note that under the selective pressure of malaria there is the complementary phenomenon of homozygous disadvantage, such that both the person homozygous for the normal β-globin allele and the person homozygous for the mutant β-globin allele are at a disadvantage despite the fact that the β-globin S/β-globin S genotype offers additional antimalarial advantage compared to the heterozygote. With regard to human leukocyte antigen (HLA) heterozygosity there is evidence for advantages (see HLA discussion later). However, while this phenomenon has been suggested for other common recessive alleles, such as CFTR ΔF508, a clear proof has been somewhat elusive .

In 2010, an important new example of heterozygous advantage with respect to selective pressure of infection in Africa was recognized. A link was made between an unlikely infectious-disease-associated gene, apoprotein L1 ( APOL1), and an increased risk of renal disease in African-Americans . Researchers went on to prove that two common variant alleles of this gene (i.e. APOL1 G1 or APOL1 G2), which are present in West African populations, are associated with protection against African trypanosomiasis, but when found in the homozygous state (G1/G1 or G2/G2) appear to be a risk for renal failure. Like the sickle hemoglobin-malaria situation, the scenario of APOL1-trypanosomiasis appears to be one where away from the selective pressure associated with infection (e.g. North America), there is a genetic disadvantage but no clear advantage to carrying the APOL1 alleles. Unlike the sickle cell-malaria scenario, the homozygous disadvantage of the variants do not likely exert pressure on reproductive fitness in Africa since renal disease typically occurs later in life, beyond the life expectancy of most native Africans.

The work of Lyons and colleagues suggests that more examples may exist, including examples of homozygous disadvantage for invasive bacterial infection. In their study of microsatellite markers in African children who died of invasive bacterial infection and controls they found that homozygosity at a relatively small sample of markers was associated with significant increases in the odds ratio for mortality due to invasive bacteria, these markers segregated differently in some cases based on Gram-positive vs. Gram negative bacteria. The most significant odds ratio (40.7; 95% confidence interval (CI), 4.28-387) was observed for Gram-negative infection in those children who were homozygous for both a site at 7q31 (D7S486) as well as a second site at 16p13.3 (D16S423). The mapping of the pathogenic genetic variants linked to this recessive disease risk has not yet been reported.

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URL: https://www.sciencedirect.com/science/article/pii/B9780123838346000471

B. Heterozygote advantage

The first case that we shall consider is heterozygote advantage. We assume that alleles A and a perform different functions such that the fitness of an individual is higher when both functions are performed. To simplify matters, we assume that all individuals carrying both A and a alleles (regardless of the number of them) have a fitness of 1(= W56 = W25 = W35 = W45 = W16 = W26 = W36), that individuals with only A alleles have a reduced fitness of 1 - s (= W55 = W15), and that individuals with only a alleles have a reduced fitness of 1 - t (= W66 = W 46). This model differs from that examined by Spofford (1969), who focused on the case of a dimeric enzyme taking into account the probability that each type of dimer would be produced. In addition, the following derivation estimates the effective selection coefficient acting on a new duplicate, whereas Spofford focused on a numerical analysis of the dynamics of the duplicate gene.

Before the appearance of the duplication, the frequency of allele A approaches ₅ = t/( s + t), at which point the mean fitness of the population is = 1 - st/( s + t) (Crow and Kimura, 1970). Without loss of generality, we label the alleles such that s ≤ t, so that the frequency of allele A is greater than or equal to . Under these assumptions, it can be shown that the leading eigenvalue describing the initial rate of spread of a gene duplicate is equal to:

Under our assumptions that s, t, ₅, ₆ > 0, this leading eigenvalue is strictly greater than one. Thus, there will always be selection favoring the spread of a duplication. When the duplicate genes are tightly linked ( r ≈ 0), the leading eigenvalue becomes 1/ , which is greater than one under our assumptions. In this case, there is a slight caveat: if the first haplotype to appear is either AA or aa, the duplication will not be positively selected until either the Aa or aA haplotype is produced by mutation, conversion, or recombination. Increasing the recombination rate above zero always reduces the leading eigenvalue and hence slows the initial spread of the duplicate gene. When selection is weak ( s, t ≪ 1) and when the genes are not very tightly linked ( r> 0), the eigenvalue is approximately:

Equation (A4) indicates that the indirect or effective selection acting on the duplicate has the same order of magnitude as selection acting directly on the A and a alleles. Furthermore, selection for the duplicate is strongest when the two functions are approximately of equal benefit( s ≈ t). Comparing the strength of selection on the duplicate (λ - 1), the duplicate experiences ( s + 1)/ t times the amount of selection when linkage is tight than when linkage is loose, assuming weak selection. This reaches a maximum of a twofold difference when s ≈ t, indicating that a tandem duplication carrying both A and a alleles is twice as likely to fix within a population (replacing λ - 1 for the selection coefficient in equation 1) and will spread twice as quickly compared to an unlinked gene duplication. The advantage of tandem duplications is that the most fit chromosomes, i.e., ones bearing both A and a alleles, are unlikely to be broken apart by recombination. This may partially explain why tandem gene duplications are common in many gene families, although another obvious explanation is that the frequency with which duplications appear in tandem is higher as a result of unequal crossing over.

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URL: https://www.sciencedirect.com/science/article/pii/S0065266002460178

Segregational Load

Similar calculations can be performed for models of balancing selection, yielding estimates of the segregational load. In the case of heterozygote advantage, the load due to a single locus is st/( s+ t) (Charlesworth and Charlesworth, 2010). Equation [4] can be used to determine the segregational load contributed by a large number of polymorphic loci with independent effects. This can be considerable, even if selection is weak. For example, 10,000 loci each with s= t=0.001 would yield a mean fitness of only 0.0067. This is so low that only a very high fecundity species would be able to produce the two surviving offspring per adult needed to maintain itself. This implies that either most molecular variation has very slight or no effects on fitness, or that the assumption of multiplicative fitnesses is unrealistic.

An extreme alternative to multiplicative fitnesses is truncation selection. Genotypes at a set of loci are assumed to be ordered with respect to their fitnesses as determined by the multiplicative fitness model; a fixed proportion of the population, containing the set of genotypes with the highest fitnesses, is allowed to survive. This is equivalent to assuming that individuals compete for a limiting resource, and that only the fittest succeed. Under these conditions, a much larger number of loci can be exposed to selection for a given total L than with multiplicative fitnesses, for the same selection intensity per locus. Less extreme forms of departure from multiplicativity can have similar but smaller effects on the total load.

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URL: https://www.sciencedirect.com/science/article/pii/B9780123847195001167

Problems with the Selectionist Hypothesis

Both hypotheses have theoretical and empirical weaknesses. For example, the intuition underlying the balance school suggests that selection in the form of heterozygote advantage underlies the observed levels of genetic variation. Interestingly, this model is unique among the classical, one-locus, two-allele models of constant viability selection in maintaining both alleles at a stable equilibrium: heterozygote advantage is both necessary and sufficient to ensure that any population with allele frequencies close to those at this equilibrium will evolve toward that equilibrium. All other classical models with constant viabilities (e.g., deleterious recessive) predict that genetic variation should eventually be depleted. (Compare Figures 1 and 2.)

Unfortunately, when this basic model is extended to more than two alleles, the situation is less clear. For a start, the very meaning of 'heterozygote advantage' becomes ambiguous. We could mean simply that each heterozygote is fitter than its two corresponding homozygotes, or we could require the stronger condition that all heterozygotes are fitter than the fittest homozygote. Ironically, whatever our definition, it turns out that heterozygote advantage is neither necessary nor sufficient to maintain all the alleles at a stable equilibrium. In other words, it is possible to find fitness parameters that do not fit our definition that afford a stable fully polymorphic equilibrium, as well as other fitnesses that do meet our definition that nevertheless lead to the elimination of one or more alleles. Lewontin et al. (1978) exhibit counterexamples to both the necessity and sufficiency of 'heterozygote advantage' in maintaining even 3 alleles at equilibrium.

A related issue is that the sorts of fitnesses that are able to maintain larger number of alleles at an equilibrium are highly unusual. In a simulation study, Lewontin et al. (1978) generated random sets of n( n+1)/2 viabilities for a population with n alleles (and hence n( n+1)/2 different genotypes) for n=2, 3, 4, 5, and 6 in different simulations, and asked what proportion of these sets allowed a stable equilibrium with all n alleles present. For n=2, heterozygote advantage is both necessary and sufficient and thus we know the answer is 1/3, since there are 3 viabilities needed (for the two homozygotes and one heterozygote) and the chance that the heterozygote fitness in the largest of the 3 viabilities is 1/3. For n>2, however, there is no intuitive explanation. Simulations showed that the proportion rapidly becomes minute: for n=3, the proportion was ~0.042, for n=5, it was 6×10 ⁻⁵, and for n=6, not one in 100 000 sets yielded a stable 6-allele polymorphism. Note that the viability sets that did maintain all n alleles did not necessarily display heterozygote advantage, however defined (except for n=2). Clearly, being able to maintain n alleles for larger values of n is a very unusual property of fitness sets.

These findings were interpreted as showing that the likelihood of such sets occurring in nature was minute. But such a conclusion is a logical fallacy: the size of parameter space is not a measure of likelihood, especially in a system that evolves over time. In another simulation study, Spencer and Marks (1988) showed that recurrent mutation at a locus could lead to the occasional successful invasion of a population by a new allele and the building up of polymorphism over time. Indeed, after 10 000 generations, with just one mutation per generation, the simulated populations possessed an average of more than 5 alleles (Marks and Spencer, 1991). These ideas have been applied to various other forms of selection (e.g., frequency-dependent selection, spatially variable selection, differential selection on males and females) and the overall conclusion is similar: variation is constructed over time under simple combinations of mutation and selection. Nevertheless, it is not clear if these models are sufficiently realistic. For example, one possible disconnect is that many of the simulations generated some form of heterozygote advantage and yet convincing cases of this form of selection acting in natural populations are extremely rare.

A different theoretical problem arises when variation at many loci is considered. Under simple models of selection such as heterozygote advantage at a single locus, the mean fitness of the population is lower than that of the ideal (heterozygous) genotype. This reduction in fitness is called the 'segregational load,' a form of 'genetic load.' When multiple loci are considered, it seems reasonable to assume that effects of each locus are independent and so fitnesses combine multiplicatively. Doing so, however, leads to an absurdity if large numbers of loci have variation maintained by these forms of selection: the mean fitness becomes ridiculously small compared to that of the ideal, multiply-heterozygous types (see Lewontin (1974) and Kimura (1983) for the details of this criticism). Different forms of selection, such as frequency-dependent selection, are less subject to this problem, but it has not been satisfactorily answered.

Finally, as mentioned above, convincing cases of genetic variation in natural populations that are actively maintained by selection are rare. In part, this absence of evidence reflects the difficulty of measuring selection in the wild, but if it is due to a real dearth of examples, then the selectionist hypothesis needs significant modification.

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Stabilizing Selection

Stabilizing selection occurs when heterozygous individuals are the most likely to survive. For that reason this fitness pattern is also referred to as heterozygote advantage. As with disruptive selection, if a population happened to start with an allele frequency exactly equal to:

p*=(w 12 −w 22 )/(2 w 12 −w 11 −w 22 )

the allele frequency would not change. When heterozygotes are more likely to survive than either homozygote, however, p* is a stable equilibrium. Selection causes small departures from p* to become even smaller with time. Moreover, the allele frequency in the population will evolve toward p* regardless of the initial allele frequency, as long as both alleles are initially present. In Figure 2, for example, w ₁₁ = 0.72, w ₁₂ = 0.9, and w ₂₂ = 0.81, and the population evolves toward p* = 0.33 regardless of whether the initial allele frequency is 0.01 or 0.99.

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G6PD deficiency is one of the most common human enzyme defects in the world carried on the X chromosome. The main mutation is sex linked - that is, it is carried on the X chromosome, and probably maintained by heterozygote advantage in females, but males have the disadvantage as they carry only one X chromosome. Adult female heterozygotes usually have a double population of RBCs, some with and some without the enzyme deficiency, with an average of about 50% of each. There are over 300 allelic variants for the disease and there are mainly five classes of the disease according to enzyme activity:

Class I - associated with chronic nonspherocytic hemolytic anemia

Class II - severely deficient enzyme (<10% residual activity)

Class III - moderately deficient enzyme (10-60% residual activity)

Class IV - normal enzyme activity (60-150%)

Class V - increased activity

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Heterozygote Advantage

In some circumstances, the effects of a recessive mutation can affect the phenotype and thus reproductive fitness of heterozygotes. This is not always a negative effect as can be seen in the condition human sickle-cell anemia. Sickle-cell carriers have a heterozygote advantage over the reproductive fitness of normal homozygotes in some environments. In most populations, sickle-cell anemia is a rare mutation, but in malarial regions of Africa as many as one in three of the population are carriers of the mutation in the hemoglobin gene. The presence of the mutant hemoglobin in heterozygotes interferes with the malarial parasite's life cycle. Heterozygotes are therefore more resistant to the debilitating effects of malaria than the normal homozygotes. This heterozygote advantage in many sickle-cell carriers outweighs the severe reproductive disadvantage of the rarer sickle-cell homozygotes. This maintains the mutation in this population at a high frequency as a polymorphism.

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Heterozygote Advantage

As just stated, in many autosomal recessive traits homozygotes for the mutant allele have reduced fitness (f < 1 to f = 0) compared to heterozygotes or those homozygous for the normal allele. There are a few disorders where environmental conditions result in the fitness of heterozygotes being greater than that for either homozygous genotype. This is termed heterozygote advantage . It is important because even a slight heterozygote advantage may act to increase the frequency of the mutant allele in the population-even if the mutant allele causes major reduction in fitness in homozygotes in that population. Those situations in which natural selection acts, at the same time, to maintain a deleterious allele in the gene pool and to remove it from the pool are termed balanced polymorphisms.

Sickle cell anemia is the best-known example of heterozygote advantage and balanced polymorphism in humans. As discussed in Chapter 12 and again in Figure 18.1, the frequency of heterozygotes for hemoglobin S (genotype AS) and the frequency of homozygotes for the mutation (SS) is higher in areas where malaria occurs than in non-malarious areas. This is explained as follows. In regions where malaria is endemic (as in West Africa), homozygotes (AA) for the normal allele are susceptible to malaria; many become infected and some die, leading to reduced fitness. SS homozygotes are even more reproductively disadvantaged because of their severe hematologic disease, their fitness approaching zero. Heterozygotes (AS), however, have red blood cells that resist infection by the malaria parasite ( Plasmodium falciparum) and burst more quickly when infected, thereby leading to the death of the parasites before they infect other cells. In this situation, the fitness of heterozygotes is greater than that for either homozygote. Accordingly, heterozygotes reproduce at a higher rate. Over time the S allele has reached a frequency of 20% (or more) in some areas of West Africa (meaning that as many as one in three people are carriers for the mutant allele). This gene frequency is much higher than can be accounted for by mutation alone. Under these circumstances, Hardy-Weinberg equilibrium is significantly perturbed. When black Africans move to countries like the United States where malaria no longer exists, one would predict that the frequency of the S allele would decline over time. It may already be beginning to do so.

Heterozygote advantage has been shown to exist for other genotypes affecting the red blood cell. Deleterious alleles for the thalassemias, certain other hemoglobinopathies, and glucose-6-phosphate dehydrogenase (G6PD)-an enzyme erythrocytes use to extract energy from glucose-are all thought to be maintained at higher than expected frequencies because they provide protection against malaria. Heterozygote advantage may also explain the high frequency of CF in whites and of a number of lipid storage diseases, including Tay-Sachs, in Ashkenazi Jews. The environmental forces responsible in these situations remain unclear.

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Natural Selection

Natural selection modifies allele and genotype frequencies and these effects depend on both the magnitude and type of selection present. Selection results in departures from Hardy-Weinberg proportions whenever genotypic fitnesses are non-multiplicative (i.e., w ² ≠ w × w) (Lachance, 2008 ). Not surprisingly, overdominance (heterozygote advantage) results in an excess of heterozygotes compared to Hardy-Weinberg expectations, and underdominance (heterozygote disadvantage) results in an excess of homozygotes. Strong directional selection, such as when one allele is a recessive lethal, leads to marked departures from Hardy-Weinberg expectations. However, weak directional selection has only modest effects on genotype frequencies, and detecting these effects can require sample sizes that are larger than 10 000 individuals (Lachance, 2009). Note that the effects of natural selection tend to be locus-specific rather than genome-wide.

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Heterotic balance (heterozygous advantage) polymorphisms develop when the fitness of heterozygotes is higher than the fitness of both homozygotes in a given population. A classic case of balanced polymorphism in human populations is sickle cell anemia.