Sickle cell disease

From Wikipedia, the free encyclopedia

Sickle cell disease
Synonyms	Sickle cell disorder
Figure (A) shows normal red blood cells flowing freely through veins. The inset shows a cross section of a normal red blood cell with normal haemoglobin. Figure (B) shows abnormal, sickled red blood cells sticking at the branching point in a vein. The inset image shows a cross-section of a sickle cell with long polymerized sickle haemoglobin (HbS) strands stretching and distorting the cell shape.
Specialty	Hematology
Symptoms	Attacks of pain, anemia, swelling in the hands and feet, bacterial infections, stroke
Complications	Chronic pain
Usual onset	5–6 months of age
Causes	Genetic
Diagnostic method	Blood test
Treatment	Vaccination, antibiotics, high fluid intake, folic acid supplementation. pain medication, blood transfusions[5][6]
Prognosis	Life expectancy 40–60 years (developed world)
Frequency	4.4 million (2015)
Deaths	114,800 (2015)

Sickle cell disease (SCD) is a group of blood disorders typically inherited from a person's parents. The most common type is known as sickle cell anaemia (SCA). It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blood cells. This leads to a rigid, sickle-like shape under certain circumstances. Problems in sickle cell disease typically begin around 5 to 6 months of age. A number of health problems may develop, such as attacks of pain ("sickle cell crisis"), anemia, swelling in the hands and feet, bacterial infections and stroke. Long-term pain may develop as people get older. The average life expectancy in the developed world is 40 to 60 years.

Sickle cell disease occurs when a person inherits two abnormal copies of the haemoglobin gene, one from each parent. This gene occurs in chromosome 11. Several subtypes exist, depending on the exact mutation in each haemoglobin gene. An attack can be set off by temperature changes, stress, dehydration and high altitude. A person with a single abnormal copy does not usually have symptoms and is said to have sickle cell trait. Such people are also referred to as carriers. Diagnosis is by a blood test, and some countries test all babies at birth for the disease. Diagnosis is also possible during pregnancy.

The care of people with sickle cell disease may include infection prevention with vaccination and antibiotics, high fluid intake, folic acid supplementation and pain medication. Other measures may include blood transfusion and the medication hydroxycarbamide (hydroxyurea). A small percentage of people can be cured by a transplant of bone marrow cells.

As of 2015, about 4.4 million people have sickle cell disease, while an additional 43 million have sickle cell trait. About 80% of sickle cell disease cases are believed to occur in Sub-Saharan Africa. It also occurs relatively frequently in parts of India, the Arabian Peninsula and among people of African origin living in other parts of the world. In 2015, it resulted in about 114,800 deaths. The condition was first described in the medical literature by the American physician James B. Herrick in 1910. In 1949, the genetic transmission was determined by E. A. Beet and J. V. Neel. In 1954, the protective effect against malaria of sickle cell trait was described.

Signs and symptoms

Sickle cell anaemia

Sickle cells in human blood: both normal red blood cells and sickle-shaped cells are present.

Normal blood cells next to a sickle blood cell, colored scanning electron microscope image

Signs of sickle cell disease usually begin in early childhood. The severity of symptoms can vary from person to person. Sickle cell disease may lead to various acute and chronic complications, several of which have a high mortality rate.

Sickle cell crisis

The terms "sickle cell crisis" or "sickling crisis" may be used to describe several independent acute conditions occurring in patients with SCD. SCD results in anaemia and crises that could be of many types including the vaso-occlusive crisis, aplastic crisis, sequestration crisis, haemolytic crisis, and others. Most episodes of sickle cell crises last between five and seven days. "Although infection, dehydration, and acidosis (all of which favor sickling) can act as triggers, in most instances, no predisposing cause is identified."

Vaso-occlusive crisis

The vaso-occlusive crisis is caused by sickle-shaped red blood cells that obstruct capillaries and restrict blood flow to an organ resulting in ischaemia, pain, necrosis, and often organ damage. The frequency, severity, and duration of these crises vary considerably. Painful crises are treated with hydration, analgesics, and blood transfusion; pain management requires opioid administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manage on nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac or naproxen. For more severe crises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia devices are commonly used in this setting. Vaso-occlusive crisis involving organs such as the penis or lungs are considered an emergency and treated with red-blood cell transfusions. Incentive spirometry, a technique to encourage deep breathing to minimise the development of atelectasis, is recommended.

Splenic sequestration crisis

Because of its narrow vessels and function in clearing defective red blood cells, the spleen is frequently affected. It is usually infarcted before the end of childhood in individuals suffering from sickle cell anaemia. This spleen damage increases the risk of infection from encapsulated organisms; preventive antibiotics and vaccinations are recommended for those lacking proper spleen function.

Splenic sequestration crises are acute, painful enlargements of the spleen, caused by intrasplenic trapping of red cells and resulting in a precipitous fall in haemoglobin levels with the potential for hypovolemic shock. Sequestration crises are considered an emergency. If not treated, patients may die within 1–2 hours due to circulatory failure. Management is supportive, sometimes with blood transfusion. These crises are transient, they continue for 3–4 hours and may last for one day.

Acute chest syndrome

Acute chest syndrome (ACS) is defined by at least two of the following signs or symptoms: chest pain, fever, pulmonary infiltrate or focal abnormality, respiratory symptoms, or hypoxemia. It is the second-most common complication and it accounts for about 25% of deaths in patients with SCD, majority of cases present with vaso-occlusive crises then they develop ACS. Nevertheless, about 80% of patients have vaso-occlusive crises during ACS.

Aplastic crisis

Aplastic crises are acute worsenings of the patient's baseline anaemia, producing pale appearance, fast heart rate, and fatigue. This crisis is normally triggered by parvovirus B19, which directly affects production of red blood cells by invading the red cell precursors and multiplying in and destroying them. Parvovirus infection almost completely prevents red blood cell production for two to three days. In normal individuals, this is of little consequence, but the shortened red cell life of SCD patients results in an abrupt, life-threatening situation. Reticulocyte counts drop dramatically during the disease (causing reticulocytopenia), and the rapid turnover of red cells leads to the drop in haemoglobin. This crisis takes 4 days to one week to disappear. Most patients can be managed supportively; some need blood transfusion.

Haemolytic crisis

Haemolytic crises are acute accelerated drops in haemoglobin level. The red blood cells break down at a faster rate. This is particularly common in patients with coexistent G6PD deficiency. Management is supportive, sometimes with blood transfusions.

Other

One of the earliest clinical manifestations is dactylitis, presenting as early as six months of age, and may occur in children with sickle cell trait. The crisis can last up to a month. Another recognised type of sickle crisis, acute chest syndrome, is characterised by fever, chest pain, difficulty breathing, and pulmonary infiltrate on a chest X-ray. Given that pneumonia and sickling in the lung can both produce these symptoms, the patient is treated for both conditions. It can be triggered by painful crisis, respiratory infection, bone-marrow embolisation, or possibly by atelectasis, opiate administration, or surgery. Hematopoietic ulcers may also occur.

Genetics

Sickle cell disease is inherited in an autosomal recessive pattern.

Distribution of the sickle cell trait, shown in pink and purple

Historical distribution of malaria (no longer endemic in Europe), shown in green

Modern distribution of malaria

Normally, humans have haemoglobin A, which consists of two alpha and two beta chains, haemoglobin A2, which consists of two alpha and two delta chains, and haemoglobin F, consisting of two alpha and two gamma chains in their bodies. Out of these three types, haemoglobin F dominates until about 6 weeks of age. Afterwards, haemoglobin A dominates throughout life. In people diagnosed with sickle cell disease, at least one of the β-globin subunits in haemoglobin A is replaced with what's known as haemoglobin S. In sickle cell anaemia, a common form of sickle cell disease, haemoglobin S replaces both β-globin subunits in the haemoglobin.

Sickle cell conditions have an autosomal recessive pattern of inheritance from parents. The types of haemoglobin a person makes in the red blood cells depend on what haemoglobin genes are inherited from her or his parents. If one parent has sickle cell anaemia and the other has sickle cell trait, then the child has a 50% chance of having sickle cell disease and a 50% chance of having sickle cell trait. When both parents have sickle cell trait, a child has a 25% chance of sickle cell disease, 25% do not carry any sickle cell alleles, and 50% have the heterozygous condition.

Sickle cell gene mutation probably arose spontaneously in different geographic areas, as suggested by restriction endonuclease analysis. These variants are known as Cameroon, Senegal, Benin, Bantu, and Saudi-Asian. Their clinical importance is because some are associated with higher HbF levels, e.g., Senegal and Saudi-Asian variants, and tend to have milder disease.

The gene defect is a known mutation of a single nucleotide (see single-nucleotide polymorphism – SNP) (GAG codon changing to GTG) of the β-globin gene, which results in glutamic acid (E/Glu) being substituted by valine (V/Val) at position 6. Haemoglobin S with this mutation is referred to as HbS, as opposed to the normal adult HbA. This is normally a benign mutation, causing no apparent effects on the secondary, tertiary, or quaternary structures of haemoglobin in conditions of normal oxygen concentration. What it does allow for, under conditions of low oxygen concentration, is the polymerization of the HbS itself. The deoxy form of haemoglobin exposes a hydrophobic patch on the protein between the E and F helices (Phe 85, Leu 88). The hydrophobic side chain of the valine residue at position 6 of the beta chain in haemoglobin is able to associate with the hydrophobic patch, causing HbS molecules to aggregate and form fibrous precipitates.

In people heterozygous for HbS (carriers of sickling haemoglobin), the polymerisation problems are minor, because the normal allele is able to produce half of the haemoglobin. In people homozygous for HbS, the presence of long-chain polymers of HbS distort the shape of the red blood cell from a smooth doughnut-like shape to ragged and full of spikes, making it fragile and susceptible to breaking within capillaries. Carriers have symptoms only if they are deprived of oxygen (for example, while climbing a mountain) or while severely dehydrated.

HBB gene (responsible for sickle cell anaemia) is located on the short (p) arm of chromosome 11 at position 15.5.

The allele responsible for sickle cell anaemia can be found on the short arm of chromosome 11, more specifically 11p15.5. A person who receives the defective gene from both father and mother develops the disease; a person who receives one defective and one healthy allele remains healthy, but can pass on the disease and is known as a carrier or heterozygote. Heterozygotes are still able to contract malaria, but their symptoms are generally less severe.

Due to the adaptive advantage of the heterozygote, the disease is still prevalent, especially among people with recent ancestry in malaria-stricken areas, such as Africa, the Mediterranean, India, and the Middle East. Malaria was historically endemic to southern Europe, but it was declared eradicated in the mid-20th century, with the exception of rare sporadic cases.

The malaria parasite has a complex lifecycle and spends part of it in red blood cells. In a carrier, the presence of the malaria parasite causes the red blood cells with defective haemoglobin to rupture prematurely, making the Plasmodium parasite unable to reproduce. Further, the polymerization of Hb affects the ability of the parasite to digest Hb in the first place. Therefore, in areas where malaria is a problem, people's chances of survival actually increase if they carry sickle cell trait (selection for the heterozygote).

In the United States, with no endemic malaria, the prevalence of sickle cell anaemia among African Americans is lower (about 0.25%) than in West Africa (about 4.0%) and is falling. Without endemic malaria, the sickle cell mutation is purely disadvantageous and tends to decline in the affected population by natural selection, and now artificially through prenatal genetic screening. However, the African American community descends from a significant admixture of several African and non-African ethnic groups and also represents the descendants of survivors of slavery and the slave trade. Thus, a lower degree of endogamy and, particularly, abnormally high health-selective pressure through slavery may be the most plausible explanations for the lower prevalence of sickle cell anaemia (and, possibly, other genetic diseases) among African Americans compared to West Africans. Another factor that limits the spread of sickle cell genes in North America is the absence of cultural proclivities to polygamy, which allows affected males to continue to seek unaffected children with multiple partners.

Pathophysiology

Scanning electron micrograph showing a mixture of red blood cells, some with round normal morphology, some with mild sickling showing elongation and bending

The loss of red blood cell elasticity is central to the pathophysiology of sickle cell disease. Normal red blood cells are quite elastic, which allows the cells to deform to pass through capillaries. In sickle cell disease, low oxygen tension promotes red blood cell sickling and repeated episodes of sickling damage the cell membrane and decrease the cell's elasticity. These cells fail to return to normal shape when normal oxygen tension is restored. As a consequence, these rigid blood cells are unable to deform as they pass through narrow capillaries, leading to vessel occlusion and ischaemia.

The actual anaemia of the illness is caused by haemolysis, the destruction of the red cells, because of their shape. Although the bone marrow attempts to compensate by creating new red cells, it does not match the rate of destruction. Healthy red blood cells typically function for 90–120 days, but sickled cells only last 10–20 days.

Diagnosis

In HbS, the complete blood count reveals haemoglobin levels in the range of 6–8 g/dl with a high reticulocyte count (as the bone marrow compensates for the destruction of sickled cells by producing more red blood cells). In other forms of sickle cell disease, Hb levels tend to be higher. A blood film may show features of hyposplenism (target cells and Howell-Jolly bodies).

Sickling of the red blood cells, on a blood film, can be induced by the addition of sodium metabisulfite. The presence of sickle haemoglobin can also be demonstrated with the "sickle solubility test". A mixture of haemoglobin S (Hb S) in a reducing solution (such as sodium dithionite) gives a turbid appearance, whereas normal Hb gives a clear solution.

Abnormal haemoglobin forms can be detected on haemoglobin electrophoresis, a form of gel electrophoresis on which the various types of haemoglobin move at varying speeds. Sickle cell haemoglobin (HgbS) and haemoglobin C with sickling (HgbSC)—the two most common forms—can be identified from there. The diagnosis can be confirmed with high-performance liquid chromatography. Genetic testing is rarely performed, as other investigations are highly specific for HbS and HbC.

An acute sickle cell crisis is often precipitated by infection. Therefore, a urinalysis to detect an occult urinary tract infection, and chest X-ray to look for occult pneumonia should be routinely performed.

People who are known carriers of the disease often undergo genetic counseling before they have a child. A test to see if an unborn child has the disease takes either a blood sample from the fetus or a sample of amniotic fluid. Since taking a blood sample from a fetus has greater risks, the latter test is usually used. Neonatal screening provides not only a method of early detection for individuals with sickle cell disease, but also allows for identification of the groups of people that carry the sickle cell trait.

Management

Treatment involves a number of measures. L-glutamine use was supported by the FDA starting at the age of 5 as it decreases complications.

Folic acid and penicillin

From birth to five years of age, penicillin daily, due to the immature immune system that makes them more prone to early childhood illnesses is recommended. Dietary supplementation of folic acid had been previously recommended by the WHO. A 2016 Cochrane review of its use found "the effect of supplementation on anaemia and any symptoms of anaemia remains unclear" due to a lack of medical evidence.

Malaria prevention

The protective effect of sickle cell trait does not apply to people with sickle cell disease; in fact, they are more vulnerable to malaria, since the most common cause of painful crises in malarial countries is infection with malaria. It has therefore been recommended that people with sickle cell disease living in malarial countries should receive anti-malarial chemoprophylaxis for life.

Vaso-occlusive crisis

Most people with sickle cell disease have intensely painful episodes called vaso-occlusive crises. However, the frequency, severity, and duration of these crises vary tremendously. Painful crises are treated symptomatically with pain medications; pain management requires opioid administration at regular intervals until the crisis has settled. For milder crises, a subgroup of patients manage on NSAIDs (such as diclofenac or naproxen). For more severe crises, most patients require inpatient management for intravenous opioids; patient-controlled analgesia (PCA) devices are commonly used in this setting. Diphenhydramine is also an effective agent that doctors frequently prescribe to help control itching associated with the use of opioids.

Acute chest crisis

Management is similar to vaso-occlusive crisis, with the addition of antibiotics (usually a quinolone or macrolide, since cell wall-deficient ["atypical"] bacteria are thought to contribute to the syndrome), oxygen supplementation for hypoxia, and close observation. Should the pulmonary infiltrate worsen or the oxygen requirements increase, simple blood transfusion or exchange transfusion is indicated. The latter involves the exchange of a significant portion of the person's red cell mass for normal red cells, which decreases the percent of haemoglobin S in the patient's blood. The patient with suspected acute chest syndrome should be admitted to the hospital with worsening A-a gradient an indication for ICU admission.

Hydroxyurea

The first approved drug for the causative treatment of sickle cell anaemia, hydroxyurea, was shown to decrease the number and severity of attacks in a study in 1995 and shown to possibly increase survival time in a study in 2003. This is achieved, in part, by reactivating fetal haemoglobin production in place of the haemoglobin S that causes sickle cell anaemia. Hydroxyurea had previously been used as a chemotherapy agent, and there is some concern that long-term use may be harmful, but this risk has been shown to be either absent or very small and it is likely that the benefits outweigh the risks.

Blood transfusion

Blood transfusions are often used in the management of sickle cell disease in acute cases and to prevent complications by decreasing the number of red blood cells (RBC) that can sickle by adding normal red blood cells. In children preventative red blood cell (RBC) transfusion therapy has been shown to reduce the risk of first stroke or silent stroke when transcranial Doppler (TCD) ultrasonography shows abnormal cerebral blood flow. In those who have sustained a prior stroke event it also reduces the risk of recurrent stroke and additional silent strokes.

Bone marrow transplant

Bone marrow transplants have proven effective in children. Bone marrow transplants are the only known cure for SCD. However, bone marrow transplants are difficult to obtain because of the specific HLA typing necessary. Ideally, a close relative (allogeneic) would donate the bone marrow necessary for transplantation.

Avascular necrosis

When treating avascular necrosis of the bone in people with sickle cell disease, the aim of treatment is to reduce or stop the pain and maintain joint mobility. Current treatment options are to rest the joint, physical therapy, pain relief medicine, joint replacement surgery, or bone grafting. High quality randomized controlled trials are needed to assess the most effective treatment option and determine if a combination of physical therapy and surgery are more effective than physical therapy alone.

Psychological therapies

Psychological therapies such as patient education, cognitive therapy, behavioural therapy and psychodynamic psychotherapy, that aim to complement current medical treatments, require further research to determine their effectiveness.

Prognosis

About 90% of people survive to age 20, and close to 50% survive beyond age 50. In 2001, according to one study performed in Jamaica, the estimated mean survival for people with sickle cell was 53 years old for men and 58 years old for women with homozygous SCD. The specific life expectancy in much of the developing world is unknown.

Complications

Sickle cell anaemia can lead to various complications, including:

• Increased risk of severe bacterial infections due to loss of functioning spleen tissue (and comparable to the risk of infections after having the spleen removed surgically). These infections are typically caused by encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae. Daily penicillin prophylaxis is the most commonly used treatment during childhood, with some haematologists continuing treatment indefinitely. Patients benefit today from routine vaccination for S. pneumoniae.
• Stroke, which can result from a progressive narrowing of blood vessels, prevents oxygen from reaching the brain. Cerebral infarction occurs in children and cerebral haemorrhage in adults.
• Silent stroke causes no immediate symptoms, but is associated with damage to the brain. Silent stroke is probably five times as common as symptomatic stroke. About 10–15% of children with SCD suffer strokes, with silent strokes predominating in the younger patients.
• Cholelithiasis (gallstones) and cholecystitis may result from excessive bilirubin production and precipitation due to prolonged haemolysis.
• Avascular necrosis (aseptic bone necrosis) of the hip and other major joints may occur as a result of ischaemia.
• Decreased immune reactions due to hyposplenism (malfunctioning of the spleen)
• Priapism and infarction of the penis
• Osteomyelitis (bacterial bone infection), the most common cause of osteomyelitis in SCD is Salmonella (especially the atypical serotypes Salmonella typhimurium, Salmonella enteritidis, Salmonella choleraesuis and Salmonella paratyphi B), followed by Staphylococcus aureus and Gram-negative enteric bacilli perhaps because intravascular sickling of the bowel leads to patchy ischaemic infarction.
• Acute papillary necrosis in the kidneys
• Leg ulcers
• In eyes, background retinopathy, proliferative retinopathy, vitreous haemorrhages, and retinal detachments can result in blindness. Regular annual eye checks are recommended.
• During pregnancy, intrauterine growth retardation, spontaneous abortion, and pre-eclampsia
• Chronic pain: Even in the absence of acute vaso-occlusive pain, many patients have unreported chronic pain.
• Pulmonary hypertension (increased pressure on the pulmonary artery) can lead to strain on the right ventricle and a risk of heart failure; typical symptoms are shortness of breath, decreased exercise tolerance, and episodes of syncope. 21% of children and 30% of adults have evidence of pulmonary hypertension when tested; this is associated with reduced walking distance and increased mortality.
• Chronic kidney failure due to sickle-cell nephropathy manifests itself with hypertension, protein loss in the urine, loss of red blood cells in urine and worsened anaemia. If it progresses to end-stage renal failure, it carries a poor prognosis.

Epidemiology

The highest frequency of sickle cell disease is found in tropical regions, particularly sub-Saharan Africa, tribal regions of India and the Middle East. Migration of substantial populations from these high prevalence areas to low prevalence countries in Europe has dramatically increased in recent decades and in some European countries sickle cell disease has now overtaken more familiar genetic conditions such as haemophilia and cystic fibrosis. In 2015, it resulted in about 114,800 deaths.

Sickle cell disease occurs more commonly among people whose ancestors lived in tropical and sub-tropical sub-Saharan regions where malaria is or was common. Where malaria is common, carrying a single sickle cell allele (trait) confers a heterozygote advantage: humans with one of the two alleles of sickle cell disease show less severe symptoms when infected with malaria.

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Africa

Three-quarters of sickle cell cases occur in Africa. A recent WHO report estimated that around 2% of newborns in Nigeria were affected by sickle cell anaemia, giving a total of 150,000 affected children born every year in Nigeria alone. The carrier frequency ranges between 10% and 40% across equatorial Africa, decreasing to 1–2% on the north African coast and less than 1% in South Africa. There have been studies in Africa that show a significant decrease in infant mortality rate, ages 2–16 months, because of the sickle cell trait. This happened in predominant areas of malarial cases.
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United States

The number of people with the disease in the United States is approximately 1 in 5,000, mostly affecting Americans of sub-Saharan African descent, according to the National Institutes of Health. In the United States, about one out of 500 African-American children and one in every 36,000 Hispanic-American children have sickle cell anaemia. It is estimated that sickle cell disease affects 90,000 Americans. Most infants with SCD born in the United States are now identified by routine neonatal screening. As of 2016 all 50 states include screening for sickle cell disease as part of their newborn screen. Patient advocates for sickle cell disease have complained that it gets less government and private research funding than similar rare diseases like cystic fibrosis, with researcher Elliott Vichinsky saying this shows racial discrimination or the role of wealth in health care advocacy.

France

As a result of population growth in African-Caribbean regions of overseas France and immigration from North and sub-Saharan Africa to mainland France, sickle cell disease has become a major health problem in France. SCD has become the most common genetic disease in the country, with an overall birth prevalence of 1/2,415 in Metropolitan France, ahead of phenylketonuria (1/10,862), congenital hypothyroidism (1/3,132), congenital adrenal hyperplasia (1/19,008) and cystic fibrosis (1/5,014) for the same reference period.

Since 2000, neonatal screening of SCD has been performed at national level for all newborns defined as being "at risk" for SCD based on ethnic origin (defined as those born to parents originating from sub-Saharan Africa, North Africa, the Mediterranean area (South Italy, Greece and Turkey), the Arabic peninsula, the French overseas islands and the Indian subcontinent).

United Kingdom

In the United Kingdom, it is thought that between 12,000 and 15,000 people have sickle cell disease  with an estimated 250,000 carriers of the condition in England alone. As the number of carriers is only estimated, all newborn babies in the UK receive a routine blood test to screen for the condition. Due to many adults in high-risk groups not knowing if they are carriers, pregnant women and both partners in a couple are offered screening so they can get counselling if they have the sickle cell trait. In addition blood donors from those in high-risk groups are also screened to confirm whether they are carriers and whether their blood filters properly. Donors who are found to be carriers are then informed and their blood, while often used for those of the same ethnic group, is not used for those with sickle cell disease who require a blood transfusion.

Middle East

In Saudi Arabia, about 4.2% of the population carry the sickle cell trait and 0.26% have sickle cell disease. The highest prevalence is in the Eastern province where approximately 17% of the population carry the gene and 1.2% have sickle cell disease. In 2005, Saudi Arabia introduced a mandatory pre-marital test including HB electrophoresis which aimed to decrease the incidence of SCD and thalassemia.

In Bahrain a study published in 1998 that covered about 56,000 people in hospitals in Bahrain found that 2% of newborns have sickle cell disease, 18% of the surveyed people have the sickle cell trait, and 24% were carriers of the gene mutation causing the disease. The country began screening of all pregnant women in 1992 and newborns started being tested if the mother was a carrier. In 2004, a law was passed requiring couples planning to get married to undergo free premarital counseling. These programs were accompanied by public education campaigns.

India and Nepal

Sickle cell disease is common in ethnic groups of central India who share a genetic linkage with African communities, where the prevalence has ranged from 9.4 to 22.2% in endemic areas of Madhya Pradesh, Rajasthan and Chhattisgarh. It is also endemic among Tharu people of Nepal and India; however, they have a sevenfold lower incidence of malaria despite living in a malaria infested zone.

Caribbean Islands

In Jamaica, 10% of the population carries the sickle cell gene, making it the most prevalent genetic disorder in the country.

History

The first modern report of sickle cell disease may have been in 1846, where the autopsy of an executed runaway slave was discussed; the key findings was the absence of the spleen. There were also reports amongst African slaves in the United States exhibiting resistance to malaria but being prone to leg ulcers. The abnormal characteristics of the red blood cells, which later lent their name to the condition, was first described by Ernest E. Irons (1877–1959), intern to the Chicago cardiologist and professor of medicine James B. Herrick (1861–1954), in 1910. Irons saw "peculiar elongated and sickle-shaped" cells in the blood of a man named Walter Clement Noel, a 20-year-old first-year dental student from Grenada. Noel had been admitted to the Chicago Presbyterian Hospital in December 1904 suffering from anaemia. Noel was readmitted several times over the next three years for "muscular rheumatism" and "bilious attacks" but completed his studies and returned to the capital of Grenada (St. George's) to practice dentistry. He died of pneumonia in 1916 and is buried in the Catholic cemetery at Sauteurs in the north of Grenada. Shortly after the report by Herrick, another case appeared in the Virginia Medical Semi-Monthly with the same title, "Peculiar Elongated and Sickle-Shaped Red Blood Corpuscles in a Case of Severe Anemia." This article is based on a patient admitted to the University of Virginia Hospital on November 15, 1910. In the later description by Verne Mason in 1922, the name "sickle cell anemia" is first used. Childhood problems related to sickle cells disease were not reported until the 1930s, despite the fact that this cannot have been uncommon in African-American populations.

The Memphis physician Lemuel Diggs, a prolific researcher into sickle cell disease, first introduced the distinction between sickle cell disease and trait in 1933, although it took until 1949 until the genetic characteristics were elucidated by James V. Neel and E.A. Beet. 1949 was the year when Linus Pauling described the unusual chemical behaviour of haemoglobin S, and attributed this to an abnormality in the molecule itself. The actual molecular change in HbS was described in the late 1950s by Vernon Ingram. The late 1940s and early 1950s saw further understanding in the link between malaria and sickle cell disease. In 1954, the introduction of haemoglobin electrophoresis allowed the discovery of particular subtypes, such as HbSC disease.

Large scale natural history studies and further intervention studies were introduced in the 1970s and 1980s, leading to widespread use of prophylaxis against pneumococcal infections amongst other interventions. Bill Cosby's Emmy-winning 1972 TV movie, To All My Friends on Shore, depicted the story of the parents of a child suffering from sickle cell disease. The 1990s saw the development of hydroxycarbamide, and reports of cure through bone marrow transplantation appeared in 2007.

Some old texts refer to it as drepanocytosis.

Society and culture

U.S. Social Security

Effective September 15, 2017, the U.S. Social Security Administration issued a Policy Interpretation Ruling providing background information on sickle cell disease and a description of how Social Security evaluates the disease during its adjudication process for disability claims.

Research

Umbilical cord blood transplant

While umbilical cord blood transplant can potentially cure the condition, a suitable donor is available in only 10% of people. About 7% of people also die as a result of the procedure and graft versus host disease may occur.

Gene therapy

In 2001, it was reported that sickle cell disease had been successfully treated in mice using gene therapy. The researchers used a viral vector to make the mice—which have essentially the same defect that causes human sickle cell disease—express production of fetal haemoglobin (HbF), which an individual normally ceases to produce shortly after birth. In humans, using hydroxyurea to stimulate the production of HbF has been known to temporarily alleviate sickle cell disease symptoms. The researchers demonstrated that this gene therapy method is a more permanent way to increase therapeutic HbF production.

Phase 1 clinical trials of gene therapy for sickle cell disease in humans were started in 2014. The clinical trials will assess the safety and initial evidence for efficacy of an autologous transplant of lentiviral vector-modified bone marrow for adults with severe sickle cell disease. As of 2016, however, no randomized controlled trials have been reported. A case report for the first person treated was published in March 2017.

Polymorphism (biology)

From Wikipedia, the free encyclopedia

Light-morph jaguar

 

Dark-morph or melanistic jaguar (about 6% of the South American population)

Polymorphism in biology and zoology is the occurrence of two or more clearly different morphs or forms, also referred to as alternative phenotypes, in the population of a species. To be classified as such, morphs must occupy the same habitat at the same time and belong to a panmictic population (one with random mating).

The term polyphenism can be used to clarify that the different forms arise from the same genotype. Genetic polymorphism is a term used somewhat differently by geneticists and molecular biologists to describe certain mutations in the genotype, such as single nucleotide polymorphisms that may not always correspond to a phenotype, but always corresponds to a branch in the genetic tree.

Polymorphism is common in nature; it is related to biodiversity, genetic variation, and adaptation. Polymorphism usually functions to retain variety of form in a population living in a varied environment. The most common example is sexual dimorphism, which occurs in many organisms. Other examples are mimetic forms of butterflies (see mimicry), and human hemoglobin and blood types.

According to the theory of evolution, polymorphism results from evolutionary processes, as does any aspect of a species. It is heritable and is modified by natural selection. In polyphenism, an individual's genetic makeup allows for different morphs, and the switch mechanism that determines which morph is shown is environmental. In genetic polymorphism, the genetic makeup determines the morph.

The term polymorphism also refers to the occurrence of structurally and functionally more than two different types of individuals, called zooids, within the same organism. It is a characteristic feature of cnidarians. For example, Obelia has feeding individuals, the gastrozooids; the individuals capable of asexual reproduction only, the gonozooids, blastostyles; and free-living or sexually reproducing individuals, the medusae.

Terminology

Although in general use, polymorphism is a very broad term. In biology, polymorphism has been given a specific meaning, being distinguishable from monomorphism (having only one form). A more specific term, when only two forms occur, is dimorphism.

• The term omits characters showing continuous variation (such as weight), though this has a heritable component. Polymorphism deals with forms in which the variation is discrete (discontinuous) or strongly bimodal or polymodal.
• Morphs must occupy the same habitat at the same time; this excludes geographical races and seasonal forms. The use of the words "morph" or "polymorphism" for what is a visibly different geographical race or variant is common, but incorrect. The significance of geographical variation is in that it may lead to allopatric speciation, whereas true polymorphism takes place in panmictic populations.
• The term was first used to describe visible forms, but nowadays it has been extended to include cryptic morphs, for instance blood types, which can be revealed by a test.
• Rare variations are not classified as polymorphisms, and mutations by themselves do not constitute polymorphisms. To qualify as a polymorphism, some kind of balance must exist between morphs underpinned by inheritance. The criterion is that the frequency of the least common morph is too high simply to be the result of new mutations or, as a rough guide, that it is greater than 1% (though that is far higher than any normal mutation rate for a single allele).

Nomenclature

Polymorphism crosses several discipline boundaries, including ecology and genetics, evolution theory, taxonomy, cytology, and biochemistry. Different disciplines may give the same concept different names, and different concepts may be given the same name. For example, there are the terms established in ecological genetics by E.B. Ford (1975), and for classical genetics by John Maynard Smith (1998). The shorter term morphism may be more accurate than polymorphism, but is not often used. It was the preferred term of the evolutionary biologist Julian Huxley (1955).

Various synonymous terms exist for the various polymorphic forms of an organism. The most common are morph and morpha, while a more formal term is morphotype. Form and phase are sometimes also used, but are easily confused in zoology with, respectively, "form" in a population of animals, and "phase" as a color or other change in an organism due to environmental conditions (temperature, humidity, etc.). Phenotypic traits and characteristics are also possible descriptions, though that would imply just a limited aspect of the body.

In the taxonomic nomenclature of zoology, the word "morpha" plus a Latin name for the morph can be added to a binomial or trinomial name. However, this invites confusion with geographically variant ring species or subspecies, especially if polytypic. Morphs have no formal standing in the ICZN. In botanical taxonomy, the concept of morphs is represented with the terms "variety", "subvariety" and "form", which are formally regulated by the ICN. Horticulturists sometimes confuse this usage of "variety" both with cultivar ("variety" in viticultural usage, rice agriculture jargon, and informal gardening lingo) and with the legal concept "plant variety" (protection of a cultivar as a form of intellectual property).

Mechanisms

Three mechanisms may cause polymorphism:

• Genetic polymorphism – where the phenotype of each individual is genetically determined
• A conditional development strategy, where the phenotype of each individual is set by environmental cues
• A mixed development strategy, where the phenotype is randomly assigned during development

Ecology

Selection, whether natural or artificial, changes the frequency of morphs within a population; this occurs when morphs reproduce with different degrees of success. A genetic (or balanced) polymorphism usually persists over many generations, maintained by two or more opposed and powerful selection pressures. Diver (1929) found banding morphs in Cepaea nemoralis could be seen in prefossil shells going back to the Mesolithic Holocene. Non-human apes have similar blood groups to humans; this strongly suggests that this kind of polymorphism is ancient, at least as far back as the last common ancestor of the apes and man, and possibly even further.

The white morph of the monarch in Hawaii is partly a result of apostatic selection.

The relative proportions of the morphs may vary; the actual values are determined by the effective fitness of the morphs at a particular time and place. The mechanism of heterozygote advantage assures the population of some alternative alleles at the locus or loci involved. Only if competing selection disappears will an allele disappear. However, heterozygote advantage is not the only way a polymorphism can be maintained. Apostatic selection, whereby a predator consumes a common morph whilst overlooking rarer morphs is possible and does occur. This would tend to preserve rarer morphs from extinction.

Polymorphism is strongly tied to the adaptation of a species to its environment, which may vary in colour, food supply, and predation and in many other ways. Polymorphism is one good way the opportunities get to be used; it has survival value, and the selection of modifier genes may reinforce the polymorphism. In addition, polymorphism seems to be associated with a higher rate of speciation.

Polymorphism and niche diversity

G. Evelyn Hutchinson, a founder of niche research, commented "It is very likely from an ecological point of view that all species, or at least all common species, consist of populations adapted to more than one niche". He gave as examples sexual size dimorphism and mimicry. In many cases where the male is short-lived and smaller than the female, he does not compete with her during her late pre-adult and adult life. Size difference may permit both sexes to exploit different niches. In elaborate cases of mimicry, such as the African butterfly Papilio dardanus, female morphs mimic a range of distasteful models, often in the same region. The fitness of each type of mimic decreases as it becomes more common, so the polymorphism is maintained by frequency-dependent selection. Thus the efficiency of the mimicry is maintained in a much increased total population.

The switch

The mechanism which decides which of several morphs an individual displays is called the switch. This switch may be genetic, or it may be environmental. Taking sex determination as the example, in humans the determination is genetic, by the XY sex-determination system. In Hymenoptera (ants, bees and wasps), sex determination is by haplo-diploidy: the females are all diploid, the males are haploid. However, in some animals an environmental trigger determines the sex: alligators are a famous case in point. In ants the distinction between workers and guards is environmental, by the feeding of the grubs. Polymorphism with an environmental trigger is called polyphenism.

The polyphenic system does have a degree of environmental flexibility not present in the genetic polymorphism. However, such environmental triggers are the less common of the two methods.

Investigative methods

Investigation of polymorphism requires use of both field and laboratory techniques. In the field:

• detailed survey of occurrence, habits and predation
• selection of an ecological area or areas, with well-defined boundaries
• capture, mark, release, recapture data (see Mark and recapture)
• relative numbers and distribution of morphs
• estimation of population sizes

And in the laboratory:

• genetic data from crosses
• population cages
• chromosome cytology if possible
• use of chromatography or similar techniques if morphs are cryptic (for example, biochemical)

Without proper field-work, the significance of the polymorphism to the species is uncertain and without laboratory breeding the genetic basis is obscure. Even with insects, the work may take many years; examples of Batesian mimicry noted in the nineteenth century are still being researched.

Genetics

Genetic polymorphism

Since all polymorphism has a genetic basis, genetic polymorphism has a particular meaning:

• Genetic polymorphism is the simultaneous occurrence in the same locality of two or more discontinuous forms in such proportions that the rarest of them cannot be maintained just by recurrent mutation or immigration, originally defined by Ford (1940). The later definition by Cavalli-Sforza & Bodmer (1971) is currently used: "Genetic polymorphism is the occurrence in the same population of two or more alleles at one locus, each with appreciable frequency", where the minimum frequency is typically taken as 1%.

The definition has three parts: a) sympatry: one interbreeding population; b) discrete forms; and c) not maintained just by mutation.

In simple words, the term polymorphism was originally used to describe variations in shape and form that distinguish normal individuals within a species from each other. These days, geneticists use the term genetic polymorphism to describe the inter-individual, functionally silent differences in DNA sequence that make each human genome unique.

Genetic polymorphism is actively and steadily maintained in populations by natural selection, in contrast to transient polymorphisms where a form is progressively replaced by another. By definition, genetic polymorphism relates to a balance or equilibrium between morphs. The mechanisms that conserve it are types of balancing selection.

Mechanisms of balancing selection

• Heterosis (or heterozygote advantage): "Heterosis: the heterozygote at a locus is fitter than either homozygote".
• Frequency dependent selection: The fitness of a particular phenotype is dependent on its frequency relative to other phenotypes in a given population. Example: prey switching, where rare morphs of prey are actually fitter due to predators concentrating on the more frequent morphs.
• Fitness varies in time and space. Fitness of a genotype may vary greatly between larval and adult stages, or between parts of a habitat range.
• Selection acts differently at different levels. The fitness of a genotype may depend on the fitness of other genotypes in the population: this covers many natural situations where the best thing to do (from the point of view of survival and reproduction) depends on what other members of the population are doing at the time.

Pleiotropism

Most genes have more than one effect on the phenotype of an organism (pleiotropism). Some of these effects may be visible, and others cryptic, so it is often important to look beyond the most obvious effects of a gene to identify other effects. Cases occur where a gene affects an unimportant visible character, yet a change in fitness is recorded. In such cases the gene's other (cryptic or 'physiological') effects may be responsible for the change in fitness. Pleiotropism is posing continual challenges for many clinical dysmorphologists in their attempt to explain birth defects which affect one or more organ system, with only a single underlying causative agent. For many pleiotropic disorders, the connection between the gene defect and the various manifestations is neither obvious, nor well understood.

"If a neutral trait is pleiotropically linked to an advantageous one, it may emerge because of a process of natural selection. It was selected but this doesn't mean it is an adaptation. The reason is that, although it was selected, there was no selection for that trait."

Epistasis

Epistasis occurs when the expression of one gene is modified by another gene. For example, gene A only shows its effect when allele B1 (at another locus) is present, but not if it is absent. This is one of the ways in which two or more genes may combine to produce a coordinated change in more than one characteristic (for instance, in mimicry). Unlike the supergene, epistatic genes do not need to be closely linked or even on the same chromosome.

Both pleiotropism and epistasis show that a gene need not relate to a character in the simple manner that was once supposed.

The origin of supergenes

Although a polymorphism can be controlled by alleles at a single locus (e.g. human ABO blood groups), the more complex forms are controlled by supergenes consisting of several tightly linked genes on a single chromosome. Batesian mimicry in butterflies and heterostyly in angiosperms are good examples. There is a long-standing debate as to how this situation could have arisen, and the question is not yet resolved.

Whereas a gene family (several tightly linked genes performing similar or identical functions) arises by duplication of a single original gene, this is usually not the case with supergenes. In a supergene some of the constituent genes have quite distinct functions, so they must have come together under selection. This process might involve suppression of crossing-over, translocation of chromosome fragments and possibly occasional cistron duplication. That crossing-over can be suppressed by selection has been known for many years.

Debate has centered round the question of whether the component genes in a super-gene could have started off on separate chromosomes, with subsequent reorganization, or if it is necessary for them to start on the same chromosome. Originally, it was held that chromosome rearrangement would play an important role. This explanation was accepted by E. B. Ford and incorporated into his accounts of ecological genetics.

However, today many believe it more likely that the genes start on the same chromosome. They argue that supergenes arose in situ. This is known as Turner's sieve hypothesis. John Maynard Smith agreed with this view in his authoritative textbook, but the question is still not definitively settled.

Relevance for evolutionary theory

Polymorphism was crucial to research in ecological genetics by E. B. Ford and his co-workers from the mid-1920s to the 1970s (similar work continues today, especially on mimicry). The results had a considerable effect on the mid-century evolutionary synthesis, and on present evolutionary theory. The work started at a time when natural selection was largely discounted as the leading mechanism for evolution, continued through the middle period when Sewall Wright's ideas on drift were prominent, to the last quarter of the 20th century when ideas such as Kimura's neutral theory of molecular evolution was given much attention. The significance of the work on ecological genetics is that it has shown how important selection is in the evolution of natural populations, and that selection is a much stronger force than was envisaged even by those population geneticists who believed in its importance, such as Haldane and Fisher.

In just a couple of decades the work of Fisher, Ford, Arthur Cain, Philip Sheppard and Cyril Clarke promoted natural selection as the primary explanation of variation in natural populations, instead of genetic drift. Evidence can be seen in Mayr's famous book Animal Species and Evolution, and Ford's Ecological Genetics. Similar shifts in emphasis can be seen in most of the other participants in the evolutionary synthesis, such as Stebbins and Dobzhansky, though the latter was slow to change.

Kimura drew a distinction between molecular evolution, which he saw as dominated by selectively neutral mutations, and phenotypic characters, probably dominated by natural selection rather than drift.

Examples

Sexual dimorphism

A female (left) and a male (right) Mallard duck (A. platyrhynchos). Like many other species of birds, Mallards display striking sexual dimorphism.

Most eukaryotes species use sexual reproduction, the division into two sexes is a dimorphism. The question of evolution of sex from asexual reproduction has engaged the attentions of biologists such as Charles Darwin, August Weismann, Ronald Fisher, George C. Williams, John Maynard Smith and W. D. Hamilton, with varied success.

Of the many issues involved, there is widespread agreement on the following: the advantage of sexual and hermaphroditic reproduction over asexual reproduction lies in the way recombination increases the genetic diversity of the ensuing population.

Human blood groups

All the common blood types, such as the ABO blood group system, are genetic polymorphisms. Here we see a system where there are more than two morphs: the phenotypes A, B, AB and O are present in all human populations, but vary in proportion in different parts of the world. The phenotypes are controlled by multiple alleles at one locus. These polymorphisms are seemingly never eliminated by natural selection; the reason came from a study of disease statistics.

Statistical research has shown that the various phenotypes are more, or less, likely to suffer a variety of diseases. For example, an individual's susceptibility to cholera (and other diarrheal infections) is correlated with their blood type: those with type O blood are the most susceptible, while those with type AB are the most resistant. Between these two extremes are the A and B blood types, with type A being more resistant than type B. This suggests that the pleiotropic effects of the genes set up opposing selective forces, thus maintaining a balance. Geographical distribution of blood groups (the differences in gene frequency between populations) is broadly consistent with the classification of "races" developed by early anthropologists on the basis of visible features.

Sickle-cell anaemia

Sickle-cell anaemia is found mostly in tropical populations in Africa and India. An individual homozygous for the recessive sickle hemoglobin, HgbS, has a short expectancy of life, whereas the life expectancy of the standard hemoglobin (HgbA) homozygote and also the heterozygote is normal (though heterozygote individuals will suffer periodic problems). The sickle-cell variant survives in the population because the heterozygote is resistant to malaria and the malarial parasite kills a huge number of people each year. This is balancing selection or genetic polymorphism, balanced between fierce selection against homozygous sickle-cell sufferers, and selection against the standard HgbA homozygotes by malaria. The heterozygote has a permanent advantage (a higher fitness) so long as malaria exists; and it has existed as a human parasite for a long time. Because the heterozygote survives, so does the HgbS allele survive at a rate much higher than the mutation rate.

Duffy system

The Duffy antigen is a protein located on the surface of red blood cells, encoded by the FY (DARC) gene. The protein encoded by this gene is a non-specific receptor for several chemokines, and is the known entry-point for the human malarial parasites Plasmodium vivax and Plasmodium knowlesi. Polymorphisms in this gene are the basis of the Duffy blood group system.

In humans, a mutant variant at a single site in the FY cis-regulatory region abolishes all expression of the gene in erythrocyte precursors. As a result, homozygous mutants are strongly protected from infection by P. vivax, and a lower level of protection is conferred on heterozygotes. The variant has apparently arisen twice in geographically distinct human populations, in Africa and Papua New Guinea. It has been driven to high frequencies on at least two haplotypic backgrounds within Africa. Recent work indicates a similar, but not identical, pattern exists in baboons (Papio cynocephalus), which suffer a mosquito-carried malaria-like pathogen, Hepatocystis kochi. Researchers interpret this as a case of convergent evolution.

G6PD

Glucose-6-phosphate dehydrogenase human polymorphism is also implicated in malarial resistance. G6PD alleles with reduced activity are maintained at a high level in endemic malarial regions, despite reduced general viability. Variant A (with 85% activity) reaches 40% in sub-Saharan Africa, but is generally less than 1% outside Africa and the Middle East.

Human taste morphisms

A famous puzzle in human genetics is the genetic ability to taste phenylthiocarbamide (phenylthiourea or PTC), a morphism which was discovered in 1931. This substance, which is bitter to some people, and tasteless to others, is of no great significance in itself, yet it is a genetic dimorphism. Because of its high frequency (which varies in different ethnic groups) it must be connected to some function of selective value. The ability to taste PTC itself is correlated with the ability to taste other bitter substances, many of which are toxic. Indeed, PTC itself is toxic, though not at the level of tasting it on litmus. Variation in PTC perception may reflect variation in dietary preferences throughout human evolution, and might correlate with susceptibility to diet-related diseases in modern populations. There is a statistical correlation between PTC tasting and liability to thyroid disease.

Fisher, Ford and Huxley tested orangutans and chimpanzees for PTC perception with positive results, thus demonstrating the long-standing existence of this dimorphism. The PTC gene, which accounts for 85% of the tasting variance, has now been analysed for sequence variation with results which suggest selection is maintaining the morphism.

MHC molecules

The genes of the major histocompatibility complex (MHC) are highly polymorphic, and this diversity plays a very important role in resistance to pathogens. This is true for other species as well.

The cuckoo

Reed warbler feeding a cuckoo chick (Cuculus canorus)

Over fifty species in this family of birds practice brood parasitism; the details are best seen in the common cuckoo (Cuculus canorus). In a season the female lays one egg in 15–20 other bird nests. She removes some or all of the host's clutch of eggs, and lays an egg which closely matches the host eggs. In Britain the cuckoo lays small eggs that match the size of the smaller host's. The eggs are thick-shelled as a defense to protect the egg if the host detects the fraud.

The intruded egg develops exceptionally quickly; when the newly hatched cuckoo is only ten hours old, and still blind, it exhibits an urge to eject the other eggs or nestlings. It rolls them into a special depression on its back and heaves them out of the nest. The cuckoo nestling is apparently able to pressure the host adults for feeding by mimicking the cries of the host nestlings. The diversity of the cuckoo's eggs is extraordinary, the forms resembling those of its most usual hosts. In Britain these are:

• Meadow pipit (Anthus pratensis): brown eggs speckled with darker brown.
• European robin (Erithacus rubecula): whitish-grey eggs speckled with bright red.
• Reed warbler (Acrocephalus scirpensis): light dull green eggs blotched with olive.
• Redstart (Phoenicurus phoenicurus): clear blue eggs.
• Hedge sparrow (Prunella modularis): clear blue eggs, unmarked, not mimicked. This bird is an uncritical fosterer; it tolerates in its nest eggs that do not resemble its own.

Each female cuckoo lays one type only; the same type laid by her mother. In this way female cuckoos are divided into groups (known as gentes, singular gens), each parasitises the host to which it is adapted. The male cuckoo has its own territory, and mates with females from any gens; thus the population (all gentes) is interbreeding.

The standard explanation of how the inheritance of gens works is as follows. The egg colour is inherited by sex chromosome. In birds sex determination is ZZ/ZW, and unlike mammals, the heterogametic sex is the female. The determining gene (or super-gene) for the inheritance of egg colour is believed to be carried on the W chromosome, which is directly transmitted in the female line. The female behaviour in choosing the host species is set by imprinting after birth, a common mechanism in bird behaviour.

Ecologically, the system of multiple hosts protects host species from a critical reduction in numbers, and maximises the egg-laying capacity of the population of cuckoos. It also extends the range of habitats where the cuckoo eggs may be raised successfully. Detailed work on the cuckoo started with E. Chance in 1922, and continues to the present day; in particular, the inheritance of gens is still a live issue.

Grove snail

The grove snail, Cepaea nemoralis, is famous for the rich polymorphism of its shell. The system is controlled by a series of multiple alleles. The shell colour series is brown (genetically the top dominant trait), dark pink, light pink, very pale pink, dark yellow and light yellow (the bottom or universal recessive trait). Bands may be present or absent; and if present from one to five in number. Unbanded is the top dominant trait, and the forms of banding are controlled by modifier genes (see epistasis).

Grove snail, dark yellow shell with single band.

In England the snail is regularly predated by the song thrush Turdus philomelos, which breaks them open on thrush anvils (large stones). Here fragments accumulate, permitting researchers to analyse the snails taken. The thrushes hunt by sight, and capture selectively those forms which match the habitat least well. Snail colonies are found in woodland, hedgerows and grassland, and the predation determines the proportion of phenotypes (morphs) found in each colony.

Two active grove snails (Cepaea nemoralis)

A second kind of selection also operates on the snail, whereby certain heterozygotes have a physiological advantage over the homozygotes. In addition, apostatic selection is likely, with the birds preferentially taking the most common morph. This is the 'search pattern' effect, where a predominantly visual predator persists in targeting the morph which gave a good result, even though other morphs are available.

Despite the predation, the polymorphism survives in almost all habitats, though the proportions of morphs varies considerably. The alleles controlling the polymorphism form a super-gene with linkage so close as to be nearly absolute. This control saves the population from a high proportion of undesirable recombinants, and it is hypothesised that selection has brought the loci concerned together.

To sum up, in this species predation by birds appears to be the main (but not the only) selective force driving the polymorphism. The snails live on heterogeneous backgrounds, and thrush are adept at detecting poor matches. The inheritance of physiological and cryptic diversity is preserved also by heterozygous advantage in the super-gene. Recent work has included the effect of shell colour on thermoregulation, and a wider selection of possible genetic influences is considered by Cook.

A similar system of genetic polymorphism occurs in the white-lipped snail Cepaea hortensis, a close relative of the grove snail. In Iceland, where there are no song thrushes, a correlation has been established between temperature and colour forms. Banded and brown morphs reach higher temperatures than unbanded and yellow snails. This may be the basis of the physiological selection found in both species of snail.

Scarlet tiger moth

The scarlet tiger moth Callimorpha (Panaxia) dominula (family Arctiidae) occurs in continental Europe, western Asia and southern England. It is a day-flying moth, noxious-tasting, with brilliant warning colour in flight, but cryptic at rest. The moth is colonial in habit, and prefers marshy ground or hedgerows. The preferred food of the larvae is the herb Comfrey (Symphytum officinale). In England it has one generation per year.

Callimorpha dominula morpha typica with spread wings. The red with black rear wings, revealed in flight, warn of its noxious taste. The front wings are cryptic, covering the rear wings at rest. Here the moth is resting but alert, and has jinked the front wings forward to reveal the warning flash.

The moth is known to be polymorphic in its colony at Cothill, about five miles (8 km) from Oxford, with three forms: the typical homozygote; the rare homozygote (bimacula) and the heterozygote (medionigra). It was studied there by Ford and later by Sheppard and their co-workers over many years. Data is available from 1939 to the present day, got by the usual field method of capture-mark-release-recapture and by genetic analysis from breeding in captivity. The records cover gene frequency and population-size for much of the twentieth century.

In this instance the genetics appears to be simple: two alleles at a single locus, producing the three phenotypes. Total captures over 26 years 1939–64 came to 15,784 homozygous dominula (i.e. typica), 1,221 heterozygous medionigra and 28 homozygous bimacula. Now, assuming equal viability of the genotypes 1,209 heterozygotes would be expected, so the field results do not suggest any heterozygous advantage. It was Sheppard who found that the polymorphism is maintained by selective mating: each genotype preferentially mates with other morphs. This is sufficient to maintain the system despite the fact that in this case the heterozygote has slightly lower viability.

Peppered moth

The peppered moth, Biston betularia, is justly famous as an example of a population responding in a heritable way to a significant change in their ecological circumstances. E.B. Ford described peppered moth evolution as "one of the most striking, though not the most profound, evolutionary changes ever actually witnessed in nature".

Although the moths are cryptically camouflaged and rest during the day in unexposed positions on trees, they are predated by birds hunting by sight. The original camouflage (or crypsis) seems near-perfect against a background of lichen growing on trees. The sudden growth of industrial pollution in the nineteenth century changed the effectiveness of the moths' camouflage: the trees became blackened by soot, and the lichen died off. In 1848 a dark version of this moth was found in the Manchester area. By 1895 98% of the peppered moths in this area were black. This was a rapid change for a species that has only one generation a year.

Biston betularia morpha typica, the standard light-coloured peppered moth.

 

Biston betularia morpha carbonaria, the melanic peppered moth.

In Europe, there are three morphs: the typical white morph (betularia or typica), and carbonaria, the melanic black morph. They are controlled by alleles at one locus, with the carbonaria being dominant. There is also an intermediate or semi-melanic morph insularia, controlled by other alleles.

A key fact, not realised initially, is the advantage of the heterozygotes, which survive better than either of the homozygotes. This affects the caterpillars as well as the moths, in spite of the caterpillars being monomorphic in appearance (they are twig mimics). In practice heterozygote advantage puts a limit to the effect of selection, since neither homozygote can reach 100% of the population. For this reason, it is likely that the carbonaria allele was in the population originally, pre-industrialisation, at a low level. With the recent reduction in pollution, the balance between the forms has already shifted back significantly.

Another interesting feature is that the carbonaria had noticeably darkened after about a century. This was seen quite clearly when specimens collected about 1880 were compared with specimens collected more recently: clearly the dark morph has been adjusted by the strong selection acting on the gene complex. This might happen if a more extreme allele was available at the same locus; or genes at other loci might act as modifiers. We do not, of course, know anything about the genetics of the original melanics from the nineteenth century.

This type of industrial melanism has only affected such moths as obtain protection from insect-eating birds by resting on trees where they are concealed by an accurate resemblance to their background (over 100 species of moth in Britain with melanic forms were known by 1980). No species which hide during the day, for instance, among dead leaves, is affected, nor has the melanic change been observed among butterflies. This is, as shown in many textbooks, "evolution in action".

Much of the early work was done by Bernard Kettlewell, whose methods came under scrutiny later on. The entomologist Michael Majerus discussed criticisms made of Kettlewell's experimental methods in his 1998 book Melanism: Evolution in Action. This book was misrepresented in some reviews, and the story picked up by creationist campaigners.

Judith Hooper, in her controversial book Of Moths and Men (2002), implied that Kettlewell's work was fraudulent or incompetent. Careful studies of Kettlewell's surviving papers by Rudge (2005) and Young (2004) found that Hooper's accusation of fraud was unjustified, and that "Hooper does not provide one shred of evidence to support this serious allegation". Majerus himself described Of Moths and Men as "littered with errors, misrepresentations, misinterpretations and falsehoods". A suitably restrained 2004 summary of opinion mostly favoured predation as the main selective force.

Starting in 2000, Majerus conducted a detailed seven-year study of moths, experimenting to assess the various criticisms. He concluded that differential bird predation was a major factor responsible for the decline in carbonaria frequency compared to typica in Cambridge during the study period, and described his results as a complete vindication of the peppered moth story. He said, "If the rise and fall of the peppered moth is one of the most visually impacting and easily understood examples of Darwinian evolution in action, it should be taught. It provides after all the proof of evolution."

Current interpretation of the available evidence is that the peppered moth is in fact a valid example of natural selection and adaptation. It illustrates a polymorphic species maintaining adaptation to a varied and sometimes changing environment.

Two-spotted ladybird beetle

Adalia bipunctata red morph

 

Adalia bipunctata black morph

Adalia bipunctata, the two-spotted ladybird, is highly polymorphic. Its basic form is red with two black spots, but it has many other forms, the most important being melanic, with black elytra and red spots. The curious fact about this morphism is that, although the melanic forms are more common in industrial areas, its maintenance has nothing to do with cryptic camouflage and predation. The Coccinellidae as a whole are highly noxious, and experiments with birds and other predators have found this species quite exceptionally distasteful. Therefore, their colour is warning (aposematic) colouration, and all the morphs are quite conspicuous against green vegetation. The field studies identify differing proportions of morphs at different times of year and in different places, which indicates a high level of selection. However, the basis of that selection is still not known for sure, though many theories have been proposed. Since all the morphs are aposematically coloured, it seems unlikely that the difference between the colour of morphs is directly under selection. Perhaps pleiotropic effects of the genes acting on colour also affect the beetle's physiology, and hence its relative fitness. A similar polymorphic system is found in many other species in this family: Harmonia axyridis is a good example.

Mid-dorsal stripe in frogs

Some frog species display polymorphism by presence/absence of a light stripe going along the central part of their back. A light mid-dorsal stripe has been shown to be determined by a simple dominant gene in Rana limnocharis, Rana ridibunda, Rana sylvatica and Rana arvalis; that means the individuals both homozygtes by allele determining the presence of stripe and heterozygotes have the stripe, whereas only the individuals homozygotic by recessive allele are non-striped. The proportions of striped specimens in populations of some frogs show clinal variations. For example, the proportion of striped Rana sylvatica in North America generally increases towards the west and north. The variations in the proportion of different color may relate to either genetic-stochastic processes. or their adaptive importance. For different colour morphs of Acris crepitans, the hypothesis about the direct adaptive value of different colour morphs (for escaping predation) competes with the hypothesis that these morphs correlate with thermotolerance. Striped specimens Rana sylvatica, striped specimens better perform in open areas. Differences in the proportion of striped frogs in Rana arvalis are explained with physiological differences between the morphs. Striped recently metamorphosed frogs have a relatively large liver, in comparison with unstriped ones, and their weight increases more rapidly. Tadpoles of striped Rana arvalis need more time for completing metamorphosis but, after metamorphosis, their growth is faster than that of unstriped froglets. In a frog widespread in Turkey and the Caucasus, Rana macrocnemis, the proportion of frogs with the stripe increases with the altitude in mountains of the Lesser Caucasus, but not in the Greater Caucasus. Given the same altitude, non-striped frogs from the Greater Caucasus grow slower and maturate later than the striped frogs from the Lesser Caucasus, which provides them selective advantage in high mountains, but their tadpoles are likely to be less resistant to overheating than those of the non-striped frogs.

Ants

Ants exhibit a range of polymorphisms. First, there is their characteristic haplodiploid sex determination system, whereby all males are haploid, and all females diploid. Second, there is differentiation between both the females and males based mostly on feeding of larvae, which determines, for example, whether the imago is capable of reproduction. Lastly, there is differentiation of size and 'duties' (particularly of females), which are usually controlled by feeding and/or age, but which may sometimes be genetically controlled. Thus the order exhibits both genetic polymorphism and extensive polyphenism.

Reindeer and caribou

Genetic polymorphism of serum transferrins in reindeer is used in population and genetic studies. Gene concentrations of alleles in populations of reindeer of the North-East of Siberia were compared with those in reindeer inhabiting Norway, the northern regions of the European part of the USSR and from North American caribou. Researchers found that frequencies of Tf alleles of the Siberian reindeer differed from all the others. It is possible that resistance to necrobacteriosis is related to concentrations of alleles in certain reindeer populations.

Hoverfly polymorphism

Xanthogramma pedissequum, a wasp mimic

 

Volucella zonaria, a large bumblebee mimic

 

Mallota sp., a bumblebee mimic

Hoverfly mimics can be seen in almost any garden in the temperate zone. The Syrphidae are a large (5600+ species) family of flies; their imagoes feed on nectar and pollen, and are well known for their mimicry of social hymenoptera. The mimicry is Batesian in nature: hoverflies are palatable but hymenoptera are generally unpalatable and may also be protected by stingers and/or armour.

Many social wasp (Vespidae) species exhibit Müllerian mimicry, where a group of unpalatable species benefit from sharing the same kind of warning (aposematic) colouration. Wasps are decidedly noxious: nasty-tasting and with a painful sting. They form a Mullerian 'ring' of similarly coloured models; the wasps are often accompanied by clusters of hover-fly mimics, who tend to arrive at the flowers at a similar time of day, and whose flight pattern is passably similar to wasp flight.

Observers in a garden can see for themselves that hoverfly mimics are quite common, usually many times more common than the models, and are (to our sight) relatively poor mimics, often easy to distinguish from real wasps. However, it has been established in other cases that imperfect mimicry can confer significant advantage to the mimic, especially if the model is really noxious. Also, not only is polymorphism absent from these mimics, it is absent in the wasps also: these facts are presumably connected.

The situation with bumblebees (Bombus) is rather different. They too are unpalatable, in the sense of being difficult to eat: their body is covered with setae (like carpet pile) and is armoured; they are sometimes described as being 'non-food'. Mostler in 1935 carried out tests of their palatability: with the exception of specialist bee-eaters, adults of 19 species of birds ate only 2% of 646 bumblebees presented to them. After various trials, Mostler attributed their avoidance mainly to mechanical difficulties in handling: one young bird took 18 minutes to subdue, kill and eat a bumblebee.

Bumblebees form Mullerian rings of species, and they do often exhibit polymorphism. The hoverfly species mimicking bumblebees are generally accurate mimics, and many of their species are polymorphic. Many of the polymorphisms are different between the sexes, for example by the mimicry being limited to one sex only.

The question is, how can the differences between social wasp mimics and bumblebee mimics be explained? Evidently if model species are common, and have overlapping distributions, they are less likely to be polymorphic. Their mimics are widespread and develop a kind of rough and ready jack-of-all-trades mimicry. But if model species are less common and have patchy distribution they develop polymorphism; and their mimics match them more exactly and are polymorphic also. The issues are currently being investigated.

Chromosome polymorphism in Drosophila

In the 1930s Dobzhansky and his co-workers collected Drosophila pseudoobscura and D. persimilis from wild populations in California and neighbouring states. Using Painter's technique they studied the polytene chromosomes and discovered that the wild populations were polymorphic for chromosomal inversions. All the flies look alike whatever inversions they carry: this is an example of a cryptic polymorphism. Accordingly, Dobzhansky favoured the idea that the morphs became fixed in the population by means of Sewall Wright's drift. However, evidence rapidly accumulated to show that natural selection was responsible:

Drosophila polytene chromosome

 

1. Values for heterozygote inversions of the third chromosome were often much higher than they should be under the null assumption: if no advantage for any form the number of heterozygotes should conform to N_s (number in sample) = p²+2pq+q² where 2pq is the number of heterozygotes.


2. Using a method invented by l'Heretier and Teissier, Dobzhansky bred populations in population cages, which enabled feeding, breeding and sampling whilst preventing escape. This had the benefit of eliminating migration as a possible explanation of the results. Stocks containing inversions at a known initial frequency can be maintained in controlled conditions. It was found that the various chromosome types do not fluctuate at random, as they would if selectively neutral, but adjust to certain frequencies at which they become stabilised. With D. persimilis he found that the caged population followed the values expected on the Hardy-Weinberg equilibrium when conditions were optimal (which disproved any idea of non-random mating), but with a restricted food supply heterozygotes had a distinct advantage.

3. Different proportions of chromosome morphs were found in different areas. There is, for example, a polymorph-ratio cline in D. robusta along an 18-mile (29 km) transect near Gatlinburg, TN passing from 1,000 feet (300 m) to 4,000 feet. Also, the same areas sampled at different times of year yielded significant differences in the proportions of forms. This indicates a regular cycle of changes which adjust the population to the seasonal conditions. For these results selection is by far the most likely explanation.

4. Lastly, morphs cannot be maintained at the high levels found simply by mutation, nor is drift a possible explanation when population numbers are high.

By the time Dobzhansky published the third edition of his book in 1951, he was persuaded that the chromosome morphs were being maintained in the population by the selective advantage of the heterozygotes, as with most polymorphisms. Later he made yet another interesting discovery. One of the inversions, known as PP, was quite rare up to 1946, but by 1958 its proportion had risen to 8%. Not only that, but the proportion was similar over an area of some 200,000 square miles (520,000 km²) in California. This cannot have happened by migration of PP morphs from, say, Mexico (where the inversion is common) because the rate of dispersal (at less than 2 km/year) is of the wrong order. The change therefore reflected a change in prevailing selection whose basis was not yet known.

Chromosomal polymorphism in general

In 1973, M. J. D. White, then at the end of a long career investigating karyotypes, gave an interesting summary of the distribution of chromosome polymorphism.

"It is extremely difficult to get an adequate idea as to what fraction of the species of eukaryote organisms actually are polymorphic for structural rearrangements of the chromosomes. In Dipterous flies with polytene chromosomes... the figure is somewhere between 60 and 80 percent... In grasshoppers pericentric inversion polymorphism is shown by only a small number of species. But in this group polymorphism for super-numerary chromosomes and chromosome regions is very strongly developed in many species."

"It is clear that the nature of natural populations is a very complicated subject, and it now appears probable that adaptation of the various genotypes to different ecological niches and frequency-dependent selection are at least as important, and probably more important in many cases, than simple heterosis (in the sense of increased viability or fecundity of the heterozygote)".

This suggests, once again, that polymorphism is a common and important aspect of adaptive evolution in natural populations.

Heterostyly

Dissection of thrum and pin flowers of Primula vulgaris

An example of a botanical genetic polymorphism is heterostyly, in which flowers occur in different forms with different arrangements of the pistils and the stamens. The system is called heteromorphic self-incompatibility, and the general 'strategy' of stamens separated from pistils is known as herkogamy.

Pin and thrum heterostyly occurs in dimorphic species of Primula, such as P. vulgaris. There are two types of flower. The pin flower has a long style bearing the stigma at the mouth and the stamens halfway down; and the thrum flower has a short style, so the stigma is halfway up the tube and the stamens are at the mouth. So when an insect in search of nectar inserts its proboscis into a long-style flower, the pollen from the stamens stick to the proboscis in exactly the part that will later touch the stigma of the short-styled flower, and vice versa.

Another most important property of the heterostyly system is physiological. If thrum pollen is placed on a thrum stigma, or pin pollen on a pin stigma, the reproductive cells are incompatible and relatively little seed is set. Effectively, this ensures out-crossing, as described by Darwin. Quite a lot is now known about the underlying genetics; the system is controlled by a set of closely linked genes which act as a single unit, a super-gene. All sections of the genus Primula have heterostyle species, altogether 354 species out of 419. Since heterostyly is characteristic of nearly all races or species, the system is at least as old as the genus.

Between 1861 and 1863, Darwin found the same kind of structure in other groups: flax (and other species of Linum); and in purple loosestrife and other species of Lythrum. Some of the Lythrum species are trimorphic, with one style and two stamens in each form.

Heterostyly is known in at least 51 genera of 18 families of Angiosperms.

White-throated sparrows

Zonotrichia albicollis black-and-white-striped morph

 

Zonotrichia albicollis brown-and-tan-striped morph

The white-throated sparrow (Zonotrichia albicollis), a passerine bird of the American sparrow family Emberizidae, shows a clear dimorphism in both sexes throughout its large range.

Their heads are either white-striped or tan-striped. These differences in plumage result from a balanced chromosomal inversion polymorphism; in white-striped (WS) birds, one copy of chromosome 2 is partly inverted, while in tan-striped (TS) birds, both copies are uninverted.
The plumage differences are paralleled by differences in behavior and breeding strategy. WS males sing more, are more aggressive and more frequently engage in extra-pair copulation than their TS counterparts. TS birds of both sexes provide more parental care than WS birds.

The polymorphism is maintained by negative assortative mating—each morph mates with its opposite. Dimorphic pairs may have an advantageous balance between parental care and aggressive territorial defense. In addition, as in many other polymorphisms, heterozygote advantage seems to help maintain this one; the proportion of WS birds homozygotic for the inversion is even lower than would be expected from the low frequency (4%) of pairings of the same morph.

In the underlying chromosomal polymorphism, the standard (ZAL2) and alternative (ZAL2m) arrangements differ by a pair of included pericentric inversions at least. ZAL2m suppresses recombination in the heterokaryotype and is evolving as a rare nonrecombining autosomal segment of the genome.

Darwin's finches

Whereas Darwin spent just five weeks in the Galápagos, and David Lack spent three months, Peter and Rosemary Grant and their colleagues have made research trips to the Galápagos for about thirty years, particularly studying Darwin's finches. Here we look briefly at the case of the Española cactus finch (Geospiza conirostris) on Isla Genovesa (formerly Tower Island) which is formed from a shield volcano, and is home to a variety of birds. These birds, like all well-studied groups, show various kinds of morphism.

Males are dimorphic in song type: songs A and B are quite distinct. Also, males with song A have shorter bills than B males. This is also a clear difference. With these beaks males are able to feed differently on their favourite cactus, the prickly pear Opuntia. Those with long beaks are able to punch holes in the cactus fruit and eat the fleshy aril pulp which surrounds the seeds, whereas those with shorter beaks tear apart the cactus base and eat the pulp and any insect larvae and pupae (both groups eat flowers and buds). This dimorphism clearly maximises their feeding opportunities during the non-breeding season when food is scarce.

Territories of type A and type B males are random if not mated but alternate if mated: no two breeding males of the same song type shared a common boundary. This initially suggested the possibility of assortative mating by female choice. However, further work showed that "the choice of a male by a female is independent of any conditioning influence of her father's song type and there is no evidence of assortative mating by bill type... Hence there is no direct evidence of reproductive subdivision in the population". In 1999 Peter Grant agreed that "sympatric speciation [in this example] is unlikely to occur".

If the population is panmixic, then Geospiza conirostris exhibits a balanced genetic polymorphism and not, as originally supposed, a case of nascent sympatric speciation. The selection maintaining the polymorphism maximises the species' niche by expanding its feeding opportunity. The genetics of this situation cannot be clarified in the absence of a detailed breeding program, but two loci with linkage disequilibrium is a possibility.

Another interesting dimorphism is for the bills of young finches, which are either "pink" or "yellow". All species of Darwin's finches exhibit this morphism, which lasts for two months. No interpretation of this phenomenon is known.

Common side-blotched lizards

Male common side-blotched lizards (Uta stansburiana) exhibit polymorphism in their throat pigmentation, and these different phenotypes are correlated with different mating strategies. Orange-throated males are the largest and most aggressive, defending large territories and keeping harems of females. Blue-throated males are of intermediate size, and guard smaller territories containing only a single female. Yellow-throated males are the smallest, and instead of holding territories they mimic females in order to sneak matings away from the other two morphs. The balance between these three morphs is maintained by frequency-dependent selection.

Common wall lizards

The common wall lizard (Podarcis muralis) displays polymorphism and has six distinct morphs which vary by the colour of their throat and underbelly (underbelly colouration seen predominantly in males). There are three "pure" morphs of colours: red, yellow and white and three "intermediate" morphs which are a combination of the colours: white-red, white-yellow and red-yellow.

Ctenophorus decresii

This lizard displays polymorphism with varying colors of their throats. The throat colors range from white and gray to bright colors of red, orange, or blue. The diversity in throat color is due to a combination of sexual selection and natural selection.

Viviparous lizard

Viviparous lizards display color polymorphism in three ventral colors: yellow, orange, and a mixture of the two. These color morphs respond to variation in density frequency-dependence within their environment.

Ctenophorus pictus

Male Ctenophorus pictus lizards display different colors. The most common are red and yellow, but colors can range from brown to orange to red/orange. These morphs are maintained in nature through a combination of selective factors: natural selection and sexual selection.

Relative frequency

Endler's survey of natural selection gave an indication of the relative importance of polymorphisms among studies showing natural selection. The results, in summary: Number of species demonstrating natural selection: 141. Number showing quantitative traits: 56. Number showing polymorphic traits: 62. Number showing both Q and P traits: 23. This shows that polymorphisms are found to be at least as common as continuous variation in studies of natural selection, and hence just as likely to be part of the evolutionary process.