Genetic Polymorphism: Blood Groups, Haemoglobin, HLA and DNA Markers

Genetic polymorphism is the occurrence in one population of two or more genetically determined forms of a trait, each too common to be explained by recurrent mutation alone. E. B. Ford gave the classic definition in 1940. A locus is called polymorphic when its rarest common allele has a frequency of about 1 per cent or more. Human examples range from the ABO and Rh blood groups, haemoglobin variants, G6PD and HLA to DNA markers such as STRs and SNPs. Polymorphisms are kept in populations by balancing selection, by drift of neutral variants and by gene flow.

This note covers the meaning and types of genetic polymorphism, the main human polymorphic systems with their Indian distribution, balanced polymorphism, DNA polymorphism and its uses in anthropology, for the UPSC Anthropology Optional. It falls under Paper I, topic 9.3 (genetic polymorphism and selection) and the topic on genetic markers (ABO, Rh, HLA and others) in the Anthropology Optional syllabus.

Key points at a glance

• Meaning: from the Greek poly, many, and morphe, form.
• Ford's definition (1940): two or more discontinuous forms occurring together, the rarest too frequent to be kept up by mutation alone.
• Threshold: conventionally, a frequency of 1 per cent or more for the less common allele.
• Types: balanced and transient; neutral and selected; protein and DNA.
• Classical markers: ABO, Rh and other blood groups; haemoglobin variants; red-cell enzymes such as G6PD; serum proteins; HLA.
• DNA markers: RFLPs, VNTRs, STRs, SNPs, and mitochondrial and Y-chromosome haplotypes.
• Classic case of balanced polymorphism: sickle-cell haemoglobin and malaria.
• India: high frequency of blood group B; HbS among tribes of the central belt; HbE in the North-East; the Bombay blood group, first described in Mumbai.

Meaning and definition

Polymorphism is "the occurrence together in the same habitat of two or more discontinuous forms of a species in such proportions that the rarest of them cannot be maintained merely by recurrent mutation". (E. B. Ford, 1940)

Three ideas are packed into the definition:

• Discontinuous forms. The variants are distinct, like blood types A and B, not points on a continuous scale like stature.
• In the same population. The forms occur together, not in separate places.
• Too common for mutation. Mutation rates are tiny. A variant present at several per cent must be maintained by some other force.

Genes occupying the same locus on a chromosome and controlling the same character are alleles. When more than one allele at a locus is common, as with the A, B and O alleles of the ABO system, the population is polymorphic for that locus. Most polymorphic traits used in anthropology are inherited in a simple Mendelian fashion, which makes their frequencies easy to calculate.

Polymorphism and related terms

A note on thresholds. For population surveys the usual cut-off is 1 per cent. Some writers on DNA variation call a site "common" only when the minor allele exceeds 5 per cent. Both figures appear in textbooks; the 1 per cent rule is the standard definition of polymorphism.

Types of polymorphism

The kinds of polymorphism discovered have always reflected the techniques available. Blood grouping revealed antigen polymorphisms, starch-gel electrophoresis revealed protein variants, and DNA methods revealed far more variation than either.

How polymorphisms are maintained

A polymorphism often persists over many generations because no single form has an overall advantage. Genetic polymorphism therefore preserves diversity within a population, which gives it the capacity to respond to new conditions.

Human polymorphic systems

1. The ABO blood group system

• Discovery. Karl Landsteiner described the ABO groups in 1900–1901.
• Inheritance. Three main alleles, A, B and O, at one locus on chromosome 9. A and B are codominant; O is recessive. This gives four phenotypes, A, B, AB and O, from six genotypes.
• A polymorphism in every population. All four phenotypes occur in most human populations, but in different proportions.

The worldwide clines in the A, B and O alleles suggest that gene flow, genetic drift and natural selection have all played a part in their distribution.

In India. ABO is the most studied genetic system of the subcontinent. Frequencies of the B allele in Indian populations are among the highest in the world.

The Bombay phenotype. In 1952 Y. M. Bhende and colleagues in Mumbai described people whose red cells lacked the H substance from which the A and B antigens are made. They type as group O but cannot safely receive ordinary group O blood. The "Bombay blood group" is an Indian contribution to the genetics of blood groups.

2. The Rh system

• Discovery. Philip Levine and Rufus Stetson reported in 1939 an antibody in a mother whose newborn had haemolytic disease. Landsteiner and Alexander Wiener described the Rh factor in 1940. Together these explained unexpected transfusion reactions and haemolytic disease of the newborn.
• Genetics. The system lies on chromosome 1. Red cells are commonly classed as Rh-positive, carrying the major D antigen, or Rh-negative, lacking it. The antigens C, c, D, E and e are those most studied, and dozens of Rh antigens are now known, making it one of the most complex human polymorphisms.
• Distribution. Rh-negative frequencies are highest in Europe, especially among the Basques, and low in East Asia and among Native Americans.
• In India. Populations of the subcontinent show high frequencies of the D allele, so Rh-negative people are relatively few. The commonest haplotype is CDe. Other systems such as Kell, Duffy, Kidd and P have been studied in fewer Indian groups.

Haemolytic disease of the newborn

When an Rh-negative mother carries an Rh-positive foetus, fetal red cells entering her circulation, mainly at delivery, may cause her to make anti-D antibodies. In a later pregnancy these antibodies cross the placenta and destroy the red cells of an Rh-positive foetus. The condition, erythroblastosis fetalis, is uncommon in a first pregnancy for this reason. Since the 1960s it has been largely prevented by giving the mother anti-D immunoglobulin after delivery.

Because selection acts against the heterozygous child in such cases, the persistence of the Rh polymorphism has been a puzzle for population genetics.

3. Blood groups and natural selection

Studies have looked for links between blood groups and disease, which would explain how the polymorphisms are kept.

If one allele gives protection against one disease and greater risk from another, opposing selective forces can keep both in the population. The strength of several of these associations is still debated.

Blood groups and the idea of race

Early workers hoped blood groups would sort humanity into clear racial types. They did not. Each blood group allele varies gradually across space, and the clines of different alleles do not run in parallel. Groups that look alike may differ in blood group frequencies, and groups that look different may be alike. Frank Livingstone summed this up in the phrase "there are no races, there are only clines". Blood group data were in fact among the first evidence against a typological view of race.

4. Haemoglobin variants

Hundreds of structural variants of human haemoglobin are known. Most are rare and never reach a frequency of 1 per cent. A few have reached high frequencies over wide areas.

The thalassaemias, disorders in the amount rather than the structure of haemoglobin, are also common in India, with carriers concentrated in some communities of the north-west, west and east.

H. Lehmann and M. Cutbush first reported sickle-cell haemoglobin among tribal populations of the Nilgiris in 1952. The sickle-cell trait has since been found in many tribal communities. India launched a National Sickle Cell Anaemia Elimination Mission in 2023, focused on screening and care in tribal areas.

Balanced polymorphism: the sickle-cell case

Strong evidence now shows that many human polymorphisms are maintained by balancing selection. The best-understood case is sickle-cell haemoglobin.

• Selection acts against both homozygotes: against HbS/HbS through anaemia, and against HbA/HbA through malaria.
• The heterozygote has the advantage as long as malaria is present, and malaria has been a human parasite for a very long time.
• Because the heterozygote survives, the HbS allele persists at a frequency far above its mutation rate.
• A. C. Allison demonstrated the protection in 1954.
• Where malaria has been eliminated, the advantage disappears and the allele slowly declines. The polymorphism is "balanced" only under particular conditions.

Other polymorphisms linked to malaria

J. B. S. Haldane suggested in 1949 that malaria might explain the high frequency of thalassaemia. Several red-cell polymorphisms are now linked with it.

• G6PD deficiency. Glucose-6-phosphate dehydrogenase protects red cells against oxidative damage. Alleles with reduced activity are common in malarial regions of Africa, the Mediterranean and Asia, including India, despite their cost. The gene is on the X chromosome. Deficient persons can suffer the breakdown of red cells after eating fava beans or taking certain drugs, such as the antimalarial primaquine, which matters for treatment programmes.
• Thalassaemias, HbE and HbC. Each appears to give partial protection.
• Duffy-negative blood group. Protects against vivax malaria.

Lactase persistence

The enzyme lactase digests lactose, the sugar in milk. In most mammals, and in most humans, its production falls after weaning. In some populations it continues into adult life.

• A dimorphism. Adults are either lactase-persistent or lactase non-persistent.
• Distribution. Persistence is common in north-western Europe and among pastoral peoples of East Africa and the Middle East, and rare in East Asia and among many Native American and African farming peoples. In India it is more frequent in the north and west than in the south and east.
• Recent selection. Persistence spread after the domestication of cattle, when milk became a food for adults. Different mutations producing the same result arose in Europe and in East Africa, an example of convergent evolution.
• Gene-culture co-evolution. A cultural practice, dairying, created the selective pressure that changed the frequency of a gene.

Differences in alcohol metabolism, for example in the enzymes that process alcohol, are another polymorphism of metabolism that interacts with culture and health.

HLA: the most polymorphic human system

The major histocompatibility complex in humans is called the human leukocyte antigen (HLA) system. Jean Dausset described the first HLA antigen in 1958. The genes lie on the short arm of chromosome 6.

• Extreme polymorphism. Thousands of alleles are known at the HLA-A, HLA-B, HLA-C, HLA-DR and HLA-DQ loci. No other human genes are so variable.
• Why. A population with many HLA types can recognise a wider range of pathogens. Heterozygote advantage and frequency-dependent selection are thought to maintain the variety.
• Transplants. HLA matching between donor and recipient reduces rejection of transplanted organs.
• Disease associations. HLA-B27 is strongly associated with ankylosing spondylitis. In West Africa an HLA-B variant has been associated with protection against severe malaria.
• In anthropology. Because HLA frequencies differ markedly among populations, they are used to trace population history and affinities.

DNA polymorphism

Studies of proteins showed that genetic variation in natural populations is very large. The full extent can be known only at the level of DNA, and it is far greater than protein studies revealed.

What a DNA polymorphism is

A DNA polymorphism is any variant in the DNA sequence that occurs in a population at a frequency above about 1 per cent. Many lie in non-coding regions and have no visible effect.

• Origin and fate. Mutation creates new variants; drift and selection decide their fate. Most new mutations are lost, and a few reach polymorphic frequencies.
• The nuclear genome. About three billion base pairs in the haploid set of 23 chromosomes.
• Mitochondrial DNA. A small circular genome of 16,569 base pairs, present in many copies in each cell. It is inherited only from the mother, so men and women alike receive their mitochondrial DNA from their mothers. Its hypervariable control region mutates several times faster than nuclear DNA. Because it is abundant, it can be recovered from bone, hair shafts and other sources that yield little nuclear DNA.
• The Y chromosome. Most of it does not recombine and passes from father to son, tracing the male line.

DNA and biochemical polymorphisms compared

Because many polymorphisms can be found in any region of the genome, researchers can choose markers to suit their question and study haplotypes, which carry more information than single markers.

How DNA polymorphisms are detected

• Restriction fragment length polymorphism (RFLP). Restriction enzymes cut DNA at specific short sequences. A variant that creates or destroys a cutting site changes the lengths of the fragments, which are separated by gel electrophoresis. In the early 1980s RFLPs were used to build the first genetic maps of the human genome.
• Polymerase chain reaction (PCR). Invented in the 1980s, PCR copies a chosen stretch of DNA millions of times from nanogram quantities, and made most modern methods possible.
• DNA sequencing. Reading the sequence directly is the gold standard. High-throughput sequencing now reads whole genomes.
• SNP arrays. Chips that test hundreds of thousands of known SNPs at once.

Kinds of DNA polymorphism

SNPs are now the main tool for studying variation within and between human populations. Large international projects have catalogued millions of them across the world's populations.

Applications of DNA polymorphisms in anthropology

1. Inferring population history and affinities. Comparing DNA sequences is the most direct and unambiguous way to measure how closely populations are related.
2. Dating. Reconstructing the pattern of mutations, and estimating when particular mutations or lineages arose.
3. Demographic history. Inferring past population size, bottlenecks, expansions and admixture.
4. Mapping disease genes. Locating genes by their association with nearby markers.
5. Tracing the spread of genes for disease and adaptation across regions.
6. Forensic and historical identification. Identifying individuals and human remains.

Genetic distances based on DNA polymorphisms show a primary division between African and non-African populations, with African populations the most diverse. This is consistent with the origin of modern humans in Africa and their later spread across the world. See our note on the human fossil record.

Significance of genetic polymorphism

• Raw material of evolution. Polymorphism is the stored variation on which selection acts when conditions change.
• Functional effects. Although the parts of the genome carrying functional polymorphisms are small, much of human adaptation and of differences in health rests on them. A single base change can alter how a protein works, as with HbS.
• Disease risk. Common variants influence susceptibility to complex conditions. The APOE ε4 allele, for example, raises the risk of Alzheimer's disease.
• Drug response. Polymorphisms in drug-metabolising enzymes, such as those of the cytochrome P450 family, make people fast or slow metabolisers of particular drugs. This is the basis of pharmacogenomics. Studies of signalling pathways, such as the insulin and IGF-1 pathway, have also linked polymorphisms to growth and longevity.
• Pathways and networks. Genome-wide surveys of polymorphism can reveal unknown pathways and the genes that regulate them.
• Forensics and identity. STR profiles identify individuals with near certainty.
• Anthropology. Polymorphisms are the markers by which human origins, migrations, admixture and adaptation are traced.

High-throughput sequencing produces data on a scale that challenges biologists, statisticians and computer scientists alike. Progress depends on collaboration across these disciplines.

Genetic polymorphism in India: a summary

For the health of tribal communities, see tribal India today.

Using this topic in a UPSC answer

• Begin with Ford's definition and explain its three elements.
• Distinguish balanced and transient polymorphism.
• Take two classical systems, ABO and Rh, with their world and Indian distribution.
• Explain balanced polymorphism through sickle cell and malaria, with a genotype-fitness table.
• Add DNA polymorphisms: what they are, why they are better markers, and their uses.
• Use Indian material: B allele, HbS among tribes, HbE in the North-East, the Bombay phenotype.
• Conclude that clines of polymorphisms, not racial types, describe human variation.

For presentation, see our guide to anthropology answer writing with diagrams, thinkers and case studies.

Frequently asked questions

What is genetic polymorphism?

Genetic polymorphism is the occurrence in a population of two or more genetically determined forms of a trait, each at a frequency too high to be maintained by recurrent mutation alone, conventionally 1 per cent or more.

Who defined polymorphism?

E. B. Ford defined it in 1940 as the occurrence together in the same habitat of two or more discontinuous forms of a species in such proportions that the rarest cannot be maintained merely by recurrent mutation.

What is the difference between balanced and transient polymorphism?

A balanced polymorphism is kept stable over many generations by opposing selective forces, as with sickle cell and malaria. A transient polymorphism is a passing stage in which one allele is replacing another.

Why is the sickle-cell trait called a balanced polymorphism?

Because selection acts against both homozygotes, against those with sickle-cell anaemia and against normal homozygotes through malaria, while the heterozygote is protected. Both alleles are therefore maintained where malaria is common.

What are examples of genetic polymorphism in humans?

Examples include the ABO and Rh blood groups, haemoglobin variants such as HbS and HbE, G6PD deficiency, lactase persistence, the HLA system, and DNA markers such as STRs and SNPs.

What is the Bombay blood group?

The Bombay phenotype is a rare condition, first described in Mumbai in 1952, in which red cells lack the H substance from which the A and B antigens are made. Such people type as O but can receive blood only from donors with the same phenotype.

Why is HLA important in anthropology?

HLA is the most polymorphic system in humans, and its allele frequencies differ greatly among populations. It is therefore useful for tracing population history, and it also matters for organ transplants and disease susceptibility.

What is a DNA polymorphism?

A DNA polymorphism is a variant in the DNA sequence, such as an SNP or a variable number of repeats, that occurs in a population at a frequency above about 1 per cent.

What is the difference between STR and SNP?

An STR is a short sequence of two to six bases repeated a variable number of times, with many alleles at each locus. An SNP is a difference at a single base, usually with two alleles. STRs are used mainly in forensics and SNPs mainly in genome-wide studies.

Why are DNA markers better than blood group markers?

DNA markers are far more numerous, mostly free of natural selection, available anywhere in the genome, detectable directly from small samples, and allow haplotypes to be studied.

Do blood groups support the classification of races?

No. Each blood group allele varies gradually across geography, and different alleles vary independently. Their distributions do not divide humanity into distinct races.