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).:11 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 polymorphisms 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.:6–7 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“.:65
- 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.:26
- 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.:17 & ch. 7
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 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 supergenesconsisting 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.:ch. 6:17–25
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 driftwere 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. This does not conflict with the account of polymorphism given here, though most[weasel words] of the ecological geneticists believed that evidence would gradually accumulate against his theory.
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.p234ch7
Apart from sexual dimorphism, there are many other examples of human genetic polymorphisms. Infectious disease has been a major factor in human mortality, and so has affected the evolution of human populations. Evidence is now strong that many polymorphisms are maintained in human populations by balancing selection.
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.:283–291
Such a balance is seen more simply in sickle-cell anaemia, which 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 allelesurvive at a rate much higher than the mutation rate (see and refs in Sickle-cell disease).
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, homozygousmutants 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 to some of us is bitter, and to others tasteless, 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 recently identified 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.