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A polymorphism is a genetic variant that appears in at least 1% of a population. (e.g., the human ABO blood groups, the human Rh factor, and the human major histocompatibility complex). By setting the cutoff at 1%, it excludes spontaneous mutations that may have occurred in - and spread through the descendants of - a single family.
All the examples above are of the protein products of alleles. These can be identified by serology - that is, using antibodies to detect the different versions of the protein. (Antibodies caused the clumping of the red blood cells in this test) and electrophoresis - if amino acid changes in the protein alter its net electrical charge, it will migrate more or less rapidly in an electrical field. Enzymes are frequently polymorphic. A population may contain two or more variants of an enzyme encoded by a single locus. The variants differ slightly in their amino acid sequence and often this causes them to migrate differently under electrophoresis. By treating the gel with the substrate for the enzyme, its presence can be visualized.
Electrophoresis of tissue extracts from 15 different green treefrogs (Hyla cinerea) reveals 4 allelic versions of the enzyme aconitase (one of the enzymes of the citric acid cycle). The results:
- Eight frogs (#2, 3, 4, 6, 7, 9, 12, and 14) were homozygous for allele M.
- Frog #8 was homozygous for allele E.
- Three frogs (#1, 11, 15) are heterozygous for the M and S alleles.
- Two (#5, 13) were heterozygous for M and E.
- Frog #10 was heterozygous for M and F.
Electrophoretic variants of an enzyme occurring in a population are called allozymes.
Restriction Fragment Length Polymorphisms (RFLPs)
Proteins are gene products and so polymorphic versions are simply reflections of allelic differences in the gene; that is, allelic differences in DNA. Often these changes create new - or abolish old - sites for restriction enzymes to cut the DNA. Digestion with the enzyme then produces DNA fragments of a different length. These can be detected by electrophoresis. Most* RFLPs are created by a change in a single nucleotide in the gene, and so these are called single nucleotide polymorphisms (SNPs).
Single Nucleotide Polymorphisms (SNPs)
Developments in DNA sequencing now make it easy to look for allelic versions of a gene by sequencing samples of the gene taken from different members of a population (or from a heterozygous individual). Alleles whose sequence reveals only a single changed nucleotide are called single nucleotide polymorphisms or SNPs. SNPs can occur in noncoding parts of the gene so they would not be seen in the protein product. They might not alter the cutting site for any known restriction enzymes so they would not be seen by RFLP analysis. As of October 2005, over one million SNPs had been identified across the human genome.
Copy Number Polymorphisms (CNPs)
Genetic analysis (using DNA chips and FISH) has revealed another class of human polymorphisms. These copy number polymorphisms are large (thousands of base pairs) duplications or deletions that are found in some people but not in others. On average, one person differs from another by 11 of these. One or more have been found on most chromosomes, and the list is probably incomplete. While most of this DNA is non-coding, functional genes are embedded in some of it. Example: AMY1, the gene encoding salivary amylase, an enzyme that digests starch. Humans vary in the number of copies of AMY1 in their genome.
- Populations whose diet is rich in starches (e.g., many Americans, Japanese) have an average of 7 copies of the gene.
- Populations with low-starch diets (e.g., nomadic tribes in Siberia whose diet is dominated by dairy products and fish) average only 5 copies.
In the case of AMY1, the more copies present, the more enzyme that is produced. How a person adapts to a change in gene number for autosomal genes is unknown (in contrast to the way that human females adjust the activity of the genes on their two X chromosomes to match that of males with their solitary X chromosome).
How are polymorphisms useful?
Polymorphism analysis is in widespread use. In tissue typing, it is use to find the best match between the donor, e.g., of a kidney, and the recipient. It is used to find disease genes (e.g., the gene for Huntington's disease was located when the presence of the disease was found to be linked to a RFLP whose location on the chromosome was known). In population studies, it is used to assess the degree of genetic diversity in a population, including:
- The McAlpine study, which produced the photo above, found that the heterozygous frogs were more successful breeders than homozygous ones.
- A search for polymorphisms in elephant seals and cheetahs has revealed that they have few or none.
- Determining whether two populations represent separate species or races of the same species. This is often critical to applying laws protecting endangered species.
Tracking migration patterns of a species (e.g., whales).
How do polymorphisms arise and persist?
They arise by mutation. But what keeps them in the population? Several factors may maintain polymorphism in a population.
- Founder Effect: If a population began with a few individuals — one or more of whom carried a particular allele — that allele may come to be represented in many of the descendants. In the 1680s Ariaantje and Gerrit Jansz emigrated from Holland to South Africa, one of them bringing along an allele for the mild metabolic disease porphyria. Today more than 30000 South Africans carry this allele and, in every case examined, can trace it back to this couple — a remarkable example of the founder effect.
- Genetic Drift: An allele may increase - or decrease - in frequency simply through chance. Not every member of the population will become a parent and not every set of parents will produce the same number of offspring. The effect, called random genetic drift, is particularly strong in small populations (e.g., 100 breeding pairs or fewer) and when the allele is neutral; that is, is neither helpful nor deleterious
Eventually the entire population may become homozygous for the allele or - equally likely - the allele may disappear. Before either of these fates occurs, the allele represents a polymorphism.
Two examples of reduced polymorphism because of genetic drift:
- By 1900, hunting of the northern elephant seal off the Pacific coast had reduced its population to only 20 survivors. Since hunting ended, the population has rebounded from this population bottleneck to some 100,000 animals today. However, these animals are homozygous at every one of the gene loci that have been examined.
- Cheetahs, the fastest of the land animals, seem to have passed through a similar period of small population size with its accompanying genetic drift. Examination of 52 different loci has failed to reveal any polymorphisms; that is, these animals are homozygous at all 52 loci. The lack of genetic variability is so profound that cheetahs will accept skin grafts from each other just as identical twins (and inbred mouse strains) do. Whether a population with such little genetic diversity can continue to adapt to a changing environment remains to be seen.
Copy Number Polymorphisms
The varying number of copies of the AMY1 gene in different human populations appears to have arisen from the evolutionary pressure of the differences in the starch content of their diet.
In regions of the world (e.g., parts of Africa) where malaria caused by Plasmodium falciparum is common, the allele for sickle-cell hemoglobin is also common. This is because children who inherit one gene for the "normal" beta chain of hemoglobin and one sickle gene are more likely to survive than either homozygote. Children homozygous for the sickle allele die young from sickle-cell disease but children homozygous for the "normal" beta chain are more susceptible to illness and death from falciparum malaria than are heterozygotes. Hence the relatively high frequency of the allele in malarial regions. When natural selection favors heterozygotes over both homozygotes, the result is balanced polymorphism. It accounts for the persistence of an allele even though it is deleterious when homozygous.
Another example: prion proteins
All human populations are polymorphic for the prion protein PrPC. It is encoded by the prion protein gene (PRNP). Two of the alleles have different codons at position 129 - one encoding methionine; the other valine. Homozygosity for either allele increases the susceptibility to prion diseases. People who are heterozygous are more resistant. A study of elderly women who had survived the kuru epidemic of the first half of the 20th century (eating the tissues of the deceased was banned in 1950) showed that 76.7% of them were heterozygotes. This table compares the gene frequencies in this population as well as in a population that never practiced mortuary feasts.
A quick calculation will show that the gene pool of the exposed women deviates widely from what would be found if the population were in Hardy-Weinberg equilibrium. In this case, strong mortality selection is the cause. The gene pool of the unexposed population is close to being in Hardy-Weinberg equilibrium. Here, again, natural selection has favored heterozygotes over both homozygotes (and led to the speculation that cannibalism may have been common earlier in human history).
Hirta is a tiny island in the North Atlantic 100 miles off the northwest coast of Scotland. In 1932 a small (107) population of domestic sheep (Ovis aries) was introduced onto the island from the neighboring island of Soay. Since then these sheep have been allowed to run wild and, since 1985, have been intensively studied. The sheep have horns and, in males, these play an important role in competition for females. The size of the horns is strongly influenced by a single gene locus, RXFP2, with two alleles: Ho+ and HoP.
- Homozygous Ho+Ho+ males have the largest horns and sire more offspring but have reduced survival.
- Homozygous HoPHoP males have smaller horns (sometime even vestigial horns called scurs). These males have less success in mating but have increased survival.
- Heterozygous Ho+HoP males are almost as successful at mating as Ho+Ho+ males and survive almost as well as HoPHoP males. On balance, then, the heterozygotes have greater overall fitness than either homozygotes — another example of balanced polymorphism. It arises as a trade-off between the opposing effects of natural selection (survival) and sexual selection (reproductive success) on a single gene locus.
You can read about these findings in Johnston, Susan. E., et al., Nature 502, 93–95, 3 October 2013.