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Changes in gene frequencies
One assumption behind the calculation of unchanging genotypic frequencies in Hardy-Weinberg equilibrium is that all genotypes have the same fitness. In genetics, fitness does not necessarily have to do with muscles; fitness is a measure of the ability to produce fertile offspring. In reality, the fitnesses of different genotypes are highly variable. The genotype with the greatest fitness is given the fitness value (w) of 1, and the lesser fitnesses are fractions of 1. For example, if snails of genotypes AA and Aa were to have an average of 100 offspring but those of genotype aa only 70, then the fitnesses of these three genotypes would be 1, 1, and 0.7, respectively. The proportional difference from the most fit is called the selection coefficient, s. Hence, s = 1 − w.
Alleles carried by less-fit individuals will be gradually lost from the population, and the relevant allele frequency will decline. This is the fundamental way in which natural selection operates in a population. Selection against dominant alleles is relatively efficient, because these are by definition expressed in the phenotype. Selection against recessive alleles is less efficient, because these alleles are sheltered in heterozygotes. Even though populations under selection technically are not in Hardy-Weinberg equilibrium, the proportions of the formula can be used as an approximation to show the relative proportions of homozygous recessives and heterozygotes. If a rare deleterious recessive allele is of frequency 1/50 in the population, then (1/50)2, or 1 out of 2,500, individuals will express the recessive phenotype and be a candidate for negative selection. Heterozygotes will be at a frequency of 2pq = 2 × 49/50 × 1/50, or about 1 in 25. In other words, the heterozygotes are 100 times more common than recessive homozygotes; hence, most of the recessive alleles in a population will escape selection.
Because of the sheltering effect of heterozygotes, selection against recessive phenotypes changes the frequency of the recessive allele slowly. Even if the most severe level of selection is imposed, giving the recessive phenotype a fitness of zero (no fertile offspring), the recessive allele frequency (expressed as a fraction of the form 1/x) will increase in denominator by 1 in every generation. Therefore, to halve an allele frequency from 1/50 to 1/100 would proceed slowly from 1/50 to 1/51, 1/52, 1/53, and so on and would take 50 generations to get to 1/100. For lower intensities of selection, the progress would be even slower.
A different type of natural selection occurs when the fitness of a heterozygote exceeds the fitness of both homozygotes. The maintenance in human populations of the severe hereditary disease sickle cell anemia is owing to this form of selection. The disease allele (HbS) produces a specific type of hemoglobin that causes distortion (sickling) of the red blood cells in which the hemoglobin is carried. (Normal hemoglobin is coded by another allele, HbA). Accordingly, the possible genotypes are HbAHbA, HbAHbS, and HbSHbS. The latter individuals are homozygous for the sickle cell allele and will develop severe anemia because the oxygen transporting property of their blood is compromised. While the condition is not lethal before birth, such individuals rarely survive long enough to reproduce. On these grounds it might be expected that the disease allele would be selected against, driving the allele frequency to very low levels. However, in tropical areas of the world, the allele and the disease are common. The explanation is that the HbAHbS heterozygote is fitter and capable of leaving more offspring than is the homozygous normal HbAHbA in an environment containing the falciparum form of malaria. This extra measure of protection is evidently provided by the sickle cell hemoglobin, which is detrimental to the malaria parasite. In malarial environments, therefore, populations that contain the sickle cell gene have advantages over populations free of this gene. The former populations are in less danger from malaria, although they “pay” for this advantage by sacrificing in every generation some individuals who die of anemia.
Genetics has shown that mutation is the ultimate source of all hereditary variation. At the level of a single gene whose normal functional allele is A, it is known that mutation can change it to a nonfunctional recessive form, a. Such “forward mutation” is more frequent than “back mutation” (reversion), which converts a into A. Molecular analysis of specific examples of mutant recessive alleles has shown that they are generally a heterogeneous set of small structural changes in the DNA, located throughout the segment of DNA that constitutes that gene. Hence, in an example from medical genetics, the disease phenylketonuria is inherited as a recessive phenotype and is ascribed to a causative allele that generally can be called k. However, sequencing alleles of many independent cases of phenylketonuria has shown that this k allele is in fact a set of many different kinds of mutational changes, which can be in any of the protein-coding regions of that gene.
Recessive deleterious mutations are relatively rare, generally in the order of 1 per 105 or 106 mutant gametes per generation. Their constant occurrence over the generations, combined with the even greater rarity of back mutations, leads to a gradual accumulation in the population. This accumulation process is called mutational pressure.
Since mutational pressure to a deleterious recessive allele and selection pressure against the homozygous recessives are forces that act in opposite directions, another type of equilibrium is attained that effectively sets the value of q. Mathematically, q is determined by the following expression in which u is the net mutation rate of A to a, and s is the selection coefficient presented above: q2 = (u/s), or q = Square root of√(u/s)
Many species engage in alternatives to random mating as normal parts of their cycle of sexual reproduction. An important exception is sexual selection, in which an individual chooses a mate on the basis of some aspect of the mate’s phenotype. The selection can be based on some display feature such as bright feathers, or it may be a simple preference for a phenotype identical to the individual’s own (positive assortative mating).
Two other important exceptions are inbreeding (mating with relatives) and enforced outbreeding. Both can shift the equilibrium proportions expected under Hardy-Weinberg calculations. For example, inbreeding increases the proportions of homozygotes, and the most extreme form of inbreeding, self-fertilization, eventually eliminates all heterozygotes.
Inbreeding and outbreeding are evolutionary strategies adopted by plants and animals living under certain conditions. Outbreeding brings gametes of different genotypes together, and the resulting individual differs from the parents. Increased levels of variation provide more evolutionary flexibility. All the showy colors and shapes of flowers are to promote this kind of exchange. In contrast, inbreeding maintains uniform genotypes, a strategy successful in stable ecological habitats.
In humans, various degrees of inbreeding have been practiced in different cultures. In most cultures today, matings of first cousins are the maximal form of inbreeding condoned by society. Apart from ethical considerations, a negative outcome of inbreeding is that it increases the likelihood of homozygosity of deleterious recessive alleles originating from common ancestors, called homozygosity by descent. The inbreeding coefficient F is a measure of the likelihood of homozygosity by descent; for example, in first-cousin marriages, F = 1/16. A large proportion of recessive hereditary diseases can be traced to first-cousin marriages and other types of inbreeding.