Box 131 Detecting adaptation in the genome

Evidence for natural selection can be revealed through examination of rates of DNA sequence evolution (reviewed in Anisimova and Liberles, 2007). The null model for these studies is that genes evolve by neutral evolutionary processes. Neutral, selectively equivalent mutations arise by chance and, in the absence of natural selection, occasionally become fixed by random genetic drift. The rate with which this happens is the neutral substitution rate. Many mutations that arise within functional genes cause deleterious changes to protein structure or function. These mutations are constrained from rising to high frequency by negative, or purifying, selection and are assumed to rarely fix between species. In contrast, mutations that are advantageous, such as those that confer resistance to disease, may rapidly rise in frequency by positive, or directional, selection. Positive selection leads to a short-term reduction in genetic diversity as the favoured allele replaces existing variation in a population. A sufficiently high number of recurrent adaptive fixations may also increase long-term divergence between species. Alternatively, multiple polymorphisms can be maintained in populations by balancing selection, which increases genetic diversity. In very rare cases, balanced polymorphism can occur when there is a heterozygote advantage, or overdominance, where heterozygote combination of two alleles has a higher fitness than homozygotes of either allele. More frequently, temporal or spatial variation in selection can maintain multiple alleles if each variant is advantageous in a different time or place.

Adaptive evolution can be detected by comparing DNA sequence of homologous genes from closely related species. This is generally achieved by comparing the rate of non-synonymous, amino acid-replacing, substitutions (dN) to the rate of synonymous substitutions (dS), which do not affect amino acid sequence. Synonymous substitutions are assumed to be invisible to selection and thus reflect neutral evolution. If all non-synonymous mutations were also selectively neutral, dN would equal dS, and the ratio dN/dS would equal one. Positive selection on amino acid substitutions would result in an increase in the rate of non-synonymous substitutions, or dN being greater than dS. The ubiquity of purifying selection, however, means that the empirically observed rate of non-synonymous substitutions over whole genes is much smaller than the rate of synonymous substitution, and dN/dS is almost always much less than one across entire genes. A more sophisticated implementation of this test, phylogenetic analysis by maximum likelihood (Yang et al., 2000), uses gene sequences from multiple species to test the hypothesis that dN/dS varies among codons in a gene, allowing localization of the target of selection to particular residues or gene regions. Another test for natural selection, the McDonald-Kreitman test (McDonald and Kreitman, 1991), uses information about polymorphism in species and divergence between species. It tests the null hypothesis that the ratio of non-synonymous and synonymous substitutions segregating within species is the same as the corresponding ratio between species. In this test, positive selection is detected as a proportional excess of non-synonymous fixed differences between species. Selection favouring allelic diversification within species, in contrast, would lead to an excess of non-synonymous polymorphisms. These tests, among others, allow inference of natural selection acting on specific genes and gene regions.

draw insight into how the immune response adapts to pathogen pressures.

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