Review
The neutral theory in the genomic era

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Abstract

A number of tests have been developed to detect positive selection at the molecular level. These tests are based on DNA polymorphism within and divergence between species. Applications of these tests have revealed a large collection of genes that have evolved under positive selection and some general insights into adaptive evolution. Recently, these tests have been applied on a genomic scale and have provided estimates of the frequency of adaptive substitutions and a critical test of the neutral theory.

Introduction

The neutral theory of molecular evolution posits that the majority of DNA variation within and between species is neutral with respect to fitness and can be described by stochastic fluctuations in a finite population [1]. The formulation of the neutral theory provided a number of predictions that could be tested using patterns of DNA polymorphism and divergence [2]. There are two approaches. In the direct approach, amino acid changes are compared to synonymous changes. Because synonymous changes are neutral or nearly neutral with respect to fitness, any difference between patterns of amino acid and synonymous changes within and/or between species can be attributed to selection on amino acid changes. In the indirect approach, selection is detected on the basis of a skew in the frequency distribution of neutral variation linked to a site that has been under selection. The frequency spectrum can also be influenced by a population's demographic history. Positive selection can be distinguished from demographic effects because selection produces a local skew in the frequency spectrum whereas demography produces a genome-wide skew. Although these methods sometimes reveal evidence for positive selection in individual genes, the neutral theory can only be addressed with a genomic estimate of the frequency of positive selection. Recent studies of genomic patterns of amino acid and synonymous polymorphism and divergence have provided insights into the mode and, in some cases, tempo of adaptive evolution.

Section snippets

Divergence

A rate of amino acid substitution (ka) greater than that of synonymous substitution (ks) is the most robust test for positive selection [3]. A large collection of rapidly evolving genes have been identified by this criteria. The majority are involved in either sexual reproduction or host–pathogen interactions [4•]. This can be explained by the continual improvement in fitness required by sexual selection [5•], and the evolutionary ‘arms race’ between a host and its pathogen [6•]. The extent to

Polymorphism

Patterns of polymorphism provide another means of detecting positive selection. The spread of an advantageous mutation through a population produces both a reduction in levels of linked neutral variation [23] and a skew in the frequency spectrum [24••]. Positive selection can be detected by a local reduction in levels of variation using the HKA test [25], which compares polymorphism and divergence between two or more regions, or on a genomic level by a positive correlation between levels of

Polymorphism and divergence

The McDonald–Kreitman (MK) test has the advantage of being able to detect positive selection in the presence of a strong selective constraint [43]. The test compares the ratio of the number of amino acid (A) to synonymous (S) polymorphic sites to the A/S ratio of fixed differences between species. If a large fraction of amino acid substitutions are driven by positive selection, the A/S ratio of divergence should be inflated above that of polymorphism. Although the power of the MK test is

Conclusions

The analysis of DNA polymorphism and divergence on a genomic scale will provide critical tests of the neutral theory of molecular evolution. Application of the MK and other A/S ratio based tests have provided substantial evidence that positive selection has inflated the rate of protein divergence above that expected on the basis of polymorphism. Future studies will need to estimate the relative contributions of changes in population size and positive selection to this pattern. The role of

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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