Abstract
BackgroundA major goal of molecular evolution is to determine how natural selection has shaped the evolution of a gene. One approach taken by methods such as K A /K S and the McDonald-Kreitman (MK) test is to compare the frequency of non-synonymous and synonymous changes. These methods, however, rely on the assumption that a change in frequency of one mutation will not affect changes in frequency of other mutations.ResultsWe demonstrate that linkage between sites can bias measures of selection based on synonymous and non-synonymous changes. Using forward simulation of a Wright-Fisher process, we show that hitch-hiking of deleterious mutations with advantageous mutations can lead to overestimation of the number of adaptive substitutions, while background selection and clonal interference can distort the site frequency spectrum to obscure the signal for positive selection. We present three diagnostics for detecting these effects of linked selection and apply them to the human influenza (H3N2) hemagglutinin gene.ConclusionVarious forms of linked selection have characteristic effects on MK-type statistics. The extent of background selection, hitch-hiking and clonal interference can be evaluated using the diagnostic statistics presented here. The diagnostics can also be used to determine how well we expect the MK statistics to perform and whether one form of the statistic may be preferable to another.
Highlights
A major goal of molecular evolution is to determine how natural selection has shaped the evolution of a gene
The effect of background selection We begin by examining the effect of negative selection and linkage without positive selection in a protein-coding region of 500 codons evolving under a Wright-Fisher process
Negative selection is described by the distribution of fitness effects (DFE) of non-synonymous changes, which are specific to each codon site
Summary
A major goal of molecular evolution is to determine how natural selection has shaped the evolution of a gene. One approach taken by methods such as KA/KS and the McDonald-Kreitman (MK) test is to compare the frequency of non-synonymous and synonymous changes. These methods, rely on the assumption that a change in frequency of one mutation will not affect changes in frequency of other mutations. In the absence of selection and accounting for the genetic code, we expect both types of changes to be probable so that the rate of non-synonymous substitutions per site (KA) is equal to the rate of synonymous substitutions per site (KS); a ratio of KA/KS > 1 indicates positive selection favouring a change. KA/KS measured in a related sample can be used as a measure of selective constraint so that an increase in the KA/KS ratio implies positive selection [7,8]
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