Abstract
A main assumption of molecular population genetics is that genomic mutation rate does not depend on sequence function. Challenging this assumption, a recent study has found a reduction in the mutation rate in exons compared to introns in somatic cells, ascribed to an enhanced exonic mismatch repair system activity. If this reduction happens also in the germline, it can compromise studies of population genomics, including the detection of selection when using introns as proxies for neutrality. Here we compile and analyze published germline de novo mutation data to test if the exonic mutation rate is also reduced in germ cells. After controlling for sampling bias in datasets with diseased probands and extended nucleotide context dependency, we find no reduction in the mutation rate in exons compared to introns in the germline. Therefore, there is no evidence that enhanced exonic mismatch repair activity determines the mutation rate in germline cells.
Highlights
A main assumption of molecular population genetics is that genomic mutation rate does not depend on sequence function
We show that de novo mutation (DNM) densities do not differ between exons and introns after accounting for trinucleotide sequence composition and an excess of nonsynonymous exonic variation arising from sampling bias
We compiled human DNM data to show that the rate of generation of new genetic variants, the mutation rate, does not significantly vary between exons and adjacent introns when accounting for sequence context
Summary
A main assumption of molecular population genetics is that genomic mutation rate does not depend on sequence function Challenging this assumption, a recent study has found a reduction in the mutation rate in exons compared to introns in somatic cells, ascribed to an enhanced exonic mismatch repair system activity. 1234567890():,; One of the most general and widely accepted predictions of the neutral theory of molecular evolution is that “the more sequence conservation, the more functional (selective) constraint on the sequence”[1] This principle explains why different functional regions in the genome have different levels of polymorphism and divergence, such as the lower variation at nonsynonymous vs synonymous sites in protein-coding genes or in exonic vs intronic sequences[2]. If the enhanced somatic exonic MMR activity found by Frigola et al.[17] could be extrapolated to the germline, as the study suggests, population and functional genomics studies would be compromised, and they should include differential exonic and intronic mutation rates as an integral part of their explanatory models
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