Germline de novo mutation rates on exons versus introns in humans

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. This reduction was 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 the footprint of selection when using introns as proxies of neutrality. Here we compiled and analyzed published germline de novo mutation (DNM) data to test if the exonic mutation rate is also reduced in germ cells. We detected ascertainment bias in studies using DNM data from diseased probands and investigated the impact of extended nucleotide context on de novo mutation rate. After controlling for these factors, we found no reduction in the mutation rate in exons compared to introns in the germline genome, in contrast to what has been previously described in somatic cells. Therefore, there is no evidence of an enhanced mismatch repair system activity in exons with respect to adjacent introns in germline cells.