Gene expression levels tune germline mutation rates through the compound effects of transcription-coupled repair and damage

Abstract Of all mammalian organs, the testis has long been observed to have the most diverse gene expression profile. To account for this widespread gene expression, we have proposed a mechanism termed ‘transcriptional scanning’, which reduces germline mutation rates through transcription-coupled repair (TCR). Our hypothesis contrasts with an earlier observation that mutation rates are overall positively correlated with gene expression levels in yeast, implying that transcription is mutagenic due to transcription-coupled damage (TCD). Here we report evidence that the compound effects of both TCR and TCD during spermatogenesis tune germline mutation rates in human, with TCR dominating in most genes, thus supporting the transcriptional scanning hypothesis. Our analyses address potentially confounding factors, distinguish the differential mutagenic effects acting on the highly expressed genes and the low-to-moderately expressed genes, and resolve concerns relating to the validation of the results using a de novo mutation dataset. We also discuss the theoretical possibility of transcriptional scanning hypothesis from an evolutionary perspective. Together, these analyses support a model by which the coupling of transcription-coupled repair and damage establishes the pattern of germline mutation rates and provide an evolutionary explanation for widespread gene expression during spermatogenesis.