Contrasting determinants of mutation rates in germline and soma

Abstract

8 9Recent studies of somatic and germline mutations have led to the identification of 2 0 a number of factors that influence point mutation rates, including CpG 2 1 methylation, expression levels, replication timing and GC content. Intriguingly, 2 2 some of the effects appear to differ between soma and germline: in particular, were taken to analyze the data, however, so it is hard to know whether these 2 6 apparent differences are real. To enable a cleaner comparison, we considered a 2 7 statistical model in which the mutation rate of a coding region is predicted by GC 2 8 content, expression levels, replication timing, and two histone repressive marks.

How Sequence Context-Dependent Mutability Drives Mutation Rate Variation in the Genome

“…The extent to which true mutation rate variation is explained by the processes simulated here will depend on the relative role that sequence context has on mutability. We know germline mutation rates have been associated with other genomic features such as histone markers, transcription rate, and replication timing ( Chen et al 2017 ; Supek and Lehner 2019 ). Indeed, our model makes a prediction that mutation rate will be higher in genes, which is in contrast to a recent empirical study in Arabidopsis thaliana that found a lower mutation rate in coding sequence ( Monroe et al 2022 ).…”

“…Investigating how molecular processes and genomic properties predict mutation is an active area of study ( Chen et al 2017 ; Supek and Lehner 2019 ), and evidence suggests that the strongest predictor of mutation rate is the sequence itself ( Michaelson et al 2012 ; Sung et al 2015 ). Although the mechanisms are not fully understood ( Sung et al 2015 ), we know that a given genomic position’s mutability is strongly influenced by not only the base itself but also the sequence at adjacent sites ( Blake et al 1992 ; Hess et al 1994 ; Aggarwala and Voight 2016 ).…”

In silicoexperiments uncover a novel mechanism underlying mutation rate evolution in sexually reproducing populations

“…It is important to note, however, that as proposed by others (1, 9-12), direct selection likely indeed always acts to lower MR because of the fitness cost of mutations. The cost of a higher MR should be manifested both in the increased phenotypic variance of offspring (with more offspring deviating from optimal trait values) and in the costs of concomitantly altered somatic MR, as germline and somatic MRs are linked, and mutations can contribute to aging, cancer and other fitness-limiting impairments (19,20,(34)(35)(36)(37)(38). Our previous modeling indicated that one mechanism to buffer the cost of somatic mutations is greater investment in somatic tissue maintenance, allowing for the evolution of higher MR and thus facilitating directional selection (52).…”

Multifactorial heterogeneity of the human mutation landscape related to DNA replication dynamics

“…For example, the spontaneous deamination of 5-methylcytosine to thymine happens almost exclusively at CpG sites 2 . On a regional and global scale, variations in mutation rates and substitution types are associated with various genetic and epigenetic factors including nucleotide content 3,4 , chromatin state [5][6][7] , three-dimensional genome organization 8 , transcription factor binding 9,10 , and DNA replication timing [11][12][13][14][15][16][17][18][19][20] .…”

“…In eukaryotic cells, DNA replication begins at multiple replication origins that fire throughout S-phase and mediate bidirectional replication until the entire genome is duplicated. Late replicating regions of the genome are broadly enriched for single nucleotide variants and mutations 11,12,[14][15][16]21,22 . The mechanisms by which mutations accumulate in later replicating regions of the genome remain incompletely understood, although evidence suggests that mismatch repair (MMR) attenuates toward the end of S-phase and contributes to these biases 16,23 .…”