Large scale variation in the rate of germ-line de novo mutation, base composition, divergence and diversity in humans

Abstract

It has long been suspected that the rate of mutation varies across the human genome at a large scale based on the divergence between humans and other species. However, it is now possible to directly investigate this question using the large number of de novo mutations (DNMs) that have been discovered in humans through the sequencing of trios. We investigate a number of questions pertaining to the distribution of mutations using more than 130,000 DNMs from three large datasets. We demonstrate that the amount and pattern of variation differs between datasets at the 1MB and 100KB scales probably as a consequence of differences in sequencing technology and processing. In particular, datasets show different patterns of correlation to genomic variables such as replication time. Never-the-less there are many commonalities between datasets, which likely represent true patterns. We show that there is variation in the mutation rate at the 100KB, 1MB and 10MB scale that cannot be explained by variation at smaller scales, however the level of this variation is modest at large scales–at the 1MB scale we infer that ~90% of regions have a mutation rate within 50% of the mean. Different types of mutation show similar levels of variation and appear to vary in concert which suggests the pattern of mutation is relatively constant across the genome. We demonstrate that variation in the mutation rate does not generate large-scale variation in GC-content, and hence that mutation bias does not maintain the isochore structure of the human genome. We find that genomic features explain less than 40% of the explainable variance in the rate of DNM. As expected the rate of divergence between species is correlated to the rate of DNM. However, the correlations are weaker than expected if all the variation in divergence was due to variation in the mutation rate. We provide evidence that this is due the effect of biased gene conversion on the probability that a mutation will become fixed. In contrast to divergence, we find that most of the variation in diversity can be explained by variation in the mutation rate. Finally, we show that the correlation between divergence and DNM density declines as increasingly divergent species are considered.

Impact of mutation rate and selection at linked sites on fine-scale DNA variation across the homininae genome

“…We find a significantly negative correlation between putatively selected DNMs and the density of conserved sites in one DNM dataset (Jónsson et al 2017), a significantly positive correlation in another dataset (Wong et al 2016), and no correlation in the third dataset (Francioli et al 2015). Such contradictory patterns have been observed before for other genomic variables and likely arise as a consequence of biases in the ascertainment of DNMs (Smith et al 2018). Thus, it is not possible to conclude that the lower coding mutation rate in functionally rich regions is driving our strong negative correlation between θ N and the density of conserved sites.…”

“…The positive correlation between diversity and our measure of the mutation rate is not surprising given that we expect regions of the genome with high rates of mutation to have high levels of diversity. Previous analyses have suggested that much of the variation in diversity at the 100KB level can be explained in terms of variation in the mutation rate (Smith et al 2018). Non-coding diversity is also positively correlated to the rate of recombination and negatively correlated to the density of conserved sites.…”

“…Neither of these methods is perfect. We currently have too few DNMs to estimate the mutation rate reliably at the 50KB scale and attempts to predict the mutation rate of DNMs based on genomic features have so far proved to be unreliable (Smith et al 2018). The divergence between species is also not a completely satisfactory measure of the mutation rate either, for several reasons.…”

“…A<>T and G<>C), since these are not affected by gBGC, a process known to affect substitution rates (Duret & Arndt 2008;Smith et al 2018) , and the rate of different types of mutation appear to be strongly correlated at the 100KB and 1MB scales, suggesting that GC-conservative mutations should therefore be a reasonable measure of the overall mutation rate (Smith et al 2018). However, the mutation rate appears to evolve at large scales (Terekhanova et al 2017;Smith et al 2018) , and some of the variation in the substitution rate is due to variation in the depth of the genealogy in the ancestors of the homininae (Phung et al 2016) . The rate of recombination, the density of selected sites and our measure of the mutation rate are correlated to each other (Table 1).…”

“…Since the rate of substitution is also correlated to the rate of recombination it seemed likely that at least part of the correlation between diversity and the rate of recombination was due to a mutagenic effect of recombination. There is now good evidence that recombination is mutagenic in humans (Pratto et al 2014;Francioli et al 2015;Arbeithuber et al 2015;Halldorsson et al 2019) and recent analyses of the correlation between diversity and the rate of mutation, as inferred from rates of de novo mutations in human trios, suggests that much, but not all, of the variation in diversity across the human genome can be explained by variation in the rate of mutation at the 100KB and 1MB scale (Smith et al 2018) . However, several lines of evidence suggest that selection at linked sites may also affect neutral and selected diversity across the human genome.…”