Extremely rare variants reveal patterns of germline mutation rate heterogeneity in humans

Abstract

A detailed understanding of the genome-wide variability of single-nucleotide germline mutation rates is essential to studying human genome evolution. Here we use ∼36 million singleton variants from 3,560 whole-genome sequences to infer fine-scale patterns of mutation rate heterogeneity. Mutability is jointly affected by adjacent nucleotide context and diverse genomic features of the surrounding region, including histone modifications, replication timing, and recombination rate, sometimes suggesting specific mutagenic mechanisms. Remarkably, GC content, DNase hypersensitivity, CpG islands, and H3K36 trimethylation are associated with both increased and decreased mutation rates depending on nucleotide context. We validate these estimated effects in an independent dataset of ∼46,000 de novo mutations, and confirm our estimates are more accurate than previously published estimates based on ancestrally older variants without considering genomic features. Our results thus provide the most refined portrait to date of the factors contributing to genome-wide variability of the human germline mutation rate.

Contrasting determinants of mutation rates in germline and soma

“…Similarly, two studies that focused on somatic mutations in non-cancerous somatic tissues, normal eyelid tissue and neurons, found mutations to be enriched in regions of low expression and repressed chromatin (Martincorena et al 2015; Lodato et al 2015). A similar effect of replication timing was identified in studies of germline mutation (Stamatoyannopoulos et al 2009; Francioli et al 2015; Besenbacher et al 2016; Carlson et al 2017). However, the effect of expression levels on germline mutation rates remains unclear: one study reported increased divergence between humans and macaques with greater germline expression (Park, Qian, and Zhang 2012), but others found no discernable effect of expression levels on mutation rates (Green et al 2003; Webster et al 2004; Polak and Arndt 2008; Hodgkinson and Eyre-Walker 2011; Francioli et al 2015).…”

A map of constrained coding regions in the human genome

“…For each region, we adjust for the CpG dinucleotide density as an independent measure of the potential mutability of the coding region. 14 While other models 5,15,16 of local mutability have been developed, the primary predictor of these studies and others 17,18 is the presence of CpG dinucleotides. We fit a linear model of the region's CpG density (the independent variable) versus its weighted length (the dependent variable).…”

Rapid evolution of the human mutation spectrum

“…However, despite the bottlenecks that are known to have affected Eurasian diversity, there is no clear trend of an increased fraction of C/G$\to$A/T relative to A/T$\to$C/G in non-Africans vs Africans, or with distance from Africa (Figure 1—figure supplement 7), and previous studies have also found little evidence for a strong genome-wide effect of BGC on the mutational spectrum in humans and great apes (Do et al, 2015; Moorjani et al, 2016a). For these reasons, we think that evolution of the mutational process is a better explanation than BGC or selection for differences that have been observed between the spectra of ultra-rare singleton variants and older human genetic variation (Carlson et al, 2017);…”