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

The BRIDGES Consortium

Research output: Contribution to journalArticlepeer-review

20 Scopus citations


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 3560 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 results 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.

Original languageEnglish (US)
Article number3753
JournalNature communications
Issue number1
StatePublished - Dec 1 2018

Bibliographical note

Funding Information:
Funding for this research was provided by US National Institutes of Health (NIH) grant R01GM118928 (S.Z. and J.L.). J.C. was supported by the NIH/National Human Genome Research Institute Genome Science Training Program (T32HG00040). The BRIDGES study was supported by NIH grants R01MH094145 (M.B. and R.M.M.) and U01MH105653 (M.B.). Additional acknowledgements from collaborating members of the BRIDGES consortium are detailed in the Supplementary Information.

Publisher Copyright:
© 2018, The Author(s).


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