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

The BRIDGES Consortium

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 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
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

Germ-Line Mutation
Mutation Rate
mutations
genome
Genes
nucleotides
Nucleotides
Genome
Histone Code
CpG Islands
Deoxyribonucleases
Base Composition
Human Genome
Histones
Genetic Recombination
Hypersensitivity
Mutation
time measurement
estimates

Cite this

Extremely rare variants reveal patterns of germline mutation rate heterogeneity in humans. / The BRIDGES Consortium.

In: Nature communications, Vol. 9, No. 1, 3753, 01.12.2018.

Research output: Contribution to journalArticle

@article{2416e6e6103c4e079f57826394632325,
title = "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 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.",
author = "{The BRIDGES Consortium} and Jedidiah Carlson and Locke, {Adam E.} and Matthew Flickinger and Matthew Zawistowski and Shawn Levy and Myers, {Richard M.} and Michael Boehnke and Kang, {Hyun Min} and Scott, {Laura J.} and Li, {Jun Z.} and Sebastian Z{\"o}llner and Devin Absher and Huda Akil and Gerome Breen and Margit Burmeister and Sarah Cohen-Woods and Iacono, {William G.} and Knowles, {James A.} and Lisa Legrand and Qing Lu and Matthew McGue and McInnis, {Melvin G.} and Pato, {Carlos N.} and Pato, {Michele T.} and Margarita Rivera and Sobell, {Janet L.} and Vincent, {John B.} and Watson, {Stanley J.}",
year = "2018",
month = "12",
day = "1",
doi = "10.1038/s41467-018-05936-5",
language = "English (US)",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - Extremely rare variants reveal patterns of germline mutation rate heterogeneity in humans

AU - The BRIDGES Consortium

AU - Carlson, Jedidiah

AU - Locke, Adam E.

AU - Flickinger, Matthew

AU - Zawistowski, Matthew

AU - Levy, Shawn

AU - Myers, Richard M.

AU - Boehnke, Michael

AU - Kang, Hyun Min

AU - Scott, Laura J.

AU - Li, Jun Z.

AU - Zöllner, Sebastian

AU - Absher, Devin

AU - Akil, Huda

AU - Breen, Gerome

AU - Burmeister, Margit

AU - Cohen-Woods, Sarah

AU - Iacono, William G.

AU - Knowles, James A.

AU - Legrand, Lisa

AU - Lu, Qing

AU - McGue, Matthew

AU - McInnis, Melvin G.

AU - Pato, Carlos N.

AU - Pato, Michele T.

AU - Rivera, Margarita

AU - Sobell, Janet L.

AU - Vincent, John B.

AU - Watson, Stanley J.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85053301709&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85053301709&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-05936-5

DO - 10.1038/s41467-018-05936-5

M3 - Article

C2 - 30218074

AN - SCOPUS:85053301709

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 3753

ER -