학술논문

Population sequencing data reveal a compendium of mutational processes in the human germ line.
Document Type
article
Source
Science (New York, N.Y.). 373(6558)
Subject
NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
TOPMed Population Genetics Working Group
Germ Cells
Oocytes
Humans
DNA Damage
DNA Mutational Analysis
DNA Replication
Transcription
Genetic
Mutagenesis
CpG Islands
Long Interspersed Nucleotide Elements
Germ-Line Mutation
Genome
Human
Algorithms
Genetic Variation
DNA Demethylation
Human Genome
Genetics
1.1 Normal biological development and functioning
Aetiology
Underpinning research
2.1 Biological and endogenous factors
Generic health relevance
General Science & Technology
Language
Abstract
Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that are resolved asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of long interspersed nuclear elements. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.