Rxivist logo

Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 57,822 bioRxiv papers from 266,142 authors.

Overlooked roles of DNA damage and maternal age in generating human germline mutations

By Ziyue Gao, Priya Moorjani, Thomas Sasani, Brent Pedersen, Aaron Quinlan, Lynn Jorde, Guy Amster, Molly Przeworski

Posted 21 May 2018
bioRxiv DOI: 10.1101/327098 (published DOI: 10.1073/pnas.1901259116)

Human germline mutations are primarily paternal in origin and their total number increases linearly with the age of the father, observations that are thought to support the textbook view that germline point mutations stem primarily from DNA replication errors. Analyzing large germline mutation datasets for humans, we uncovered two lines of evidence that call this understanding into question. First, despite the drastic increase in the ratio of male to female germ cell divisions after the onset of spermatogenesis, the ratio of paternal to maternal mutations is already 3:1 by puberty and barely increases with the age of the parents, pointing to a substantial contribution of damage-induced mutations. Supporting this hypothesis, C to G transversions and CpG transitions, which together constitute about a 1/3 of point mutations, show sex-specific age dependencies indicative of double-strand break repair and methylation-associated damage, respectively. Second, the age of a mother influences not only the number of mutations that her child inherits on the maternal genome, but also the number of mutations on the paternal genome, as expected if children of older mothers accumulate more mutations in embryogenesis. Together, these findings reveal that, rather than arising predominantly from pre-zygotic replication errors, the parental age effects on germline mutations reflect a combination of higher damage rates in males and a maternal age effect on early development.

Download data

  • Downloaded 2,078 times
  • Download rankings, all-time:
    • Site-wide: 1,915 out of 57,822
    • In genetics: 187 out of 3,318
  • Year to date:
    • Site-wide: 5,234 out of 57,822
  • Since beginning of last month:
    • Site-wide: 33,970 out of 57,822

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


Sign up for the Rxivist weekly newsletter! (Click here for more details.)


News