Pedigree-based and phylogenetic methods support surprising patterns of mutation rate and spectrum in the gray mouse lemur

C. Ryan Campbell, George P. Tiley, Jelmer W. Poelstra, Kelsie E. Hunnicutt, Peter A. Larsen, Hui Jie Lee, Jeffrey L. Thorne, Mario dos Reis, Anne D. Yoder

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Mutations are the raw material on which evolution acts, and knowledge of their frequency and genomic distribution is crucial for understanding how evolution operates at both long and short timescales. At present, the rate and spectrum of de novo mutations have been directly characterized in relatively few lineages. Our study provides the first direct mutation-rate estimate for a strepsirrhine (i.e., the lemurs and lorises), which comprises nearly half of the primate clade. Using high-coverage linked-read sequencing for a focal quartet of gray mouse lemurs (Microcebus murinus), we estimated the mutation rate to be among the highest calculated for a mammal at 1.52 × 10–8 (95% credible interval: 1.28 × 10−8–1.78 × 10−8) mutations/site/generation. Further, we found an unexpectedly low count of paternal mutations, and only a modest overrepresentation of mutations at CpG sites. Despite the surprising nature of these results, we found both the rate and spectrum to be robust to the manipulation of a wide range of computational filtering criteria. We also sequenced a technical replicate to estimate a false-negative and false-positive rate for our data and show that any point estimate of a de novo mutation rate should be considered with a large degree of uncertainty. For validation, we conducted an independent analysis of context-dependent substitution types for gray mouse lemur and five additional primate species for which de novo mutation rates have also been estimated. These comparisons revealed general consistency of the mutation spectrum between the pedigree-based and the substitution-rate analyses for all species compared.

Original languageEnglish (US)
Pages (from-to)233-244
Number of pages12
JournalHeredity
Volume127
Issue number2
DOIs
StatePublished - Aug 2021

Bibliographical note

Funding Information:
The authors thank our handling editor, as well as Matt Hahn and two anonymous reviewers, who provided critical feedback that improved the paper. We thank the Duke Lemur Center staff, especially Erin Ehmke, Bobby Schopler, and Cathy Williams, for providing tissue samples. Priya Moorjani, Susanne Pfeifer, Jonathan Pritchard, Molly Przeworski, and Meredith Yeager all provided helpful discussions in the development of this project. We especially thank Jonathan Pritchard for his suggestion that substitution-rate analysis could be useful for verifying the observed mutation-rate spectrum. We would like to acknowledge the assistance of the Duke Molecular Physiology Institute Molecular Genomics core for the generation of data for the paper. This study was funded by a National Science Foundation Grant DEB-1354610 and Duke University research funds to ADY and she gratefully acknowledges support from the John Simon Guggenheim Foundation and the Alexander von Humboldt Foundation during the writing phase of this project. JLT was supported by National Science Foundation Grant DEB-1754142. This is a Duke Lemur Center publication.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to The Genetics Society.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

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