Evolution of the Mutation Rate and Spectrum in Diverging Human and Ape Populations

Event Details

Type

Center for Studies in Physics and Biology Seminars

Speaker(s)

Kelley Harris, Ph.D., assistant professor, University of Washington

Speaker bio(s)

Recent studies of hominoid variation have shown that mutation rates and spectra can evolve rapidly, contradicting the fixed molecular clock model. The relative mutation rates of three-base-pair motifs differ significantly among great ape lineages, implying that multiple unknown modifiers of DNA replication fidelity have arisen and fixed on each branch of the ape phylogeny. Such mutator alleles might directly modify DNA replication or repair, or might instead act indirectly by modifying traits like reproduction or chromatin structure. Certain mechanisms of action are expected to create mutations in specific regions of the genome, meaning that the spatial distribution of lineage-specific mutations is informative about their causality. To harness this source of information, the Harris lab measured mutation spectra of several functional compartments (such as late-replicating regions) whose attributes are known or suspected to affect their mutation rates. Using genetic diversity from 88 great apes, they find that most functional compartments are imprinted by localized mutational signatures but that these signatures explain very little of the mutational divergence between species. Rather, compartment-specific signatures layer with species-specific signatures to create mutational portraits that reflect both lineage and function. In particular, they identify a mutation signature enriched in endogenous retroviruses that seems to co-segregate with the experimentally-measured intensity of the hydroxymethylation of retrovirus-derived DNA. Their results suggest that cis-acting mutational modifiers are highly conserved between species and rapid mutation spectrum evolution is driven primarily by trans-acting modifiers.

Open to

Public

Contact

Melanie Lee

Phone

(212) 327-8636

Sponsor

Melanie Lee
(212) 327-8636
leem@rockefeller.edu