Clustered mutations in hominid genome evolution are consistent with APOBEC3G enzymatic activity

Yishay Pinto, Orshay Gabay, Leonardo Arbiza, Aaron J. Sams, Alon Keinan, Erez Y. Levanon

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


The gradual accumulation of mutations by any of a number of mutational processes is a major driving force of divergence and evolution. Here, we investigate a potentially novel mutational process that is based on the activity of members of the AID/ APOBEC family of deaminases. This gene family has been recently shown to introduce-in multiple types of cancer-enzyme- induced clusters of co-occurring somatic mutations caused by cytosine deamination. Going beyond somatic mutations, we hypothesized that APOBEC3-following its rapid expansion in primates-can introduce unique germline mutation clusters that can play a role in primate evolution. In this study, we tested this hypothesis by performing a comprehensive comparative genomic screen for APOBEC3-induced mutagenesis patterns across different hominids. We detected thousands of mutation clusters introduced along primate evolution which exhibit features that strongly fit the known patterns of APOBEC3G mutagenesis. These results suggest that APOBEC3G-induced mutations have contributed to the evolution of all genomes we studied. This is the first indication of site-directed, enzyme-induced genome evolution, which played a role in the evolution of both modern and archaic humans. This novel mutational mechanism exhibits several unique features, such as its higher tendency to mutate transcribed regions and regulatory elements and its ability to generate clusters of concurrent point mutations that all occur in a single generation. Our discovery demonstrates the exaptation of an anti-viral mechanism as a new source of genomic variation in hominids with a strong potential for functional consequences.

Original languageEnglish
Pages (from-to)579-587
Number of pages9
JournalGenome Research
Issue number5
StatePublished - May 2016

Bibliographical note

Funding Information:
We thank Binyamin Knisbacher, Avital Sarusi, and Amos Schaffer for a critical reading of an early version of the manuscript and helpful comments. We thank Eli Eisenberg for helpful discussions. We also thank Keren Levanon and Sarit Aviel-Ronen for their help in the interpretation of public immunohistochemistry data. This work was supported by the European Research Council (grant no. 311257), and the I-CORE Program of the Planning, and Budgeting Committee in Israel (grants no. 41/11 and 1796/12; to E.Y.L.) and US National Institutes of Health (NIH) grants R01HG006 and R01GM108805 (to A.K.).

Publisher Copyright:
© 2016 Pinto et al.


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