Document Type

Article

Publication Date

11-19-2021

Publication Title

BMC biology [electronic resource]

Keywords

JMG

JAX Source

BMC Biol 2021 Nov 19; 19(1):239

Volume

19

Issue

1

First Page

239

Last Page

239

ISSN

1741-7007

PMID

34794440

DOI

https://doi.org/10.1186/s12915-021-01165-3

Grant

Jackson Laboratory (JAX) Pyewacket Postdoctoral Fellowship Award and a JAX Scholar Award to RAL.

Abstract

BACKGROUND: Through human-aided dispersal over the last ~ 10,000 years, house mice (Mus musculus) have recently colonized diverse habitats across the globe, promoting the emergence of new traits that confer adaptive advantages in distinct environments. Despite their status as the premier mammalian model system, the impact of this demographic and selective history on the global patterning of disease-relevant trait variation in wild mouse populations is poorly understood.

RESULTS: Here, we leveraged 154 whole-genome sequences from diverse wild house mouse populations to survey the geographic organization of functional variation and systematically identify signals of positive selection. We show that a significant proportion of wild mouse variation is private to single populations, including numerous predicted functional alleles. In addition, we report strong signals of positive selection at many genes associated with both complex and Mendelian diseases in humans. Notably, we detect a significant excess of selection signals at disease-associated genes relative to null expectations, pointing to the important role of adaptation in shaping the landscape of functional variation in wild mouse populations. We also uncover strong signals of selection at multiple genes involved in starch digestion, including Mgam and Amy1. We speculate that the successful emergence of the human-mouse commensalism may have been facilitated, in part, by dietary adaptations at these loci. Finally, our work uncovers multiple cryptic structural variants that manifest as putative signals of positive selection, highlighting an important and under-appreciated source of false-positive signals in genome-wide selection scans.

CONCLUSIONS: Overall, our findings highlight the role of adaptation in shaping wild mouse genetic variation at human disease-associated genes. Our work also highlights the biomedical relevance of wild mouse genetic diversity and underscores the potential for targeted sampling of mice from specific populations as a strategy for developing effective new mouse models of both rare and common human diseases.

Comments

This article is licensed under a Creative Commons Attribution 4.0 International License.

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