4.5 Article

Whole-genome sequencing reveals the genetic mechanisms of domestication in classical inbred mice

Journal

GENOME BIOLOGY
Volume 23, Issue 1, Pages -

Publisher

BMC
DOI: 10.1186/s13059-022-02772-1

Keywords

Mus musculus; Domestication; Positively selected gene; Genome sequencing; Alternative splicing

Funding

  1. Strategic Priority Research Program of the Chinese Academy of Sciences [XDB11050300, XDPB16]
  2. Key Program of National Natural Science Foundation of China [31330013]
  3. External Cooperation Program of Chinese Academy of Sciences [152111KYSB20150023, 152111KYSB20160089]
  4. State Key Laboratory of Integrated Management of Pest Insects and Rodents [IPM1615]
  5. Czech Science Foundation [16-23773S]

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Our study reveals that classical inbred mice experienced high selection pressure during domestication under laboratory conditions. The positively selected genes identified are closely related to behavior and the nervous system in mice. The Astn2 mutation, particularly the SNP rs27900929 (T>C), may be linked to tameness and is associated with the ratio of the two Astn2 (a/b) isoforms.
Background The laboratory mouse was domesticated from the wild house mouse. Understanding the genetics underlying domestication in laboratory mice, especially in the widely used classical inbred mice, is vital for studies using mouse models. However, the genetic mechanism of laboratory mouse domestication remains unknown due to lack of adequate genomic sequences of wild mice. Results We analyze the genetic relationships by whole-genome resequencing of 36 wild mice and 36 inbred strains. All classical inbred mice cluster together distinctly from wild and wild-derived inbred mice. Using nucleotide diversity analysis, Fst, and XP-CLR, we identify 339 positively selected genes that are closely associated with nervous system function. Approximately one third of these positively selected genes are highly expressed in brain tissues, and genetic mouse models of 125 genes in the positively selected genes exhibit abnormal behavioral or nervous system phenotypes. These positively selected genes show a higher ratio of differential expression between wild and classical inbred mice compared with all genes, especially in the hippocampus and frontal lobe. Using a mutant mouse model, we find that the SNP rs27900929 (T>C) in gene Astn2 significantly reduces the tameness of mice and modifies the ratio of the two Astn2 (a/b) isoforms. Conclusion Our study indicates that classical inbred mice experienced high selection pressure during domestication under laboratory conditions. The analysis shows the positively selected genes are closely associated with behavior and the nervous system in mice. Tameness may be related to the Astn2 mutation and regulated by the ratio of the two Astn2 (a/b) isoforms.

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