Genic constraint against nonsynonymous variation across the mouse genome

Area of Science:

• Evolutionary genetics
• Comparative genomics
• Mammalian genetics

Background:

• Selective constraint, or variation depletion due to negative selection, offers insights into variant functional impact and disease mechanisms.
• Characterizing selective constraint in mice, a key mammalian model, is currently limited.
• This study introduces a novel metric to quantify mouse gene constraint.

Purpose of the Study:

• To quantify mouse gene constraint using the nonsynonymous observed expected ratio (NOER).
• To investigate the relationship between mouse gene constraint and gene function.
• To assess the utility of mouse models for studying human disease variants.

Main Methods:

• Calculated NOER using whole-genome sequencing data from wild mouse populations (Mus musculus sp and Mus spretus).
• Correlated mouse gene constraint with the number of knockout phenotypes.
• Examined the relationship between mouse gene constraint and pathogenic variant sites in human orthologues.

Main Results:

• Mouse gene constraint positively correlates with the number of knockout phenotypes, suggesting stronger constraint on pleiotropic genes.
• Mouse gene constraint shows a positive correlation with pathogenic variant sites in human orthologues.
• NOER effectively quantifies gene constraint and its functional associations in mice.

Conclusions:

• NOER serves as a valuable resource for assessing genetic variant fitness consequences in mice.
• Findings underscore the significance of pleiotropy in selective constraint and the relevance of mouse models for human disease research.
• Further studies with larger sample sizes can enhance constraint estimates and inter-species comparisons.