Work

Tolerance of nonsynonymous variation is closely correlated between human and mouse orthologues

Year: 2019

Type: preprint

Abstract: ABSTRACT Genic constraint describes how tolerant a gene is of nonsynonymous variation before it is removed from the population by negative selection. Here, we provide the first estimates of intraspecific constraint for mouse genes genome-wide, and show constraint is positively correlated between human and mouse orthologues (r = 0.806). We assess the relationships between mouse gene constraint and knockout phenotypes, showing gene constraint is positively associated with pleiotropy (ie an increased number of phenotype associations (R 2 = 0.65)), in addition to an enrichment in lethal, developmental, and craniofacial knockout phenotypes amongst the most constrained genes. Finally, we show mouse constraint can be used to predict human genes associated with Mendelian disease, and is positively correlated with an increase in the number of known pathogenic variants in the human orthologue (R 2 = 0.23). Our metrics of mouse and human constraint are available to inform future research using mouse models.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.1101/657981

Authors: George Powell, Michelle Simon, Sara Pulit, Ann-Marie Mallon, Cecilia M. Lindgren

Institutions: University of Oxford, Mary Lyon Centre at MRC Harwell, Broad Institute, Centre for Human Genetics, Harvard University

Language: English

Topic: Genomics and Rare Diseases

Subfield: Genetics

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funder: Medical Research Council