Leveraging Base Pair Mammalian Constraint to Understand Genetic Variation and Human Disease.

ABSTRACT: Although thousands of genomic regions have been associated with heritable human diseases, attempts to elucidate biological mechanisms are impeded by a general inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function that is agnostic to cell type or disease mechanism. Here, single base phyloP scores from the whole genome alignment of 240 placental mammals identified 3.5% of the human genome as significantly constrained, and likely functional. We compared these scores to large-scale genome annotation, genome-wide association studies (GWAS), copy number variation, clinical genetics findings, and cancer data sets. Evolutionarily constrained positions are enriched for variants explaining common disease heritability (mor

SUBMITTER: Sullivan PF 

PROVIDER: S-EPMC10028973 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature