Ancestry adjustment improves genome-wide estimates of regional intolerance
Authors/Creators
- 1. Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA
- 2. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- 3. Institute for Genomic Medicine, Columbia University, New York, NY
- 4. Department of Genetics Washington University St. Louis, MO
- 5. Department of Biostatistics and Bioinformatics, Duke University, Durham, NC
- 6. Department of Biostatistics Columbia University, New York, NY
Description
Genomic regions subject to purifying selection are more likely to carry disease causing mutations than regions not under selection. Cross species conservation is often used to identify such regions but with limited resolution to detect selection on short evolutionary timescales such as that occurring in only one species. In contrast, genetic intolerance looks for depletion of variation relative to expectation within a species, allowing species specific features to be identified. When estimating the intolerance of noncoding sequence, methods strongly leverage variant frequency distributions. As the expected distributions depend on ancestry, if not properly controlled for, ancestral population source may obfuscate signals of selection. We demonstrate that properly incorporating ancestry in intolerance estimation greatly improved variant classification. We provide a genomewide intolerance map that is conditional on ancestry and likely to be particularly valuable for variant prioritization.
Notes
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Additional details
Related works
- Is part of
- Journal article: 10.1093/genetics/iyac050 (DOI)