Improved Pathogenic Variant Localization via a Hierarchical Model of Sub-regional Intolerance.
LIMBR
RVIS
conservation
constraint
domains
exons
genic sub-region
intolerance
negative selection
pathogenic
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
07 02 2019
07 02 2019
Historique:
received:
20
09
2018
accepted:
21
12
2018
pubmed:
29
1
2019
medline:
20
11
2019
entrez:
29
1
2019
Statut:
ppublish
Résumé
Different parts of a gene can be of differential importance to development and health. This regional heterogeneity is also apparent in the distribution of disease-associated mutations, which often cluster in particular regions of disease-associated genes. The ability to precisely estimate functionally important sub-regions of genes will be key in correctly deciphering relationships between genetic variation and disease. Previous methods have had some success using standing human variation to characterize this variability in importance by measuring sub-regional intolerance, i.e., the depletion in functional variation from expectation within a given region of a gene. However, the ability to precisely estimate local intolerance was restricted by the fact that only information within a given sub-region is used, leading to instability in local estimates, especially for small regions. We show that borrowing information across regions using a Bayesian hierarchical model stabilizes estimates, leading to lower variability and improved predictive utility. Specifically, our approach more effectively identifies regions enriched for ClinVar pathogenic variants. We also identify significant correlations between sub-region intolerance and the distribution of pathogenic variation in disease-associated genes, with AUCs for classifying de novo missense variants in Online Mendelian Inheritance in Man (OMIM) genes of up to 0.86 using exonic sub-regions and 0.91 using sub-regions defined by protein domains. This result immediately suggests that considering the intolerance of regions in which variants are found may improve diagnostic interpretation. We also illustrate the utility of integrating regional intolerance into gene-level disease association tests with a study of known disease-associated genes for epileptic encephalopathy.
Identifiants
pubmed: 30686509
pii: S0002-9297(18)30503-2
doi: 10.1016/j.ajhg.2018.12.020
pmc: PMC6369453
pii:
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
299-309Informations de copyright
Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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