Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy
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Söylemez, Onuralp
Ozanturk, Aysegül
Akle, Sebastian
Mokry, Jill Anne
Sadeghpour, Azita
McFadden, Kelsey
Lewis, Richard A.
Dollfus, Hélène
Davis, Erica E.
Katsanis, Nicholas
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https://doi.org/10.1101/362707Metadata
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Kousi, Maria, Soylemez, Onuralp, Ozanturk, Aysegul, Mourtzi, Niki, Akle, Sebastian, Jungreis, Irwin, Muller, Jean, Cassa, Christopher A, Brand, Harrison, Mokry, Jill Anne, Wolf, Maxim Y, Sadeghpour, Azita, McFadden, Kelsey, Lewis, Richard A, Talkowski, Michael E, Dollfus, Helene, Kellis, Manolis, Davis, Erica E, Sunyaev, Shamil R, and Katsanis, Nicholas. "Evidence for Secondary-variant Genetic Burden and Non-random Distribution across Biological Modules in a Recessive Ciliopathy." Nature Genetics 52, no. 11 (2020): 1145-150.Abstract
The influence of genetic background on driver mutations is well established; however, the mechanisms by which the background interacts with Mendelian loci remains unclear. We performed a systematic secondary-variant burden analysis of two independent Bardet-Biedl syndrome (BBS)1 cohorts with known recessive biallelic pathogenic mutations in one of 17 BBS genes for each individual. We observed a significant enrichment of trans-acting rare nonsynonymous secondary variants compared to either population controls or to a cohort of individuals with a non-BBS diagnosis and recessive variants in the same gene set. Strikingly, we found a significant over-representation of secondary alleles in chaperonin-encoding genes, a finding corroborated by the observation of epistatic interactions involving this complex in vivo. These data indicate a complex genetic architecture for BBS that informs the biological properties of disease modules and presents a model paradigm for secondary-variant burden analysis in recessive disorders.Citable link to this page
https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37373202
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