RT Journal Article
SR Electronic
T1 Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 362707
DO 10.1101/362707
A1 Maria Kousi
A1 Onuralp Söylemez
A1 Aysegül Ozanturk
A1 Sebastian Akle
A1 Irwin Jungreis
A1 Jean Muller
A1 Christopher A. Cassa
A1 Harrison Brand
A1 Jill Anne Mokry
A1 Maxim Y. Wolf
A1 Azita Sadeghpour
A1 Kelsey McFadden
A1 Richard A. Lewis
A1 Michael E. Talkowski
A1 Hélène Dollfus
A1 Manolis Kellis
A1 Erica E. Davis
A1 Shamil R. Sunyaev
A1 Nicholas Katsanis
YR 2018
UL http://biorxiv.org/content/early/2018/07/05/362707.abstract
AB 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) 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.