Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy

Kousi, M.; Soylemez, O.; Ozanturk, A.; Akle, S.; Jungreis, I.; Muller, J.; Cassa, C. A.; Brand, H.; Rosenfeld, J. A.; Wolf, M. Y.; Sadeghpour, A.; McFadden, K.; Lewis, R. A.; Talkowski, M. E.; Dollfus, H.; Kellis, M.; Davis, E. E.; Sunyaev, S. R.; Katsanis, N.

doi:10.1101/362707

bioRxiv · 10.1101/362707

Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy

Kousi, M.·Soylemez, O.·Ozanturk, A.·Akle, S.·Jungreis, I.·Muller, J.·Cassa, C. A.·Brand, H.·Rosenfeld, J. A.·Wolf, M. Y.·Sadeghpour, A.·McFadden, K.·Lewis, R. A.·Talkowski, M. E.·Dollfus, H.·Kellis, M.·Davis, E. E.·Sunyaev, S. R.·Katsanis, N.

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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) 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.

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Kousi, M., Soylemez, O., Ozanturk, A., Akle, S., Jungreis, I., Muller, J., Cassa, C. A., Brand, H., Rosenfeld, J. A., Wolf, M. Y., Sadeghpour, A., McFadden, K., Lewis, R. A., Talkowski, M. E., Dollfus, H., Kellis, M., Davis, E. E., Sunyaev, S. R., Katsanis, N.. 2018-07-05. Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy. https://doi.org/10.1101/362707

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