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

Maria Kousi; Onuralp Söylemez; Aysegül Ozanturk; Niki Mourtzi; Sebastian Akle; Irwin Jungreis; Jean Muller; Christopher A. Cassa; Harrison Brand; Jill Anne Mokry; Maxim Y. Wolf; Azita Sadeghpour; Kelsey McFadden; Richard A. Lewis; Michael E. Talkowski; Hélène Dollfus; Manolis Kellis; Erica E. Davis; Shamil R. Sunyaev; Nicholas Katsanis

doi:10.1038/s41588-020-0707-1

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

Maria Kousi, Onuralp Söylemez, Aysegül Ozanturk, Niki Mourtzi, Sebastian Akle, Irwin Jungreis, Jean Muller, Christopher A. Cassa, Harrison Brand, Jill Anne Mokry, Maxim Y. Wolf, Azita Sadeghpour, Kelsey McFadden, Richard A. Lewis, Michael E. Talkowski, Hélène Dollfus, Manolis Kellis, Erica E. Davis, Shamil R. Sunyaev, Nicholas Katsanis^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

The influence of genetic background on driver mutations is well established; however, the mechanisms by which the background interacts with Mendelian loci remain unclear. We performed a systematic secondary-variant burden analysis of two independent cohorts of patients with Bardet–Biedl syndrome (BBS) 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 in patients with BBS compared with either population controls or 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 for secondary-variant burden analysis in recessive disorders.

Original language	English (US)
Pages (from-to)	1145-1150
Number of pages	6
Journal	Nature Genetics
Volume	52
Issue number	11
DOIs	https://doi.org/10.1038/s41588-020-0707-1
State	Published - Nov 1 2020

ASJC Scopus subject areas

Genetics

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Kousi, M., Söylemez, O., Ozanturk, A., Mourtzi, N., Akle, S., Jungreis, I., Muller, J., Cassa, C. A., Brand, H., Mokry, 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. (2020). Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy. Nature Genetics, 52(11), 1145-1150. https://doi.org/10.1038/s41588-020-0707-1

Kousi, Maria ; Söylemez, Onuralp ; Ozanturk, Aysegül ; 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, Hélène ; Kellis, Manolis ; Davis, Erica E. ; Sunyaev, Shamil R. ; Katsanis, Nicholas. / Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy. In: Nature Genetics. 2020 ; Vol. 52, No. 11. pp. 1145-1150.

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

abstract = "The influence of genetic background on driver mutations is well established; however, the mechanisms by which the background interacts with Mendelian loci remain unclear. We performed a systematic secondary-variant burden analysis of two independent cohorts of patients with Bardet–Biedl syndrome (BBS) 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 in patients with BBS compared with either population controls or 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 for secondary-variant burden analysis in recessive disorders.",

author = "Maria Kousi and Onuralp S{\"o}ylemez and Ayseg{\"u}l Ozanturk and Niki Mourtzi and Sebastian Akle and Irwin Jungreis and Jean Muller and Cassa, {Christopher A.} and Harrison Brand and Mokry, {Jill Anne} and Wolf, {Maxim Y.} and Azita Sadeghpour and Kelsey McFadden and Lewis, {Richard A.} and Talkowski, {Michael E.} and H{\'e}l{\`e}ne Dollfus and Manolis Kellis and Davis, {Erica E.} and Sunyaev, {Shamil R.} and Nicholas Katsanis",

note = "Funding Information: We thank the patients and their families for participating in this study, as well as their caring physicians who provided clinical information and referred the patients for diagnostic analyses. We are grateful to C. Glodosky and A. Krentz from PreventionGenetics and R. Haws from Marshfield Clinic for providing information on clinical BBS exome data. We thank A.-S. Jaeger and M. Antin for technical assistance. This study was supported by NIH grants GM121317-13, HD042601 and DK072301 (to N.K.), grants R35GM127131, R01MH101244 and U01HG00908 (to S.R.S.) and R01 HG004037 (to I.J.), as well as GENCODE Wellcome Trust grant U41 HG007234 (to I.J.). R.A.L. is a senior scientific investigator of research to prevent blindness. N.K. is a distinguished Valerie and George D. Kennedy professor.",

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Kousi, M, Söylemez, O, Ozanturk, A, Mourtzi, N, Akle, S, Jungreis, I, Muller, J, Cassa, CA, Brand, H, Mokry, JA, Wolf, MY, Sadeghpour, A, McFadden, K, Lewis, RA, Talkowski, ME, Dollfus, H, Kellis, M, Davis, EE, Sunyaev, SR & Katsanis, N 2020, 'Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy', Nature Genetics, vol. 52, no. 11, pp. 1145-1150. https://doi.org/10.1038/s41588-020-0707-1

Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy. / Kousi, Maria; Söylemez, Onuralp; Ozanturk, Aysegül; 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, Hélène; Kellis, Manolis; Davis, Erica E.; Sunyaev, Shamil R.; Katsanis, Nicholas.

In: Nature Genetics, Vol. 52, No. 11, 01.11.2020, p. 1145-1150.

Research output: Contribution to journal › Article › peer-review

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T1 - Evidence for secondary-variant genetic burden and non-random distribution across biological modules in a recessive ciliopathy

AU - Kousi, Maria

AU - Söylemez, Onuralp

AU - Ozanturk, Aysegül

AU - Mourtzi, Niki

AU - Akle, Sebastian

AU - Jungreis, Irwin

AU - Muller, Jean

AU - Cassa, Christopher A.

AU - Brand, Harrison

AU - Mokry, Jill Anne

AU - Wolf, Maxim Y.

AU - Sadeghpour, Azita

AU - McFadden, Kelsey

AU - Lewis, Richard A.

AU - Talkowski, Michael E.

AU - Dollfus, Hélène

AU - Kellis, Manolis

AU - Davis, Erica E.

AU - Sunyaev, Shamil R.

AU - Katsanis, Nicholas

N1 - Funding Information: We thank the patients and their families for participating in this study, as well as their caring physicians who provided clinical information and referred the patients for diagnostic analyses. We are grateful to C. Glodosky and A. Krentz from PreventionGenetics and R. Haws from Marshfield Clinic for providing information on clinical BBS exome data. We thank A.-S. Jaeger and M. Antin for technical assistance. This study was supported by NIH grants GM121317-13, HD042601 and DK072301 (to N.K.), grants R35GM127131, R01MH101244 and U01HG00908 (to S.R.S.) and R01 HG004037 (to I.J.), as well as GENCODE Wellcome Trust grant U41 HG007234 (to I.J.). R.A.L. is a senior scientific investigator of research to prevent blindness. N.K. is a distinguished Valerie and George D. Kennedy professor.

PY - 2020/11/1

Y1 - 2020/11/1

N2 - The influence of genetic background on driver mutations is well established; however, the mechanisms by which the background interacts with Mendelian loci remain unclear. We performed a systematic secondary-variant burden analysis of two independent cohorts of patients with Bardet–Biedl syndrome (BBS) 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 in patients with BBS compared with either population controls or 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 for secondary-variant burden analysis in recessive disorders.

AB - The influence of genetic background on driver mutations is well established; however, the mechanisms by which the background interacts with Mendelian loci remain unclear. We performed a systematic secondary-variant burden analysis of two independent cohorts of patients with Bardet–Biedl syndrome (BBS) 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 in patients with BBS compared with either population controls or 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 for secondary-variant burden analysis in recessive disorders.

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