The effects of common structural variants on 3D chromatin structure

Omar Shanta; Amina Noor; Mark J.P. Chaisson; Ashley D. Sanders; Xuefang Zhao; Ankit Malhotra; David Porubsky; Tobias Rausch; Eugene J. Gardner; Oscar L. Rodriguez; Li Guo; Ryan L. Collins; Xian Fan; Jia Wen; Robert E. Handsaker; Susan Fairley; Zev N. Kronenberg; Xiangmeng Kong; Fereydoun Hormozdiari; Dillon Lee; Aaron M. Wenger; Alex R. Hastie; Danny Antaki; Thomas Anantharaman; Peter A. Audano; Harrison Brand; Stuart Cantsilieris; Han Cao; Eliza Cerveira; Chong Chen; Xintong Chen; Chen Shan Chin; Zechen Chong; Nelson T. Chuang; Christine C. Lambert; Deanna M. Church; Laura Clarke; Andrew Farrell; Joey Flores; Timur Galeey; Madhusudan Gujral; Victor Guryev; William Haynes Heaton; Jonas Korlach; Sushant Kumar; Jee Young Kwon; Ernest T. Lam; Jong Eun Lee; Joyce Lee; Wan Ping Lee; Sau Peng Lee; Shantao Li; Patrick Marks; Karine Viaud-Martinez; Sascha Meiers; Katherine M. Munson; Fabio C.P. Navarro; Bradley J. Nelson; Conor Nodzak; Amina Noor; Sofia Kyriazopoulou-Panagiotopoulou; Andy W.C. Pang; Gabriel Rosanio; Mallory Ryan; Adrian Stütz; Diana C.J. Spierings; Alistair Ward; Anne Marie E. Welch; Ming Xiao; Wei Xu; Chengsheng Zhang; Qihui Zhu; Xiangqun Zheng-Bradley; Ernesto Lowy; Sergei Yakneen; Steven McCarroll; Goo Jun; Li Ding; Chong Lek Koh; Paul Flicek; Ken Chen; Mark B. Gerstein; Pui Yan Kwok; Peter M. Lansdorp; Gabor T. Marth; Jonathan Sebat; Xinghua Shi; Ali Bashir; Kai Ye; Scott E. Devine; Michael E. Talkowski; Ryan E. Mills; Tobias Marschall; Jan O. Korbel; Evan E. Eichler; Charles Lee; Jonathan Sebat

doi:10.1186/s12864-020-6516-1

The effects of common structural variants on 3D chromatin structure

Omar Shanta, Amina Noor, Mark J.P. Chaisson, Ashley D. Sanders, Xuefang Zhao, Ankit Malhotra, David Porubsky, Tobias Rausch, Eugene J. Gardner, Oscar L. Rodriguez, Li Guo, Ryan L. Collins, Xian Fan, Jia Wen, Robert E. Handsaker, Susan Fairley, Zev N. Kronenberg, Xiangmeng Kong, Fereydoun Hormozdiari, Dillon LeeAaron M. Wenger, Alex R. Hastie, Danny Antaki, Thomas Anantharaman, Peter A. Audano, Harrison Brand, Stuart Cantsilieris, Han Cao, Eliza Cerveira, Chong Chen, Xintong Chen, Chen Shan Chin, Zechen Chong, Nelson T. Chuang, Christine C. Lambert, Deanna M. Church, Laura Clarke, Andrew Farrell, Joey Flores, Timur Galeey, Madhusudan Gujral, Victor Guryev, William Haynes Heaton, Jonas Korlach, Sushant Kumar, Jee Young Kwon, Ernest T. Lam, Jong Eun Lee, Joyce Lee, Wan Ping Lee, Sau Peng Lee, Shantao Li, Patrick Marks, Karine Viaud-Martinez, Sascha Meiers, Katherine M. Munson, Fabio C.P. Navarro, Bradley J. Nelson, Conor Nodzak, Amina Noor, Sofia Kyriazopoulou-Panagiotopoulou, Andy W.C. Pang, Gabriel Rosanio, Mallory Ryan, Adrian Stütz, Diana C.J. Spierings, Alistair Ward, Anne Marie E. Welch, Ming Xiao, Wei Xu, Chengsheng Zhang, Qihui Zhu, Xiangqun Zheng-Bradley, Ernesto Lowy, Sergei Yakneen, Steven McCarroll, Goo Jun, Li Ding, Chong Lek Koh, Paul Flicek, Ken Chen, Mark B. Gerstein, Pui Yan Kwok, Peter M. Lansdorp, Gabor T. Marth, Jonathan Sebat, Xinghua Shi, Ali Bashir, Kai Ye, Scott E. Devine, Michael E. Talkowski, Ryan E. Mills, Tobias Marschall, Jan O. Korbel, Evan E. Eichler, Charles Lee, Jonathan Sebat

Biostatistics and Biomedical Informatics

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

20 Scopus citations

Abstract

Background: Three-dimensional spatial organization of chromosomes is defined by highly self-interacting regions 0.1-1 Mb in size termed Topological Associating Domains (TADs). Genetic factors that explain dynamic variation in TAD structure are not understood. We hypothesize that common structural variation (SV) in the human population can disrupt regulatory sequences and thereby influence TAD formation. To determine the effects of SVs on 3D chromatin organization, we performed chromosome conformation capture sequencing (Hi-C) of lymphoblastoid cell lines from 19 subjects for which SVs had been previously characterized in the 1000 genomes project. We tested the effects of common deletion polymorphisms on TAD structure by linear regression analysis of nearby quantitative chromatin interactions (contacts) within 240 kb of the deletion, and we specifically tested the hypothesis that deletions at TAD boundaries (TBs) could result in large-scale alterations in chromatin conformation. Results: Large (> 10 kb) deletions had significant effects on long-range chromatin interactions. Deletions were associated with increased contacts that span the deleted region and this effect was driven by large deletions that were not located within a TAD boundary (nonTB). Some deletions at TBs, including a 80 kb deletion of the genes CFHR1 and CFHR3, had detectable effects on chromatin contacts. However for TB deletions overall, we did not detect a pattern of effects that was consistent in magnitude or direction. Large inversions in the population had a distinguishable signature characterized by a rearrangement of contacts that span its breakpoints. Conclusions: Our study demonstrates that common SVs in the population impact long-range chromatin structure, and deletions and inversions have distinct signatures. However, the effects that we observe are subtle and variable between loci. Genome-wide analysis of chromatin conformation in large cohorts will be needed to quantify the influence of common SVs on chromatin structure.

Original language	English
Article number	95
Journal	BMC Genomics
Volume	21
Issue number	1
DOIs	https://doi.org/10.1186/s12864-020-6516-1
State	Published - Jan 30 2020

Funding

Funders	Funder number
National Cancer Institute	R01CA094143
National Cancer Institute

Keywords

Chromatin
Deletion
Hi-C
Inversion
Structural variation
TAD
TAD fusion

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10.1186/s12864-020-6516-1

Cite this

Shanta, O., Noor, A., Chaisson, M. J. P., Sanders, A. D., Zhao, X., Malhotra, A., Porubsky, D., Rausch, T., Gardner, E. J., Rodriguez, O. L., Guo, L., Collins, R. L., Fan, X., Wen, J., Handsaker, R. E., Fairley, S., Kronenberg, Z. N., Kong, X., Hormozdiari, F., ... Sebat, J. (2020). The effects of common structural variants on 3D chromatin structure. BMC Genomics, 21(1), Article 95. https://doi.org/10.1186/s12864-020-6516-1

@article{89d6761ef31d48e78fe8d6ee86867d32,

title = "The effects of common structural variants on 3D chromatin structure",

abstract = "Background: Three-dimensional spatial organization of chromosomes is defined by highly self-interacting regions 0.1-1 Mb in size termed Topological Associating Domains (TADs). Genetic factors that explain dynamic variation in TAD structure are not understood. We hypothesize that common structural variation (SV) in the human population can disrupt regulatory sequences and thereby influence TAD formation. To determine the effects of SVs on 3D chromatin organization, we performed chromosome conformation capture sequencing (Hi-C) of lymphoblastoid cell lines from 19 subjects for which SVs had been previously characterized in the 1000 genomes project. We tested the effects of common deletion polymorphisms on TAD structure by linear regression analysis of nearby quantitative chromatin interactions (contacts) within 240 kb of the deletion, and we specifically tested the hypothesis that deletions at TAD boundaries (TBs) could result in large-scale alterations in chromatin conformation. Results: Large (> 10 kb) deletions had significant effects on long-range chromatin interactions. Deletions were associated with increased contacts that span the deleted region and this effect was driven by large deletions that were not located within a TAD boundary (nonTB). Some deletions at TBs, including a 80 kb deletion of the genes CFHR1 and CFHR3, had detectable effects on chromatin contacts. However for TB deletions overall, we did not detect a pattern of effects that was consistent in magnitude or direction. Large inversions in the population had a distinguishable signature characterized by a rearrangement of contacts that span its breakpoints. Conclusions: Our study demonstrates that common SVs in the population impact long-range chromatin structure, and deletions and inversions have distinct signatures. However, the effects that we observe are subtle and variable between loci. Genome-wide analysis of chromatin conformation in large cohorts will be needed to quantify the influence of common SVs on chromatin structure.",

keywords = "Chromatin, Deletion, Hi-C, Inversion, Structural variation, TAD, TAD fusion",

author = "Omar Shanta and Amina Noor and Chaisson, {Mark J.P.} and Sanders, {Ashley D.} and Xuefang Zhao and Ankit Malhotra and David Porubsky and Tobias Rausch and Gardner, {Eugene J.} and Rodriguez, {Oscar L.} and Li Guo and Collins, {Ryan L.} and Xian Fan and Jia Wen and Handsaker, {Robert E.} and Susan Fairley and Kronenberg, {Zev N.} and Xiangmeng Kong and Fereydoun Hormozdiari and Dillon Lee and Wenger, {Aaron M.} and Hastie, {Alex R.} and Danny Antaki and Thomas Anantharaman and Audano, {Peter A.} and Harrison Brand and Stuart Cantsilieris and Han Cao and Eliza Cerveira and Chong Chen and Xintong Chen and Chin, {Chen Shan} and Zechen Chong and Chuang, {Nelson T.} and Lambert, {Christine C.} and Church, {Deanna M.} and Laura Clarke and Andrew Farrell and Joey Flores and Timur Galeey and Madhusudan Gujral and Victor Guryev and Heaton, {William Haynes} and Jonas Korlach and Sushant Kumar and Kwon, {Jee Young} and Lam, {Ernest T.} and Lee, {Jong Eun} and Joyce Lee and Lee, {Wan Ping} and Lee, {Sau Peng} and Shantao Li and Patrick Marks and Karine Viaud-Martinez and Sascha Meiers and Munson, {Katherine M.} and Navarro, {Fabio C.P.} and Nelson, {Bradley J.} and Conor Nodzak and Amina Noor and Sofia Kyriazopoulou-Panagiotopoulou and Pang, {Andy W.C.} and Gabriel Rosanio and Mallory Ryan and Adrian St{\"u}tz and Spierings, {Diana C.J.} and Alistair Ward and Welch, {Anne Marie E.} and Ming Xiao and Wei Xu and Chengsheng Zhang and Qihui Zhu and Xiangqun Zheng-Bradley and Ernesto Lowy and Sergei Yakneen and Steven McCarroll and Goo Jun and Li Ding and Koh, {Chong Lek} and Paul Flicek and Ken Chen and Gerstein, {Mark B.} and Kwok, {Pui Yan} and Lansdorp, {Peter M.} and Marth, {Gabor T.} and Jonathan Sebat and Xinghua Shi and Ali Bashir and Kai Ye and Devine, {Scott E.} and Talkowski, {Michael E.} and Mills, {Ryan E.} and Tobias Marschall and Korbel, {Jan O.} and Eichler, {Evan E.} and Charles Lee and Jonathan Sebat",

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s).",

year = "2020",

month = jan,

day = "30",

doi = "10.1186/s12864-020-6516-1",

language = "English",

volume = "21",

journal = "BMC Genomics",

issn = "1471-2164",

publisher = "BioMed Central",

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Shanta, O, Noor, A, Chaisson, MJP, Sanders, AD, Zhao, X, Malhotra, A, Porubsky, D, Rausch, T, Gardner, EJ, Rodriguez, OL, Guo, L, Collins, RL, Fan, X, Wen, J, Handsaker, RE, Fairley, S, Kronenberg, ZN, Kong, X, Hormozdiari, F, Lee, D, Wenger, AM, Hastie, AR, Antaki, D, Anantharaman, T, Audano, PA, Brand, H, Cantsilieris, S, Cao, H, Cerveira, E, Chen, C, Chen, X, Chin, CS, Chong, Z, Chuang, NT, Lambert, CC, Church, DM, Clarke, L, Farrell, A, Flores, J, Galeey, T, Gujral, M, Guryev, V, Heaton, WH, Korlach, J, Kumar, S, Kwon, JY, Lam, ET, Lee, JE, Lee, J, Lee, WP, Lee, SP, Li, S, Marks, P, Viaud-Martinez, K, Meiers, S, Munson, KM, Navarro, FCP, Nelson, BJ, Nodzak, C, Noor, A, Kyriazopoulou-Panagiotopoulou, S, Pang, AWC, Rosanio, G, Ryan, M, Stütz, A, Spierings, DCJ, Ward, A, Welch, AME, Xiao, M, Xu, W, Zhang, C, Zhu, Q, Zheng-Bradley, X, Lowy, E, Yakneen, S, McCarroll, S, Jun, G, Ding, L, Koh, CL, Flicek, P, Chen, K, Gerstein, MB, Kwok, PY, Lansdorp, PM, Marth, GT, Sebat, J, Shi, X, Bashir, A, Ye, K, Devine, SE, Talkowski, ME, Mills, RE, Marschall, T, Korbel, JO, Eichler, EE, Lee, C & Sebat, J 2020, 'The effects of common structural variants on 3D chromatin structure', BMC Genomics, vol. 21, no. 1, 95. https://doi.org/10.1186/s12864-020-6516-1

TY - JOUR

T1 - The effects of common structural variants on 3D chromatin structure

AU - Shanta, Omar

AU - Noor, Amina

AU - Chaisson, Mark J.P.

AU - Sanders, Ashley D.

AU - Zhao, Xuefang

AU - Malhotra, Ankit

AU - Porubsky, David

AU - Rausch, Tobias

AU - Gardner, Eugene J.

AU - Rodriguez, Oscar L.

AU - Guo, Li

AU - Collins, Ryan L.

AU - Fan, Xian

AU - Wen, Jia

AU - Handsaker, Robert E.

AU - Fairley, Susan

AU - Kronenberg, Zev N.

AU - Kong, Xiangmeng

AU - Hormozdiari, Fereydoun

AU - Lee, Dillon

AU - Wenger, Aaron M.

AU - Hastie, Alex R.

AU - Antaki, Danny

AU - Anantharaman, Thomas

AU - Audano, Peter A.

AU - Brand, Harrison

AU - Cantsilieris, Stuart

AU - Cao, Han

AU - Cerveira, Eliza

AU - Chen, Chong

AU - Chen, Xintong

AU - Chin, Chen Shan

AU - Chong, Zechen

AU - Chuang, Nelson T.

AU - Lambert, Christine C.

AU - Church, Deanna M.

AU - Clarke, Laura

AU - Farrell, Andrew

AU - Flores, Joey

AU - Galeey, Timur

AU - Gujral, Madhusudan

AU - Guryev, Victor

AU - Heaton, William Haynes

AU - Korlach, Jonas

AU - Kumar, Sushant

AU - Kwon, Jee Young

AU - Lam, Ernest T.

AU - Lee, Jong Eun

AU - Lee, Joyce

AU - Lee, Wan Ping

AU - Lee, Sau Peng

AU - Li, Shantao

AU - Marks, Patrick

AU - Viaud-Martinez, Karine

AU - Meiers, Sascha

AU - Munson, Katherine M.

AU - Navarro, Fabio C.P.

AU - Nelson, Bradley J.

AU - Nodzak, Conor

AU - Noor, Amina

AU - Kyriazopoulou-Panagiotopoulou, Sofia

AU - Pang, Andy W.C.

AU - Rosanio, Gabriel

AU - Ryan, Mallory

AU - Stütz, Adrian

AU - Spierings, Diana C.J.

AU - Ward, Alistair

AU - Welch, Anne Marie E.

AU - Xiao, Ming

AU - Xu, Wei

AU - Zhang, Chengsheng

AU - Zhu, Qihui

AU - Zheng-Bradley, Xiangqun

AU - Lowy, Ernesto

AU - Yakneen, Sergei

AU - McCarroll, Steven

AU - Jun, Goo

AU - Ding, Li

AU - Koh, Chong Lek

AU - Flicek, Paul

AU - Chen, Ken

AU - Gerstein, Mark B.

AU - Kwok, Pui Yan

AU - Lansdorp, Peter M.

AU - Marth, Gabor T.

AU - Sebat, Jonathan

AU - Shi, Xinghua

AU - Bashir, Ali

AU - Ye, Kai

AU - Devine, Scott E.

AU - Talkowski, Michael E.

AU - Mills, Ryan E.

AU - Marschall, Tobias

AU - Korbel, Jan O.

AU - Eichler, Evan E.

AU - Lee, Charles

AU - Sebat, Jonathan

PY - 2020/1/30

Y1 - 2020/1/30

N2 - Background: Three-dimensional spatial organization of chromosomes is defined by highly self-interacting regions 0.1-1 Mb in size termed Topological Associating Domains (TADs). Genetic factors that explain dynamic variation in TAD structure are not understood. We hypothesize that common structural variation (SV) in the human population can disrupt regulatory sequences and thereby influence TAD formation. To determine the effects of SVs on 3D chromatin organization, we performed chromosome conformation capture sequencing (Hi-C) of lymphoblastoid cell lines from 19 subjects for which SVs had been previously characterized in the 1000 genomes project. We tested the effects of common deletion polymorphisms on TAD structure by linear regression analysis of nearby quantitative chromatin interactions (contacts) within 240 kb of the deletion, and we specifically tested the hypothesis that deletions at TAD boundaries (TBs) could result in large-scale alterations in chromatin conformation. Results: Large (> 10 kb) deletions had significant effects on long-range chromatin interactions. Deletions were associated with increased contacts that span the deleted region and this effect was driven by large deletions that were not located within a TAD boundary (nonTB). Some deletions at TBs, including a 80 kb deletion of the genes CFHR1 and CFHR3, had detectable effects on chromatin contacts. However for TB deletions overall, we did not detect a pattern of effects that was consistent in magnitude or direction. Large inversions in the population had a distinguishable signature characterized by a rearrangement of contacts that span its breakpoints. Conclusions: Our study demonstrates that common SVs in the population impact long-range chromatin structure, and deletions and inversions have distinct signatures. However, the effects that we observe are subtle and variable between loci. Genome-wide analysis of chromatin conformation in large cohorts will be needed to quantify the influence of common SVs on chromatin structure.

AB - Background: Three-dimensional spatial organization of chromosomes is defined by highly self-interacting regions 0.1-1 Mb in size termed Topological Associating Domains (TADs). Genetic factors that explain dynamic variation in TAD structure are not understood. We hypothesize that common structural variation (SV) in the human population can disrupt regulatory sequences and thereby influence TAD formation. To determine the effects of SVs on 3D chromatin organization, we performed chromosome conformation capture sequencing (Hi-C) of lymphoblastoid cell lines from 19 subjects for which SVs had been previously characterized in the 1000 genomes project. We tested the effects of common deletion polymorphisms on TAD structure by linear regression analysis of nearby quantitative chromatin interactions (contacts) within 240 kb of the deletion, and we specifically tested the hypothesis that deletions at TAD boundaries (TBs) could result in large-scale alterations in chromatin conformation. Results: Large (> 10 kb) deletions had significant effects on long-range chromatin interactions. Deletions were associated with increased contacts that span the deleted region and this effect was driven by large deletions that were not located within a TAD boundary (nonTB). Some deletions at TBs, including a 80 kb deletion of the genes CFHR1 and CFHR3, had detectable effects on chromatin contacts. However for TB deletions overall, we did not detect a pattern of effects that was consistent in magnitude or direction. Large inversions in the population had a distinguishable signature characterized by a rearrangement of contacts that span its breakpoints. Conclusions: Our study demonstrates that common SVs in the population impact long-range chromatin structure, and deletions and inversions have distinct signatures. However, the effects that we observe are subtle and variable between loci. Genome-wide analysis of chromatin conformation in large cohorts will be needed to quantify the influence of common SVs on chromatin structure.

KW - Chromatin

KW - Deletion

KW - Hi-C

KW - Inversion

KW - Structural variation

KW - TAD

KW - TAD fusion

UR - http://www.scopus.com/inward/record.url?scp=85078713205&partnerID=8YFLogxK

U2 - 10.1186/s12864-020-6516-1

DO - 10.1186/s12864-020-6516-1

M3 - Article

C2 - 32000688

AN - SCOPUS:85078713205

SN - 1471-2164

VL - 21

JO - BMC Genomics

JF - BMC Genomics

IS - 1

M1 - 95

ER -

The effects of common structural variants on 3D chromatin structure

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