Assembly and analysis of 100 full MHC haplotypes from the Danish population

Jacob M. Jensen; Palle Villesen; Rune M. Friborg; Thomas Mailund; Søren Besenbacher; Lasse Maretty Sørensen; Bent Petersen; Jonas Andreas Sibbesen; Siyang Liu; Laurits Skov; Kirstine G Belling; Christian Theil Have; Jose M. G. Izarzugaza; Marie Grosjean; Jette Bork-Jensen; Jakob Grove; Thomas D. Als; Shujia Huang; Yuqi Chang; Ruiqi Xu; Weijian Ye; Junhua Rao; Xiaosen Guo; Jihua Sun; Hongzhi Cao; Chen Ye; Johan V. Beusekom; Thomas Espeseth; Esben Flindt; Anders E. Halager; Stephanie Le Hellard; Christina M. Hultman; Francesco Lescai; Shengting Li; Ole Lund; Peter Løngren; Maria Luisa Matey-Hernandez; Ole Mors; Christian N. S. Pedersen; Thomas Sicheritz-Pontén; Patrick Sullivan; Ali Syed; David Westergaard; Rachita Yadav; Ning Li; Xun Xu; Torben Hansen; Lars Bolund; Anders Krogh; Thorkild I. A. Sørensen; Oluf Borbye Pedersen; Ramneek Gupta; Simon Rasmussen; Anders D. Børglum; Jun Wang; Hans Rudolf Lytchoff Eiberg; Karsten Kristiansen; Søren Brunak; Mikkel Heide Schierup

doi:10.1101/gr.218891.116

Assembly and analysis of 100 full MHC haplotypes from the Danish population

Jacob M. Jensen^*, Palle Villesen, Rune M. Friborg, Thomas Mailund, Søren Besenbacher, Lasse Maretty Sørensen, Bent Petersen, Jonas Andreas Sibbesen, Siyang Liu, Laurits Skov, Kirstine G Belling, Christian Theil Have, Jose M. G. Izarzugaza, Marie Grosjean, Jette Bork-Jensen, Jakob Grove, Thomas D. Als, Shujia Huang, Yuqi Chang, Ruiqi XuWeijian Ye, Junhua Rao, Xiaosen Guo, Jihua Sun, Hongzhi Cao, Chen Ye, Johan V. Beusekom, Thomas Espeseth, Esben Flindt, Anders E. Halager, Stephanie Le Hellard, Christina M. Hultman, Francesco Lescai, Shengting Li, Ole Lund, Peter Løngren, Maria Luisa Matey-Hernandez, Ole Mors, Christian N. S. Pedersen, Thomas Sicheritz-Pontén, Patrick Sullivan, Ali Syed, David Westergaard, Rachita Yadav, Ning Li, Xun Xu, Torben Hansen, Lars Bolund, Anders Krogh, Thorkild I. A. Sørensen, Oluf Borbye Pedersen, Ramneek Gupta, Simon Rasmussen, Anders D. Børglum, Jun Wang, Hans Rudolf Lytchoff Eiberg, Karsten Kristiansen, Søren Brunak, Mikkel Heide Schierup

^*Corresponding author af dette arbejde

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Abstract

Genes in the major histocompatibility complex (MHC, also known as HLA) play a critical role in the immune response and variation within the extended 4-Mb region shows association with major risks of many diseases. Yet, deciphering the underlying causes of these associations is difficult because the MHC is the most polymorphic region of the genome with a complex linkage disequilibrium structure. Here, we reconstruct full MHC haplotypes from de novo assembled trios without relying on a reference genome and perform evolutionary analyses. We report 100 full MHC haplotypes and call a large set of structural variants in the regions for future use in imputation with GWAS data. We also present the first complete analysis of the recombination landscape in the entire region and show how balancing selection at classical genes have linked effects on the frequency of variants throughout the region.

Originalsprog	Engelsk
Tidsskrift	Genome Research
Vol/bind	27
Udgave nummer	9
Sider (fra-til)	1597-1607
Antal sider	11
ISSN	1088-9051
DOI	https://doi.org/10.1101/gr.218891.116
Status	Udgivet - sep. 2017

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10.1101/gr.218891.116Licens: CC BY

Jensen_2017_Assembly_and_analysisForlagets udgivne version, 7,13 MBLicens: CC BY

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Jensen, J. M., Villesen, P., Friborg, R. M., Mailund, T., Besenbacher, S., Sørensen, L. M., Petersen, B., Sibbesen, J. A., Liu, S., Skov, L., Belling, K. G., Have, C. T., Izarzugaza, J. M. G., Grosjean, M., Bork-Jensen, J., Grove, J., Als, T. D., Huang, S., Chang, Y., ... Schierup, M. H. (2017). Assembly and analysis of 100 full MHC haplotypes from the Danish population. Genome Research, 27(9), 1597-1607. https://doi.org/10.1101/gr.218891.116

Jensen, JM, Villesen, P, Friborg, RM, Mailund, T, Besenbacher, S, Sørensen, LM, Petersen, B , Sibbesen, JA, Liu, S, Skov, L, Belling, KG, Have, CT, Izarzugaza, JMG, Grosjean, M, Bork-Jensen, J, Grove, J, Als, TD, Huang, S, Chang, Y, Xu, R, Ye, W, Rao, J, Guo, X, Sun, J, Cao, H, Ye, C, Beusekom, JV, Espeseth, T, Flindt, E, Halager, AE, Hellard, SL, Hultman, CM, Lescai, F, Li, S, Lund, O, Løngren, P, Matey-Hernandez, ML, Mors, O, Pedersen, CNS, Sicheritz-Pontén, T, Sullivan, P, Syed, A, Westergaard, D, Yadav, R, Li, N, Xu, X, Hansen, T, Bolund, L, Krogh, A , Sørensen, TIA , Pedersen, OB, Gupta, R, Rasmussen, S, Børglum, AD, Wang, J, Eiberg, HRL , Kristiansen, K , Brunak, S & Schierup, MH 2017, 'Assembly and analysis of 100 full MHC haplotypes from the Danish population', Genome Research, bind 27, nr. 9, s. 1597-1607. https://doi.org/10.1101/gr.218891.116

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title = "Assembly and analysis of 100 full MHC haplotypes from the Danish population",

abstract = "Genes in the major histocompatibility complex (MHC, also known as HLA) play a critical role in the immune response and variation within the extended 4-Mb region shows association with major risks of many diseases. Yet, deciphering the underlying causes of these associations is difficult because the MHC is the most polymorphic region of the genome with a complex linkage disequilibrium structure. Here, we reconstruct full MHC haplotypes from de novo assembled trios without relying on a reference genome and perform evolutionary analyses. We report 100 full MHC haplotypes and call a large set of structural variants in the regions for future use in imputation with GWAS data. We also present the first complete analysis of the recombination landscape in the entire region and show how balancing selection at classical genes have linked effects on the frequency of variants throughout the region.",

author = "Jensen, {Jacob M.} and Palle Villesen and Friborg, {Rune M.} and Thomas Mailund and S{\o}ren Besenbacher and S{\o}rensen, {Lasse Maretty} and Bent Petersen and Sibbesen, {Jonas Andreas} and Siyang Liu and Laurits Skov and Belling, {Kirstine G} and Have, {Christian Theil} and Izarzugaza, {Jose M. G.} and Marie Grosjean and Jette Bork-Jensen and Jakob Grove and Als, {Thomas D.} and Shujia Huang and Yuqi Chang and Ruiqi Xu and Weijian Ye and Junhua Rao and Xiaosen Guo and Jihua Sun and Hongzhi Cao and Chen Ye and Beusekom, {Johan V.} and Thomas Espeseth and Esben Flindt and Halager, {Anders E.} and Hellard, {Stephanie Le} and Hultman, {Christina M.} and Francesco Lescai and Shengting Li and Ole Lund and Peter L{\o}ngren and Matey-Hernandez, {Maria Luisa} and Ole Mors and Pedersen, {Christian N. S.} and Thomas Sicheritz-Pont{\'e}n and Patrick Sullivan and Ali Syed and David Westergaard and Rachita Yadav and Ning Li and Xun Xu and Torben Hansen and Lars Bolund and Anders Krogh and S{\o}rensen, {Thorkild I. A.} and Pedersen, {Oluf Borbye} and Ramneek Gupta and Simon Rasmussen and B{\o}rglum, {Anders D.} and Jun Wang and Eiberg, {Hans Rudolf Lytchoff} and Karsten Kristiansen and S{\o}ren Brunak and Schierup, {Mikkel Heide}",

year = "2017",

month = sep,

doi = "10.1101/gr.218891.116",

language = "English",

volume = "27",

pages = "1597--1607",

journal = "Genome Research",

issn = "1088-9051",

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TY - JOUR

T1 - Assembly and analysis of 100 full MHC haplotypes from the Danish population

AU - Jensen, Jacob M.

AU - Villesen, Palle

AU - Friborg, Rune M.

AU - Mailund, Thomas

AU - Besenbacher, Søren

AU - Sørensen, Lasse Maretty

AU - Petersen, Bent

AU - Sibbesen, Jonas Andreas

AU - Liu, Siyang

AU - Skov, Laurits

AU - Belling, Kirstine G

AU - Have, Christian Theil

AU - Izarzugaza, Jose M. G.

AU - Grosjean, Marie

AU - Bork-Jensen, Jette

AU - Grove, Jakob

AU - Als, Thomas D.

AU - Huang, Shujia

AU - Chang, Yuqi

AU - Xu, Ruiqi

AU - Ye, Weijian

AU - Rao, Junhua

AU - Guo, Xiaosen

AU - Sun, Jihua

AU - Cao, Hongzhi

AU - Ye, Chen

AU - Beusekom, Johan V.

AU - Espeseth, Thomas

AU - Flindt, Esben

AU - Halager, Anders E.

AU - Hellard, Stephanie Le

AU - Hultman, Christina M.

AU - Lescai, Francesco

AU - Li, Shengting

AU - Lund, Ole

AU - Løngren, Peter

AU - Matey-Hernandez, Maria Luisa

AU - Mors, Ole

AU - Pedersen, Christian N. S.

AU - Sicheritz-Pontén, Thomas

AU - Sullivan, Patrick

AU - Syed, Ali

AU - Westergaard, David

AU - Yadav, Rachita

AU - Li, Ning

AU - Xu, Xun

AU - Hansen, Torben

AU - Bolund, Lars

AU - Krogh, Anders

AU - Sørensen, Thorkild I. A.

AU - Pedersen, Oluf Borbye

AU - Gupta, Ramneek

AU - Rasmussen, Simon

AU - Børglum, Anders D.

AU - Wang, Jun

AU - Eiberg, Hans Rudolf Lytchoff

AU - Kristiansen, Karsten

AU - Brunak, Søren

AU - Schierup, Mikkel Heide

PY - 2017/9

Y1 - 2017/9

N2 - Genes in the major histocompatibility complex (MHC, also known as HLA) play a critical role in the immune response and variation within the extended 4-Mb region shows association with major risks of many diseases. Yet, deciphering the underlying causes of these associations is difficult because the MHC is the most polymorphic region of the genome with a complex linkage disequilibrium structure. Here, we reconstruct full MHC haplotypes from de novo assembled trios without relying on a reference genome and perform evolutionary analyses. We report 100 full MHC haplotypes and call a large set of structural variants in the regions for future use in imputation with GWAS data. We also present the first complete analysis of the recombination landscape in the entire region and show how balancing selection at classical genes have linked effects on the frequency of variants throughout the region.

AB - Genes in the major histocompatibility complex (MHC, also known as HLA) play a critical role in the immune response and variation within the extended 4-Mb region shows association with major risks of many diseases. Yet, deciphering the underlying causes of these associations is difficult because the MHC is the most polymorphic region of the genome with a complex linkage disequilibrium structure. Here, we reconstruct full MHC haplotypes from de novo assembled trios without relying on a reference genome and perform evolutionary analyses. We report 100 full MHC haplotypes and call a large set of structural variants in the regions for future use in imputation with GWAS data. We also present the first complete analysis of the recombination landscape in the entire region and show how balancing selection at classical genes have linked effects on the frequency of variants throughout the region.

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U2 - 10.1101/gr.218891.116

DO - 10.1101/gr.218891.116

M3 - Journal article

C2 - 28774965

AN - SCOPUS:85028744509

SN - 1088-9051

VL - 27

SP - 1597

EP - 1607

JO - Genome Research

JF - Genome Research

IS - 9

ER -

Assembly and analysis of 100 full MHC haplotypes from the Danish population

Abstract

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