Recombination and mutation shape variations in the major histocompatibility complex

Yuying Sun; Fang Yuan; Ling Wang; Dongfa Dai; Zhijian Zhang; Fei Liang; Nan Liu; Juan Long; Xiao Zhao; Yongzhi Xi

doi:10.1016/j.jgg.2022.03.006

Volume 49 Issue 12

Dec. 2022

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Article Navigation > Journal of Genetics and Genomics > 2022 > 49(12): 1151-1161

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Recombination and mutation shape variations in the major histocompatibility complex

doi: 10.1016/j.jgg.2022.03.006

a. Department of Immunology and National Immunoassay Laboratory, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China;
b. Institute of Beijing 307 Hospital, Anhui Medical University, Hefei, Anhui 230032, China

Funds:

This research was supported by grants from the National Key Basic Research Development Program of China (grants No. 2009CB522401 and 2003CB515509, and AWS14C014) to Y. X. and Y. S. We would like to thank Hongzhi Cao, Xuehan Zhuang, Tao Zhang, Xiaomin Liu, Xiao Liu, Yuanwei Zhang, Rui Ye, Hui Jiang, Jing Hua Wu, and Xun Xu at the BGI-Shenzhen for their assistance with the sequencing and bioinformatics analysis.

Received Date: 2021-09-18
Accepted Date: 2022-03-08
Rev Recd Date: 2022-03-07
Publish Date: 2022-03-28

Abstract

Abstract

The major histocompatibility complex (MHC) is closely associated with numerous diseases, but its high degree of polymorphism complicates the discovery of disease-associated variants. In principle, recombination and de novo mutations are two critical factors responsible for MHC polymorphisms. However, direct evidence for this hypothesis is lacking. Here, we report the generation of fine-scale MHC recombination and de novo mutation maps of ∼5 Mb by deep sequencing (> 100×) of the MHC genome for 17 MHC recombination and 30 non-recombination Han Chinese families (a total of 190 individuals). Recombination hotspots and Han-specific breakpoints are located in close proximity at haplotype block boundaries. The average MHC de novo mutation rate is higher than the genome-wide de novo mutation rate, particularly in MHC recombinant individuals. Notably, mutation and recombination generated polymorphisms are located within and outside linkage disequilibrium regions of the MHC, respectively, and evolution of the MHC locus was mainly controlled by positive selection. These findings provide insights on the evolutionary causes of the MHC diversity and may facilitate the identification of disease-associated genetic variants.
- Major histocompatibility complex (MHC),
- Recombination,
- De novo mutation,
- Positive selection,
- Disease-associated genetic variants

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References

Allcock, R.J., 2012. The major histocompatibility complex: a paradigm for studies of the human genome. Methods. Mol. Biol. 882, 1-7

Allcock, R.J., Atrazhev, A.M., Beck, S., de Jong, P.J., Elliott, J.F., Forbes, S., Halls, K., Horton, R., Osoegawa, K., Rogers, J., Sawcer, S., Todd, J.A., Trowsdale, J., Wang, Y., Williams, S., 2002. The MHC haplotype project: a resource for HLA-linked association studies. Tissue Antigens 59, 520-521

Barrett, J.C., Fry, B., Maller, J., Daly, M.J., 2005. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263-265

Baudat, F., Buard, J., Grey, C., Fledel-Alon, A., Ober, C., Przeworski, M., Coop, G., de Massy, B., 2010. PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice. Science 327, 836-840

Berg, I.L., Neumann, R., Lam, K.W., Sarbajna, S., Odenthal-Hesse, L., May, C.A., Jeffreys, A.J., 2010. PRDM9 variation strongly influences recombination hot-spot activity and meiotic instability in humans. Nat. Genet. 42, 859-863

Blaha, D.T., Anderson, S.D., Yoakum, D.M., Hager, M.V., Zha, Y., Gajewski, T.F., Kranz, D.M., 2019. High-throughput stability screening of neoantigen/HLA complexes improves immunogenicity predictions. Cancer Immunol. Res. 7, 50-61

Browning, S.R., Browning, B.L., 2007. Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. Am. J. Hum. Genet. 81, 1084-1097

Cao, H., Wu, J., Wang, Y., Jiang, H., Zhang, T., Liu, X., Xu, Y., Liang, D., Gao, P., Sun, Y., Gifford, B., D'Ascenzo, M., Liu, X., Tellier, L.C., Yang, F., Tong, X., Chen, D., Zheng, J., Li, W., Richmond, T., Xu, X., Wang, J., Li, Y., 2013. An integrated tool to study MHC region: accurate SNV detection and HLA genes typing in human MHC region using targeted high-throughput sequencing. PLoS One 8, e69388

Carrington, M., 1999. Recombination within the human MHC. Immunol. Rev. 167, 245-256

Conrad, D.F., Keebler, J.E., DePristo, M.A., Lindsay, S.J., Zhang, Y., Casals, F., Idaghdour, Y., Hartl, C.L., Torroja, C., Garimella, K.V., Zilversmit, M., Cartwright, R., Rouleau, G.A., Daly, M., Stone, E.A., Hurles, M.E., Awadalla, P., Genomes, P., 2011. Variation in genome-wide mutation rates within and between human families. Nat. Genet. 43, 712-714

Coop, G., Wen, X., Ober, C., Pritchard, J.K., Przeworski, M., 2008. High-resolution mapping of crossovers reveals extensive variation in fine-scale recombination patterns among humans. Science 319, 1395-1398

Cullen, M., Perfetto, S.P., Klitz, W., Nelson, G., Carrington, M., 2002. High-resolution patterns of meiotic recombination across the human major histocompatibility complex. Am. J. Hum. Genet. 71, 759-776

de Bakker, P.I., McVean, G., Sabeti, P.C., Miretti, M.M., Green, T., Marchini, J., Ke, X., Monsuur, A.J., Whittaker, P., Delgado, M., Morrison, J., Richardson, A., Walsh, E.C., Gao, X., Galver, L., Hart, J., Hafler, D.A., Pericak-Vance, M., Todd, J.A., Daly, M.J., Trowsdale, J., Wijmenga, C., Vyse, T.J., Beck, S., Murray, S.S., Carrington, M., Gregory, S., Deloukas, P., Rioux, J.D., 2006. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat. Genet. 38, 1166-1172

de Bakker, P.I., Yelensky, R., Pe'er, I., Gabriel, S.B., Daly, M.J., Altshuler, D., 2005. Efficiency and power in genetic association studies. Nat. Genet. 37, 1217-1223

Dendrou, C.A., Petersen, J., Rossjohn, J., Fugger, L., 2018. HLA variation and disease. Nat. Rev. Immunol. 18, 325-339

Excoffier, L., Laval, G., Schneider, S., 2007. Arlequin (version 3.0): an integrated software package for population genetics data analysis. Evol. Bioinform. Online 1, 47-50

Francioli, L.C., Polak, P.P., Koren, A., Menelaou, A., Chun, S., Renkens, I., Genome of the Netherlands, C., van Duijn, C.M., Swertz, M., Wijmenga, C., van Ommen, G., Slagboom, P.E., Boomsma, D.I., Ye, K., Guryev, V., Arndt, P.F., Kloosterman, W.P., de Bakker, P.I.W., Sunyaev, S.R., 2015. Genome-wide patterns and properties of de novo mutations in humans. Nat. Genet. 47, 822-826

Fry, B.J., 2005. Computational information design

Gragert, L., Madbouly, A., Freeman, J., Maiers, M., 2013. Six-locus high resolution HLA haplotype frequencies derived from mixed-resolution DNA typing for the entire US donor registry. Hum. Immunol. 74, 1313-1320

Hinch, A.G., Tandon, A., Patterson, N., Song, Y., Rohland, N., Palmer, C.D., Chen, G.K., Wang, K., Buxbaum, S.G., Akylbekova, E.L., Aldrich, M.C., Ambrosone, C.B., Amos, C., Bandera, E.V., Berndt, S.I., Bernstein, L., Blot, W.J., Bock, C.H., Boerwinkle, E., Cai, Q., Caporaso, N., Casey, G., Cupples, L.A., Deming, S.L., Diver, W.R., Divers, J., Fornage, M., Gillanders, E.M., Glessner, J., Harris, C.C., Hu, J.J., Ingles, S.A., Isaacs, W., John, E.M., Kao, W.H., Keating, B., Kittles, R.A., Kolonel, L.N., Larkin, E., Le Marchand, L., McNeill, L.H., Millikan, R.C., Murphy, A., Musani, S., Neslund-Dudas, C., Nyante, S., Papanicolaou, G.J., Press, M.F., Psaty, B.M., Reiner, A.P., Rich, S.S., Rodriguez-Gil, J.L., Rotter, J.I., Rybicki, B.A., Schwartz, A.G., Signorello, L.B., Spitz, M., Strom, S.S., Thun, M.J., Tucker, M.A., Wang, Z., Wiencke, J.K., Witte, J.S., Wrensch, M., Wu, X., Yamamura, Y., Zanetti, K.A., Zheng, W., Ziegler, R.G., Zhu, X., Redline, S., Hirschhorn, J.N., Henderson, B.E., Taylor, H.A., Jr., Price, A.L., Hakonarson, H., Chanock, S.J., Haiman, C.A., Wilson, J.G., Reich, D., Myers, S.R., 2011. The landscape of recombination in African Americans. Nature 476, 170-175

Horton, R., Gibson, R., Coggill, P., Miretti, M., Allcock, R.J., Almeida, J., Forbes, S., Gilbert, J.G., Halls, K., Harrow, J.L., Hart, E., Howe, K., Jackson, D.K., Palmer, S., Roberts, A.N., Sims, S., Stewart, C.A., Traherne, J.A., Trevanion, S., Wilming, L., Rogers, J., de Jong, P.J., Elliott, J.F., Sawcer, S., Todd, J.A., Trowsdale, J., Beck, S., 2008. Variation analysis and gene annotation of eight MHC haplotypes: the MHC Haplotype Project. Immunogenetics 60, 1-18

Jeffreys, A.J., Kauppi, L., Neumann, R., 2001. Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat. Genet. 29, 217-222

Jeffreys, A.J., May, C.A., 2004. Intense and highly localized gene conversion activity in human meiotic crossover hot spots. Nat. Genet. 36, 151-156

Jonsson, H., Sulem, P., Kehr, B., Kristmundsdottir, S., Zink, F., Hjartarson, E., Hardarson, M.T., Hjorleifsson, K.E., Eggertsson, H.P., Gudjonsson, S.A., Ward, L.D., Arnadottir, G.A., Helgason, E.A., Helgason, H., Gylfason, A., Jonasdottir, A., Jonasdottir, A., Rafnar, T., Frigge, M., Stacey, S.N., Th Magnusson, O., Thorsteinsdottir, U., Masson, G., Kong, A., Halldorsson, B.V., Helgason, A., Gudbjartsson, D.F., Stefansson, K., 2017. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature 549, 519-522

Kishore, A., Petrek, M., 2018. Next-generation sequencing based HLA typing: deciphering immunogenetic aspects of sarcoidosis. Front Genet. 9, 503

Knight, J., Spain, S.L., Capon, F., Hayday, A., Nestle, F.O., Clop, A., Wellcome Trust Case Control, C., Genetic Analysis of Psoriasis, C., Consortium, I.c.f.P., Barker, J.N., Weale, M.E., Trembath, R.C., 2012. Conditional analysis identifies three novel major histocompatibility complex loci associated with psoriasis. Hum. Mol. Genet. 21, 5185-5192

Kong, A., Frigge, M.L., Masson, G., Besenbacher, S., Sulem, P., Magnusson, G., Gudjonsson, S.A., Sigurdsson, A., Jonasdottir, A., Jonasdottir, A., Wong, W.S., Sigurdsson, G., Walters, G.B., Steinberg, S., Helgason, H., Thorleifsson, G., Gudbjartsson, D.F., Helgason, A., Magnusson, O.T., Thorsteinsdottir, U., Stefansson, K., 2012. Rate of de novo mutations and the importance of father's age to disease risk. Nature 488, 471-475

Kong, A., Thorleifsson, G., Gudbjartsson, D.F., Masson, G., Sigurdsson, A., Jonasdottir, A., Walters, G.B., Jonasdottir, A., Gylfason, A., Kristinsson, K.T., Gudjonsson, S.A., Frigge, M.L., Helgason, A., Thorsteinsdottir, U., Stefansson, K., 2010. Fine-scale recombination rate differences between sexes, populations and individuals. Nature 467, 1099-1103

Koskela, S., Ritari, J., Hyvarinen, K., Kwan, T., Niittyvuopio, R., Itala-Remes, M., Pastinen, T., Partanen, J., 2018. Hidden genomic MHC disparity between HLA-matched sibling pairs in hematopoietic stem cell transplantation. Sci. Rep. 8, 5396

Lechler, R., Warrens, A., 1999. HLA in health & disease

Liu, X., Ong, R.T., Pillai, E.N., Elzein, A.M., Small, K.S., Clark, T.G., Kwiatkowski, D.P., Teo, Y.Y., 2013. Detecting and characterizing genomic signatures of positive selection in global populations. Am. J. Hum. Genet. 92, 866-881

Lobkovsky, A.E., Levi, L., Wolf, Y.I., Maiers, M., Gragert, L., Alter, I., Louzoun, Y., Koonin, E.V., 2019. Multiplicative fitness, rapid haplotype discovery, and fitness decay explain evolution of human MHC. Proc. Natl. Acad. Sci. U S A 116, 14098-14104

McVean, G.A., Myers, S.R., Hunt, S., Deloukas, P., Bentley, D.R., Donnelly, P., 2004. The fine-scale structure of recombination rate variation in the human genome. Science 304, 581-584

Miretti, M.M., Walsh, E.C., Ke, X., Delgado, M., Griffiths, M., Hunt, S., Morrison, J., Whittaker, P., Lander, E.S., Cardon, L.R., Bentley, D.R., Rioux, J.D., Beck, S., Deloukas, P., 2005. A high-resolution linkage-disequilibrium map of the human major histocompatibility complex and first generation of tag single-nucleotide polymorphisms. Am. J. Hum. Genet. 76, 634-646

Morishima, Y., Kashiwase, K., Matsuo, K., Azuma, F., Morishima, S., Onizuka, M., Yabe, T., Murata, M., Doki, N., Eto, T., Mori, T., Miyamura, K., Sao, H., Ichinohe, T., Saji, H., Kato, S., Atsuta, Y., Kawa, K., Kodera, Y., Sasazuki, T., Japan Marrow Donor, P., 2015. Biological significance of HLA locus matching in unrelated donor bone marrow transplantation. Blood 125, 1189-1197

Myers, S., Bottolo, L., Freeman, C., McVean, G., Donnelly, P., 2005. A fine-scale map of recombination rates and hotspots across the human genome. Science 310, 321-324

Myers, S., Freeman, C., Auton, A., Donnelly, P., McVean, G., 2008. A common sequence motif associated with recombination hot spots and genome instability in humans. Nat. Genet. 40, 1124-1129

Nei, M., 1987. Molecular Evolutionary Genetics Columbia Univ. Press, New York

Paul, P., Nag, D., Chakraborty, S., 2016. Recombination hotspots: Models and tools for detection. DNA Repair (Amst) 40, 47-56

Sabeti, P.C., Reich, D.E., Higgins, J.M., Levine, H.Z., Richter, D.J., Schaffner, S.F., Gabriel, S.B., Platko, J.V., Patterson, N.J., McDonald, G.J., Ackerman, H.C., Campbell, S.J., Altshuler, D., Cooper, R., Kwiatkowski, D., Ward, R., Lander, E.S., 2002. Detecting recent positive selection in the human genome from haplotype structure. Nature 419, 832-837

Saxena, A., McDonnell, E., Ramos, P.S., Sajuthi, S., Marion, M.C., Langefeld, C.D., Buyon, J.P., Clancy, R.M., 2012. Preferential transmission of genetic risk variants of candidate loci at 6p21 from asymptomatic grandparents to mothers of children with neonatal lupus. Arthritis Rheum. 64, 931-939

Shiina, T., Hosomichi, K., Inoko, H., Kulski, J.K., 2009. The HLA genomic loci map: expression, interaction, diversity and disease. J. Hum. Genet. 54, 15-39

Sun, Y., Kong, F., Ren, S., Yuan, F., Liang, F., Liu, N., Jin, L., Xi, Y., 2007. Severe acute graft-vs-host disease in a patient with acute monocytic leukemia having a recombination event between HLA-A/B loci from a multiple recombinant family. Tissue Antigens 70, 499-505

Tamura, K., Peterson, D., Peterson, N., Stecher, G., Nei, M., Kumar, S., 2011. MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol. Biol. Evol. 28, 2731-2739

Traherne, J.A., Horton, R., Roberts, A.N., Miretti, M.M., Hurles, M.E., Stewart, C.A., Ashurst, J.L., Atrazhev, A.M., Coggill, P., Palmer, S., Almeida, J., Sims, S., Wilming, L.G., Rogers, J., de Jong, P.J., Carrington, M., Elliott, J.F., Sawcer, S., Todd, J.A., Trowsdale, J., Beck, S., 2006. Genetic analysis of completely sequenced disease-associated MHC haplotypes identifies shuffling of segments in recent human history. PLoS Genet. 2, e9

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