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Meiotic recombinations within major histocompatibility complex of human embryos

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Abstract

We studied the rate and pattern of recombinations within the extended major histocompatibility complex (MHC) locus of the human embryos obtained during preimplantation genetic diagnosis (PGD) for HLA compatibility. Recombinant allele frequency was on average 5.33 %, and recombination rate was 0.44 cM/Mb in the 12.2 Mb of the extended MHC locus. Recombination rate varied up to 14-fold (0.19–2.73 cM/Mb) between cases, and maternal recombination rate was on average 3.8 times higher than paternal alleles. More than 69 % of the recombination hot spots were clustered within the extended class II region where the recombination rate was 5.4 times more than that in extended class I region. These findings indicate the potential of PGD to study the mechanisms of linkage disequilibrium within MHC locus of human embryos, demonstrate the recombination characteristics within extended MHC loci of human embryos in comparison to sperm and family studies, and point to the significance of design and interpretation of PGD for HLA compatibility to avoid misdiagnosis because of meiotic recombinations.

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References

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Berg IL, Neumann R, Sarbajna S, Odenthal-Hesse L, Butler NJ, Jeffreys AJ (2011) Variants of the protein PRDM9 differentially regulate a set of human meiotic recombination hotspots highly active in African populations. Proc Natl Acad Sci U S A 108:12378–12383

    Article  PubMed  CAS  Google Scholar 

  • Broman KW, Murray JC, Sheffield VC, White RL, Weber JL (1998) Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am J Hum Genet 63:861–869

    Article  PubMed  CAS  Google Scholar 

  • Carrington M, Stephens JC, Klitz W, Begovich AB, Erlich HA, Mann D (1994) Major histocompatibility complex class II haplotypes and linkage disequilibrium values observed in the CEPH families. Hum Immunol 41:234–240

    Article  PubMed  CAS  Google Scholar 

  • Carrington M (1999) Recombination within the human MHC. Immunol Rev 167:245–256

    Article  PubMed  CAS  Google Scholar 

  • Chowdhury R, Bois PR, Feingold E, Sherman SL, Cheung VG (2009) Genetic analysis of variation in human meiotic recombination. PLoS Genet 5:e1000648

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Crawford DC, Bhangale T, Li N, Hellenthal G, Rieder MJ, Nickerson DA, Stephens M (2004) Evidence for substantial fine-scale variation in recombination rates across the human genome. Nat Genet 36:700–706

    Article  PubMed  CAS  Google Scholar 

  • Cullen M, Erlich H, Klitz W, Carrington M (1995) Molecular mapping of a recombination hotspot located in the second intron of the human TAP2 locus. Am J Hum Genet 56:1350–1358

    PubMed  CAS  Google Scholar 

  • Cullen M, Noble J, Erlich H, Thorpe K, Beck S, Klitz W, Trowsdale J, Carrington M (1997) Characterization of recombination in the HLA class II region. Am J Hum Genet 60:397–407

    PubMed  CAS  Google Scholar 

  • Cullen M, Perfetto SP, 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

    Article  PubMed  Google Scholar 

  • Fiorentino F, Kahraman S, Karadayi H, Biricik A, Sertyel S, Karlikaya G, Saglam Y, Podini D, Nuccitelli A, Baldi M (2005) Short tandem repeats haplotyping of the HLA region in preimplantation HLA matching. Eur J Hum Genet 13:953–958

    Article  PubMed  CAS  Google Scholar 

  • Hinch AG, Tandon A, Patterson N, Song Y, Rohland N, Palmer CD, Chen GK, Wang K et al (2011) The landscape of recombination in African Americans. Nature 476:170–175

    Article  PubMed  CAS  Google Scholar 

  • International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437:1299–1320

    Article  Google Scholar 

  • International HapMap 3 Consortium (2010) Integrating common and rare genetic variation in diverse human populations. Nature 467:52–58

    Article  Google Scholar 

  • Jeffreys AJ, Kauppi L, Neumann R (2001) Intensely punctate meiotic recombination in the class II region of the major histocompatibility complex. Nat Genet 29:217–222

    Article  PubMed  CAS  Google Scholar 

  • Jeffreys AJ, Ritchie A, Neumann R (2000) High resolution analysis of haplotype diversity and meiotic crossover in the human TAP2 recombination hotspot. Hum Mol Genet 9:725–733

    Article  PubMed  CAS  Google Scholar 

  • Jeffreys AJ, Neumann R, Panayi M, Myers S, Donnelly P (2005) Human recombination hot spots hidden in regions of strong marker association. Nat Genet 37:601–606

    Article  PubMed  CAS  Google Scholar 

  • Keinan A, Reich D (2010) Human population differentiation is strongly correlated with local recombination rate. PLoS Genet 6:e1000886

    Article  PubMed  Google Scholar 

  • Khakoo SI, Carrington M (2006) KIR and disease: a model system or system of models? Immunol Rev 214:186–201

    Article  PubMed  CAS  Google Scholar 

  • Khil PP, Camerini-Otero RD (2010) Genetic crossovers are predicted accurately by the computed human recombination map. PLoS Genet 6:e1000831

    Article  PubMed  Google Scholar 

  • Koeleman BP, Lie BA, Undlien DE, Dudbridge F, Thorsby E, de Vries RR, Cucca F, Roep BO, Giphart MJ, Todd JA (2004) Genotype effects and epistasis in type 1 diabetes and HLA-DQ trans dimer associations with disease. Genes Immun 5:381–388

    Article  PubMed  CAS  Google Scholar 

  • Kong A, Gudbjartsson DF, Sainz J, Jonsdottir GM, Gudjonsson SA, Richardsson B, Sigurdardottir S, Barnard J, Hallbeck B, Masson G, Shlien A, Palsson ST, Frigge ML, Thorgeirsson TE, Gulcher JR, Stefansson K (2002) A high-resolution recombination map of the human genome. Nat Genet 31:241–247

    PubMed  CAS  Google Scholar 

  • Kong E, Thorleifsson G, Gudbjartsson DF, Masson G, Sigurdsson A, Jonasdottir A, Bragi Walters G, Jonasdottir A, Gylfason A, Kristinsson KT, Gudjonsson SA, Frigge ML, Helgason A, Thorsteinsdottir U, Stefansson K (2010) Fine-scale recombination rate differences between sexes, populations and individuals. Nature 467:1099–1103

    Article  PubMed  CAS  Google Scholar 

  • Kong A, Thorleifsson G, Stefansson H, Masson G, Helgason A, Gudbjartsson DF, Jonsdottir GM, Gudjonsson SA, Sverrisson S, Thorlacius T, Jonasdottir A, Hardarson GA, Palsson ST, Frigge ML, Gulcher JR, Thorsteinsdottir U, Stefansson K (2008) Sequence variants in the RNF212 gene associate with genome-wide recombination rate. Science 319:1398–1401

    Article  PubMed  CAS  Google Scholar 

  • Martin M, Mann D, Carrington M (1995) Recombination rates across the HLA complex: use of microsatellites as a rapid screen for recombinant chromosomes. Hum Mol Genet 4:423–428

    Article  PubMed  CAS  Google Scholar 

  • McVean GA, Myers SR, Hunt S, Deloukas P, Bentley DR, Donnelly P (2004) The fine-scale structure of recombination rate variation in the human genome. Science 304:581–584

    Article  PubMed  CAS  Google Scholar 

  • Myers S, Bowden R, Tumian A, Bontrop RE, Freeman C, MacFie TS, McVean G, Donnelly P (2010) Drive against hotspot motifs in primates implicates the PRDM9 gene in meiotic recombination. Science 327:876–879

    Article  PubMed  CAS  Google Scholar 

  • Parham P (2005) MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol 5:201–214

    Article  PubMed  CAS  Google Scholar 

  • Parvanov ED, Petkov PM, Paigen K (2010) Prdm9 controls activation of mammalian recombination hotspots. Science 327:835

    Article  PubMed  CAS  Google Scholar 

  • Roeder GS (1997) Meiotic chromosomes: it takes two to tango. Genes Dev 11:2600–2621

    Article  PubMed  CAS  Google Scholar 

  • Sanchez-Mazas A, Djoulah S, Busson M, Monnier L, de Gouville I, Poirier JC, Dehay C, Charron D, Excoffier L, Schneider S, Langaney A, Dausset J, Hors J (2000) A linkage disequilibrium map of the MHC region based on the analysis of 14 loci haplotypes in 50 French families. Eur J Hum Genet 8:33–41

    Article  PubMed  CAS  Google Scholar 

  • Stefansson H, Helgason A, Thorleifsson G, Steinthorsdottir V, Masson G, Barnard J, Baker A, Jonasdottir A, Ingason A, Gudnadottir VG, Desnica N, Hicks A, Gylfason A, Gudbjartsson DF, Jonsdottir GM, Sainz J, Agnarsson K, Birgisdottir B, Ghosh S, Olafsdottir A, Cazier JB, Kristjansson K, Frigge ML, Thorgeirsson TE, Gulcher JR, Kong A, Stefansson K (2005) A common inversion under selection in Europeans. Nat Genet 37:129–137

    Article  PubMed  CAS  Google Scholar 

  • Thomsen M, Neugebauer M, Arnaud J, Borot N, Sevin A, Baur M, Cambon-Thomsen A (1994) Recombination fractions in the HLA system based on the data set “provinces Françaises”: indications of haplotype-specific recombination rates. Eur J Immunogenet 21:33–43

    Article  PubMed  CAS  Google Scholar 

  • Traherne JA (2008) Human MHC architecture and evolution: implications for disease association studies. Int J Immunogenet 35:179–192

    Article  PubMed  CAS  Google Scholar 

  • Van de Velde H, De Rycke M, De Man C, De Hauwere K, Fiorentino F, Kahraman S, Pennings G, Verpoest W, Devroey P, Liebaers I (2009) The experience of two European preimplantation genetic diagnosis centres on human leukocyte antigen typing. Hum Reprod 24:732–740

    Article  PubMed  Google Scholar 

  • van Endert PM, Lopez MT, Patel SD, Monaco JJ, McDevitt HO (1992) Genomic polymorphism, recombination, and linkage disequilibrium in human major histocompatibility complex-encoded antigen-processing genes. Proc Natl Acad Sci U S A 89:11594–11597

    Article  PubMed  Google Scholar 

  • Vandiedonck C, Knight JC (2009) The human major histocompatibility complex as a paradigm in genomics research. Brief Funct Genomics Proteomics 8:379–394

    Article  CAS  Google Scholar 

  • Verlinsky Y, Rechitsky S, Sharapova T, Morris R, Taranissi M, Kuliev A (2004) Preimplantation HLA testing. JAMA 291:2079–2085

    Article  PubMed  CAS  Google Scholar 

  • Yu J, Lazzeroni L, Qin J, Huang MM, Navidi W, Erlich H, Arnheim N (1996) Individual variation in recombination among human males. Am J Hum Genet 59:1186–1192

    PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Dr. Engin Oral and Dr. Necati Findikli at Istanbul International Hospital for providing IVF embryos.

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Correspondence to Ender Altiok.

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Taylan, F., Altiok, E. Meiotic recombinations within major histocompatibility complex of human embryos. Immunogenetics 64, 839–844 (2012). https://doi.org/10.1007/s00251-012-0644-y

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