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Analysis of archaic human haplotypes suggest 5-hmC to act as epigenetic guide for meiotic point recombination

Bernett Lee, Samantha Cyrill, Wendy Lee, Rosella Melchiotti, Anand Andiappan, Michael Poidinger, Olaf Rötzschke
doi: https://doi.org/10.1101/227702
Bernett Lee
1Singapore Immunology Network (SIgN), Agency of Science Technology and Research (A*STAR), 8A Biomedical Drive, Singapore 138648;
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Samantha Cyrill
1Singapore Immunology Network (SIgN), Agency of Science Technology and Research (A*STAR), 8A Biomedical Drive, Singapore 138648;
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Wendy Lee
1Singapore Immunology Network (SIgN), Agency of Science Technology and Research (A*STAR), 8A Biomedical Drive, Singapore 138648;
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Rosella Melchiotti
1Singapore Immunology Network (SIgN), Agency of Science Technology and Research (A*STAR), 8A Biomedical Drive, Singapore 138648;
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Anand Andiappan
1Singapore Immunology Network (SIgN), Agency of Science Technology and Research (A*STAR), 8A Biomedical Drive, Singapore 138648;
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Michael Poidinger
1Singapore Immunology Network (SIgN), Agency of Science Technology and Research (A*STAR), 8A Biomedical Drive, Singapore 138648;
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Olaf Rötzschke
1Singapore Immunology Network (SIgN), Agency of Science Technology and Research (A*STAR), 8A Biomedical Drive, Singapore 138648;
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  • For correspondence: bernett_lee@immunol.a-star.edu.sg samanthacyrril@u.nus.edu wendy_lee@immunol.a-star.edu.sg rossella.melchiotti@kcl.ac.uk anand_andiappan@immunol.a-star.edu.sg Michael_Poidinger@immunol.a-star.edu.sg Olaf_Rotzschke@immunol.a-star.edu.sg
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Abstract

Meiotic “point recombination” refers to homologue recombination events affecting only individual SNPs. Driven mostly by gene conversion, it is common process that allows for a gradual adaptation and maturation of haplotypes during genetic evolution. In contrast to crossover recombination it is not tied to predetermined recombination sites and therefore assumed to occur largely randomly. Our analysis of archaic human haplotypes however revealed striking differences in the local point recombination rate. A linkage-study of 1.9 million SNPs defined by the sequence of denisovan hominids revealed low rates in introns and quiescent intergenic regions but high rates in splice sites, exons, 5’- and 3’-UTRs, and CpG islands. Correlations with ChIP-Seq tracks from ENCODE and other public sources identified a number of epigenetic modifications, that associated directly with these recombination events. A particularly tight association was observed for 5-hydroxymethylcytosine marks (5hmC). The mark was enriched in virtually all of the functional regions associated with elevated point recombination rates, including CpG islands and ‘poised’ bivalent regions. As intermediate of oxidative demethylation, 5hmC is also a marker of recently opened gene loci. The data, thus, supports a model of ‘guided’ evolution, in which point recombination is directed by 5hmC marks towards the functionally relevant regions.

  • List of abbreviations

    5hmC
    5-hydroxymethylcytosine
    5mC
    5-methylcytosine
    BivFlank
    Bivalent flanking region
    bp
    Base-pairs
    CGI
    CpG Islands
    ChIP-seq
    Chromatin Immunoprecipitation and Sequencing
    CO
    Crossover
    DDR
    DNA damage repair
    Denisovan h
    Denisovan hominid
    DMC1
    Meiotic recombination protein, RecA homolog
    ENCODE
    Encyclopedia of DNA elements
    EnhBiv
    Bivalent enhancer
    fa
    Absolute frequency of derived alleles
    FitCons
    Fitness consequence
    GWAVA
    Genome-wide annotation of variants
    H. sapiens
    Homo sapiens
    hap
    Core haplotype
    HLA
    Human Leukocyte Antigen
    kb
    Kilo-basepairs
    LD
    Linkage disequilibrium
    LWK
    Luhya from Webuye, Kenya
    MHC
    Major Histocompatibility Complex
    NCO
    Non-Crossover
    PRC2
    Polycomb repressive complex 2
    ReprPC
    Polycomb Repressed Regions
    ReprPCWk
    Weak Polycomb Repressed Regions
    SNP
    Single Nucleotide Polymorphism
    TEI
    Transgenerational Epigenetic Inheritence
    TSS
    Transcriptional start site
    TssBiv
    Bivalent transcriptional start site
    Tx
    Transcribed Region
    TxFlank
    Flanking a transcribed region
    TxWk
    Weakly transcribed region
    UTR
    Untranslated Region
    ZNF
    Zinc Finger
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    Posted December 02, 2017.
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    Analysis of archaic human haplotypes suggest 5-hmC to act as epigenetic guide for meiotic point recombination
    Bernett Lee, Samantha Cyrill, Wendy Lee, Rosella Melchiotti, Anand Andiappan, Michael Poidinger, Olaf Rötzschke
    bioRxiv 227702; doi: https://doi.org/10.1101/227702
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    Analysis of archaic human haplotypes suggest 5-hmC to act as epigenetic guide for meiotic point recombination
    Bernett Lee, Samantha Cyrill, Wendy Lee, Rosella Melchiotti, Anand Andiappan, Michael Poidinger, Olaf Rötzschke
    bioRxiv 227702; doi: https://doi.org/10.1101/227702

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