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Human Common Haplotypes Carry Signatures of “Great Admixture” between Ancient Lineages and GC-Biased Gene Conversion

Dutta, Rajib
http://rave.ohiolink.edu/etdc/view?acc_num=mco1507810392963753

Abstract Details

2017, Doctor of Philosophy (PhD), University of Toledo, Biomedical Sciences (Molecular Medicine).
This dissertation is comprised of two chapters based on different projects. Chapter 1 focuses on a large-scale bioinformatics computation of the 1000 Genomes database to investigate the origin of modern human beings. Our group has previously shown that clusters of very rare SNPs are unique and powerful markers of genetic relatedness between and within populations. In the current study, we study the more frequent SNPs and their non-random arrangement in haplotypes to uncover events leading to the creation of modern human beings. Inferring history from genomic sequences is challenging and problematic because chromosomes are mosaics of thousands of small Identical-by-descent (IBD) fragments, each of them having their own unique story. However, the main events in recent evolution can be deciphered from comparative analysis of numerous loci. A paradox of why humans, whose effective population size is only 104, have nearly three million frequent SNPs is formulated and examined by studying 5398 loci evenly covering all human autosomes. Common haplotypes built from frequent SNPs that are present in people from various populations were examined. We demonstrated highly non-random arrangement of alleles in common haplotypes. Abundance of mutually exclusive pairs of common haplotypes (which have different alleles at every polymorphic position, so-called Yin/Yang haplotypes) was observed in 56% of loci. A novel widely spread category of common haplotypes named Mosaic has been described. Mosaic consists of numerous pieces of Yin/Yang haplotypes and represents an ancestral stage of one of them. Evaluation of possible scenarios for the appearance of large number of frequent human SNPs and their characteristic arrangement in Yin/Yang common haplotypes have been performed with an advanced genomic simulation algorithm, GEMA. Computer modeling demonstrated that the observed arrangement of 2.9 million frequent SNPs could not originate from a sole stand-alone population. A “Great Admixture” event has been proposed that can explain peculiarities with frequent SNP distributions. This Great Admixture presumably occurred 100-300 thousand years ago between two ancestral populations that had been separated from each other about a million years ago. Chapter 2 focuses on quantifying the GC-Biased Gene Conversion (gBGC) in humans. gBGC is one of the important theories put forward to explain profound long-range non-randomness in nucleotide compositions along mammalian chromosomes. Nucleotide changes due to gBGC are hard to distinguish from regular mutations. Here, we present an algorithm for analysis of millions of known SNPs that detects a subset of so-called “SNP flip-over” events representing recent gBGC nucleotide changes, which occurred in previous generations via non-crossover meiotic recombination. This algorithm has been applied in a large-scale analysis of 1092 sequenced human genomes. Altogether, 56,328 regions on all autosomes have been examined, which revealed 223,955 putative gBGC cases leading to SNP flip-overs. We detected a strong bias (11.7% ± 0.2% excess) in AT->GC over GC->AT base pair changes within the entire set of putative gBGC cases. Moreover, gBGC was observed 1.8 times more often in African populations compared to Europeans. On average, a human gamete acquires 7 SNP flip-over events, in which one allele is replaced by its complementary allele during the process of meiotic non-crossover recombination. In each meiosis event, on average, gBGC results in replacement of 7 AT base pairs by GC base pairs, while only 6 GC pairs are replaced by AT pairs. Therefore, every human gamete is enriched by one GC pair. Happening over millions of years of evolution, this bias may be a noticeable force in changing the nucleotide composition landscape along chromosomes.
Alexei Fedorov (Committee Chair)
Andrew Beavis (Committee Member)
Sadik Khuder (Committee Member)
Nicolai Modyanov (Committee Member)
Robert Trumbly (Committee Member)
Biomedical Research

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Citations

  • Dutta, R. (2017). Human Common Haplotypes Carry Signatures of “Great Admixture” between Ancient Lineages and GC-Biased Gene Conversion [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1507810392963753

    APA Style (7th edition)

  • Dutta, Rajib. Human Common Haplotypes Carry Signatures of “Great Admixture” between Ancient Lineages and GC-Biased Gene Conversion . 2017. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1507810392963753.

    MLA Style (8th edition)

  • Dutta, Rajib. "Human Common Haplotypes Carry Signatures of “Great Admixture” between Ancient Lineages and GC-Biased Gene Conversion ." Doctoral dissertation, University of Toledo, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=mco1507810392963753

    Chicago Manual of Style (17th edition)

mco1507810392963753
301
© , some rights reserved.Creative Commons License Human Common Haplotypes Carry Signatures of “Great Admixture” between Ancient Lineages and GC-Biased Gene Conversion by Rajib Dutta is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.