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Malaria is one of the strongest evolutionary selective forces on the human genome. Because malaria is widespread and has high mortality, diverse genetic adaptations have evolved that provide resistance to malaria. Island Melanesia is a malaria-endemic region that has been isolated somewhat from outside populations as well as within the islands themselves. The purpose of this thesis was to investigate whether the same malaria resistance loci were under positive selection in Island Melanesia and in Africa, and to determine whether these mutations arose in Island Melanesia through a common origin or independently via convergent evolution.This thesis used a SNP-based outlier approach to ascertain signals of selection for malaria candidate loci in the Human Genome Diversity Panel (HGPD-CEPH) database, which contains 660,755 genotyped SNPs and has been used extensively to study population genomics. Summaries of allele frequencies at these SNPs were compared between two Island Melanesian populations and six African populations in order to identify potential signals of selection in genomic regions surrounding candidate genes for malaria resistance. To capture Melanesian-specific change, Population Branch Statistics (PBS) were calculated to assess which of the two populations had undergone positive selection relative to a third anchor population (in this thesis, Europe). An empirical distribution of PBS values was constructed for each population comparison, and an average genome-wide PBS value was computed using all 660,755 SNPs. For each population comparison, significant branch lengths were evaluated for positive selection with respect to the genome-wide average PBS values. Results indicated that the genes DARC, CD36, GYPC, and HBA1 play an important role in malaria resistance in Island Melanesia, and several resistance loci emerged as strong outliers in the population comparisons between Melanesia and Africa, indicating that they have likely been influenced by strong positive selection in Melanesian populations. DARC was implicated in malaria resistance in Melanesia and in Africa, but different SNPs have been favored in each location, supporting the convergent evolution of malaria resistance. DARC was the only candidate gene that showed universally strong signals in both Bougainville and Papuan populations, which suggests that it is important throughout the region. Specifically the SNP rs12075 in the DARC gene was targeted by selection in both of these populations but not in the African populations surveyed, suggesting convergent evolution of malaria resistance between populations Melanesia and Africa, but not within Melanesia at this locus. CD36, GYPC, and HBA1 all exhibited longer branch lengths for Bougainville alone, suggesting that they are under selection in that population, but not in the population from Papua New Guinea. These findings suggest that allelic differences at this locus may be the result of convergent evolution of malaria resistance in Melanesia, since populations in Bougainville and Papua are advancing different, independent adaptive strategies. A more representative sample of Island Melanesia and sequencing data could improve our understanding of local patterns of evolution of malaria resistance in Melanesia. |
