Examining the impact of Neanderthal DNA on modern human biology
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Examining the impact of Neanderthal DNA on modern human biology


Recent genomic studies have revealed that all present-day non-African populations inherit $1 - 4\%$ of their genetic ancestry from a population related to the Neanderthals. Due to the high divergence of Neanderthals and modern humans, this introgression event introduced many novel mutations into non-African populations. Although introgression between archaic and modern humans have previously been documented, the biological consequences of these admixture events on modern humans are not fully understood. In this thesis, we examine these introgressed mutations to help elucidate the biological differences between Neanderthals and modern humans, as well as determine the selective forces that have acted on our genomes in the approximately 50,000 years since Neanderthal introgression occurred.

We first examine the impact Neanderthal introgression has on a single phenotype, Major Depressive Disorder, in more than 10,000 Han Chinese individuals who were diagnosed using structured clinical interviews. A recent examination of Neanderthal informative mutations (NIMs) among a large cohort of Europeans showed that these markers explained some proportions of the phenotypic risk of depression. Our results found no association between the NIMs and MDD, as well as a difference in the variance explained by the NIMs upon the phenotype vs Europeans. These results demonstrate the impact due to Neanderthal ancestry on one type of trait, MDD, appears to differ between Han Chinese and Europeans.

We expanded upon a single phenotype by looking at the impact of Neanderthal introgression on wide range of phenotypes in white British individuals in the UK Biobank. We present a fine mappingstrategy for prioritizing causal NIMs that enables the identification of sets of NIMs that can credibly exert influence on specific phenotypes. We identify NIMs in a number of functionally important genes, including a premature stop codon in the FCGR2A gene, and a start codon loss in COQ10, pinpointing introgressed alleles in immune-related genes that could have and continue to modulate human phenotype.

We then propose a pipeline that is able leverage information from Neanderthal introgressed alleles in order to identify Human-specific mutations that rose to near fixation in modern human populations, and examine how theyimpact modern human phenotypes. We discover two regions of the genome that are confidently fixed-derived and have associations with a number of phenotypes, and are in close proximity to genes that are related to immunity suggesting that these regions may have importance in development of immune response in modern humans.

Finally, we look to highlight possible mechanisms for how complex traits evolved in human history by examining the genetic contribution of Neanderthalancestry. We performed forward-in-time population genetic simulations to model the evolution of Neanderthal and non-Neanderthal alleles according to a demographic model relating modern humans and Neanderthals, to try an understand the evolutionary models that could explain observations of enriched or depleted contributions of Neanderthal ancestry to phenotypic variance seen in real data. We develop simulations of models of directional, stabilizing and disruptive selection, as well as propose two modified directional and stabilizing selection models, and find that most models lead to NIM heritability that is comparable or lower than non-introgressed SNPs, however our two modified models are able to present an increase in NIM heritability, suggesting possible mechanisms for how complex traits evolved in human history by examining the genetic contribution of Neanderthal ancestry.

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