Comparative genomic and epigenomic analyses of human and non-human primate evolution

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Xu, Ke
Yi, Soojin V.
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Primates are one of the best characterized phylogenies with vast amounts of comparative data available, including genomic sequences, gene expression, and epigenetic modifications. Thus, they provide an ideal system to study sequence evolution, regulatory evolution, epigenetic evolution as well as their interplays. Comparative studies of primate genomes can also shed light on molecular basis of human-specific traits. This dissertation is mainly composed of three chapters studying human and non-human primate evolution. The first study investigated evolutionary rate difference between sex chromosome and autosomes across diverse primate species. The second study developed an unbiased approach without the need of prior information to identify genomic segments under accelerated evolution. The third study investigated interplay between genomic and epigenomic evolution of humans and chimpanzees. Research advance 1: evolutionary rates of the X chromosome are predicted to be different from those of autosomes. A theory based on neutral mutation predicts that the X chromosome evolves slower than autosomes (slow-X evolution) because the numbers of cell division differ between spermatogenesis and oogenesis. A theory based on natural selection predicts an opposite direction (fast-X evolution) because newly arising beneficial mutations on the autosomes are usually recessive or partially recessive and not exposed to natural selection. A strong slow-X evolution is also predicted to counteract the effect of fast-X evolution. In our research, we simultaneously studied slow-X evolution, fast-X evolution as well as their interaction in a phylogeny of diverse primates. We showed that slow-X evolution exists in all the examined species, although their degrees differ, possibly due to their different life history traits such as generation times. We showed that fast-X evolution is lineage-specific and provided evidences that fast-X evolution is more evident in species with relatively weak slow-X evolution. We discussed potential contribution of various degrees of slow-X evolution on the conflicting population genetic inferences about human demography. Research advance 2: human-specific traits have long been considered to reside in the genome. There has been a surge of interest to identify genomic regions with accelerated evolution rate in the human genome. However, these studies either rely on a priori knowledge or sliding windows of arbitrary sizes. My research provided an unbiased approach based on previously developed “maximal segment” algorithm to identify genomic segments with accelerated lineage-specific substitution rate. Under this framework, we identified a large number of human genomic segments with clustered human-specific substitutions (named “maximal segments” after the algorithm). Our identified human maximal segments cover a significant amount of previously identified human accelerated regions and overlap with genes enriched in developmental processes. We demonstrated that the underlying evolutionary forces driving the maximal segments included regionally increased mutation rate, biased gene conversion and positive selection. Research advance 3: DNA methylation is one of the most common epigenetic modifications and plays a significant role in gene regulation. How DNA methylation status varies on the evolutionary timescale is not well understood. In this study, we investigated the role of genetic changes in shaping DNA methylation divergence between humans and chimpanzees in their sperm and brain, separately. We find that for orthologous promoter regions, CpG dinucleotide content difference is negatively correlated with DNA methylation level difference in the sperm but not in the brain, which may be explained by the fact that CpG depleting mutations better reflect germline DNA methylation levels. For the aligned sites of orthologous promoter regions, sequence divergence is positively correlated with methylation divergence for both tissues. We showed that the evolution of DNA methylation can be affected by various genetic factors including transposable element insertions, CpG depleting mutations and CpG generating mutations.
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