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ItemMolecular analyses of avian sex chromosomes and sex chromosome-like autosomes(Georgia Institute of Technology, 2019-07-26) Sun, DanSex chromosomes have originated multiple times throughout eukaryotes. In species with the XY sex-determination system, dosage compensation (a process that balances expression of sex-linked genes between sexes) is often efficient, and its epigenetic basis has been well studied. However, the extent of epigenetic differentiation between sexes in female-heterogametic systems (ZW), which generally lack complete compensation, is poorly understood. Here, I examined the genome-wide DNA methylation landscapes between males and females in mammalian and avian species. In contrast to the X chromosome in mammals, birds display highly similar methylation patterns between sexes on the Z chromosome. Despite this, in chicken and potentially other species in the Galloanserae lineage, two extremely localized regions with pronounced methylation differentiation were observed, including a previously identified locus (referred to as ‘male hypermethylated [MHM1]’) and a novel locus (referred to as ‘MHM2’). The two MHM loci bear remarkably similar molecular features and potential function in reducing male-to-female expression ratios of their neighboring genes. Therefore, DNA methylation is employed to solve dose problems for genes potentially essential to females, at least twice in the evolutionary history of the Galloanserae lineage. In the white-throated sparrow, a pair of autosomes that are distinguished by chromosomal inversions resemble sex chromosomes. In this species, two plumage morphs that mate almost exclusively with each other display striking behavioral differences: within the same sex, birds of the white-striped morph (ZAL2/ZAL2m) display more territorial aggression and less nestling provision than birds of the tan-striped morph (ZAL2/ZAL2). A detailed genomic comparison between a tan bird and a rare ZAL2m homozygote revealed subtle nucleotide differences between ZAL2 and ZAL2m as well as weak degeneration of the non-recombining ZAL2m chromosome. Nevertheless, a large proportion of genes exhibit allelic differential expression in the brain. Intriguingly, similar to the evolutionary path taken by sex chromosomes across many taxa, dosage compensation evolved as a mechanism to re-balance expression between morphs in this nascent autosomal system. Last, I examined the DNA methylation landscape of the white-throated sparrow. Differences in DNA methylation between chicks and adults are pervasive across the genome, with hypermethylation in adults consistent with the overexpression of DNA methyltransferases. Functional enrichment analysis revealed that the observed changes in methylation are likely involved in development. In contrast to the widespread age effects, morph influences are most prominent on the ZAL2/ZAL2m chromosomes. Notably, allelic differences in DNA methylation and allelic differences in gene expression are significantly linked. Taken together, these findings offer new insights into the epigenetic regulation of gene expression in avian sex chromosomes and sex chromosome-like autosomes.
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ItemThe evolutionary significance of DNA methylation in human genome(Georgia Institute of Technology, 2013-10-28) Zeng, JiaIn eukaryotic genomes ranging from plants to mammals, DNA methylation is a major epigenetic modification of DNA by adding a methyl group exclusively to cytosine residuals. In mammalian genomes such as humans, these cytosine bases are usually followed by guanine. Although it does not change the primary DNA sequence, this covalent modification plays critical roles in several regulatory processes and can impact gene activity in a heritable fashion. What is more important, DNA methylation is essential for mammalian embryonic development and aberrant DNA methylation is implicated in several human diseases, in particular in neuro-developmental syndromes (such as the fragile X and Rett syndromes) and cancer. These biological significances disclose the importance of understanding genomic patterns and function role of DNA methylation in human, as a initial step to get to know the epigenotype and its manner in connecting the phenotype and genotype. Two key papers back in 1975 independently suggested that methylation of CpG dinucleotides in vertebrates could be established de novo and inherited through somatic cell divisions by protein machineries of DNA methyltransferases that recognizes hemi-methylated CpG palindromes. They also indicated that the methyl group could be recognized by DNA-binding proteins and that DNA methylation directly silences gene expression. After almost four decades, several key points in these foundation papers are proved to be true. Take the mammalian genome for example, there are several findings indicating the epigenetic repression of gene expression by DNA methylation. These include X-chromosome inactivation, gene imprinting and suppressing the proliferation of transposable elements and repeat elements of viral or retroviral origin. In addition to these, many novel roles of DNA methylation have also been revealed. For example, DNA methylation can regulate alternative splicing by preventing CTCF, an evolutionarily conserved zinc-finger protein, binding to DNA. By using the technique of fluorescence resonance energy transfer (FRET) and fluorescence polarization, DNA methylation has also been shown to increase nucleosome compaction through DNA-histone contacts. What is more important, DNA methylation is essential for mammalian embryonic development and aberrant change of DNA methylation has been related to disease such as cancer. However, it is also notable there are several lines of evidence contradicting the relationship between DNA methylation and gene silencing. For example, comparison of DNA methylation levels in human genome on the active and inactive X chromosomes showed reduced methylation specifically over gene bodies on inactive X chromosomes. Not only in human, DNA methylation is found to be usually targeted to the transcription units of actively transcribed genes in invertebrate species. These results prove that the function of DNA methylation is challenging to be unravel. Besides, due to the development of sequencing technique, whole genome DNA methylation profiles have been detected in diverse species. Comparing genomic patterns of DNA methylation shows considerable variation among taxa, especially between vertebrates and invertebrates. However, even though extensive studies reveal the patterns and functions of DNA methylation in different species, in the mean time, they also highlight the limits to our understanding of this complex epigenetic system. During my Ph.D., in order to perform in-depth studies of DNA methylation in diverse animals as a way to understand the complexity of DNA methylation and its functions, I dedicated my efforts in investigating and analyzing the DNA methylation profiles in diverse species, ranging from insects to primates, including both model and non-model organisms. This dissertation, which constitutes an important part of my research, mainly focuses on the DNA methylation profile in primates including human and chimpanzee. In general, I will use three chapters to elucidate my work in generating and interpreting the whole genome DNA methylation data. Firstly, we generated nucleotide-resolution whole-genome methylation maps of the prefrontal cortex of multiple humans and chimpanzees, then comprehensive comparative studies for these DNA methylation maps have been performed, by integrating data on gene expression as well. This work demonstrates that differential DNA methylation might be an important molecular mechanism driving gene-expression divergence between human and chimpanzee brains and also potentially contribute to the human-specific traits, such as evolution of disease vulnerabilities. Secondly , we performed global analyses of CpG islands (CGIs) methylation across multiple methylomes of distinctive cellular origins in human. The results from this work show that the human CpG islands can be distinctly classified into different clusters solely based upon the DNA methylation profiles, and these CpG islands clusters reflect their distinctive nature at many biological levels, including both genomic characteristics and evolutionary features. Moreover, these CpG islands clusters are non-randomly associated with several important biological phenomena and processes such as diseases, aging, and gene imprinting. These new findings shed lights in deciphering the regulatory mechanisms of CpG islands in human health and diseases. At last, by utilizing the DNA methylome from human sperm and genetic map generated from the International HapMap Consortium project, we investigated the hypothesis suggesting a potential role of germ line DNA methylation in affecting meiotic recombination, which is essential for successful meiosis and various evolutionary processes. Even thought the results imply that DNA methylation is a important factor affecting regional recombination rate, the strength of correlation between these two is not as strong as the previous report. Besides, high-throughput analyses indicate that other epigenetic modifications, tri-methylation of histone 3 lysine 4 and histone 3 lysine 27 are also global features at the recombination hotspots, and may interact with methylation to affect the recombination pattern simultaneously. This work suggests epigenetic mechanisms as additional factors affecting recombination, which cannot be fully explained by the DNA sequence itself. In summary, I hope the results from these work can expand our knowledge regarding the common and variable patterns of DNA methylation in different taxa, and shed light about the function role and its major change during animal evolution.
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ItemComparative genomic and epigenomic analyses of human and non-human primate evolution(Georgia Institute of Technology, 2013-08-23) Xu, KePrimates 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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ItemGenetic variation in fast-evolving East African cichlid fishes: an evolutionary perspective(Georgia Institute of Technology, 2011-06-23) Loh, Yong-Hwee EddieCichlid fishes from the East African Rift lakes Victoria, Tanganyika and Malawi represent a preeminent example of replicated and rapid evolutionary radiation. In this single natural system, numerous morphological (eg. jaw and tooth shape, color patterns, visual sensitivity), behavioral (eg. bower-building) and physiological (eg. development, neural patterning) phenotypes have emerged, much akin to a mutagenic screen. This dissertation encompasses three studies that seek to decipher the underpinnings of such rapid evolutionary diversification, investigated via the genetic variation in East African cichlids. We generated a valuable cichlid genomic resource of five low-coverage Lake Malawi cichlid genomes, from which the general properties of the genome were characterized. Nucleotide diversity of Malawi cichlids was low at 0.26%, and a sample genotyping study found that biallelic polymorphisms segregate widely throughout the Malawi species flock, making each species a mosaic of ancestrally polymorphic genomes. A second genotyping study expanded our evolutionary analysis to cover the entire East African cichlid radiation, where we found that more than 40% of single nucleotide polymorphisms (SNPs) were ancestral polymorphisms shared across multiple lakes. Bayesian analysis of genetic structure in the data supported the hypothesis that riverine species had contributed significantly to the genomes of Malawi cichlids and that Lake Malawi cichlids are not monophyletic. Both genotyping studies also identified interesting loci involved in important sensory as well as developmental pathways that were well differentiated between species and lineages. We also investigated cichlid genetic variation in relation to the evolution of microRNA regulation, and found that divergent selection on miRNA target sites may have led to differential gene expression, which contributed to the diversification of cichlid species. Overall, the patterns of cichlid genetic variation seem to be dominated by the phenomena of extensive sharing of ancestral polymorphisms. We thus believe that standing genetic variation in the form of ancestrally inherited polymorphisms, as opposed to variations arising from new mutations, provides much of the genetic diversity on which selection acts, allowing for the rapid and repeated adaptive radiation of East African cichlids.
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ItemMolecular evolution in the social insects(Georgia Institute of Technology, 2011-04-01) Hunt, Brendan G.Social insects are ecologically dominant because of their specialized, cooperative castes. Reproductive queens lay eggs, while workers take part in brood rearing, nest defense, and foraging. These cooperative castes are a prime example of phenotypic plasticity, whereby a single genetic code gives rise to variation in form and function based on environmental differences. Thus, social insects are well suited for studying mechanisms which give rise to and maintain phenotypic plasticity. At the molecular level, phenotypic plasticity coincides with the differential expression of genes. This dissertation examines the molecular evolution of genes with differential expression between discrete phenotypic or environmental contexts, represented chiefly by female queen and worker castes in social insects. The studies included herein examine evolution at three important levels of biological information: (i) gene expression, (ii) modifications to DNA in the form of methylation, and (iii) protein-coding sequence. From these analyses, a common theme has emerged: genes with differential expression among castes frequently exhibit signatures of relaxed selective constraint relative to ubiquitously expressed genes. Thus, genes associated with phenotypic plasticity paradoxically exhibit modest importance to overall fitness but exceptional evolutionary potential, as illustrated by the success of the social insects.
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ItemEvolutionary impacts of DNA methylation on vertebrate genomes(Georgia Institute of Technology, 2008-08-25) Elango, NavinDNA methylation is an epigenetic modification in which a methyl group is covalently added to the DNA. In vertebrate genomes methylation occurs almost exclusively at cytosines immediately followed by a guanine (CpG dinucleotides). Two important aspects of DNA methylation have inspired several recent scientific investigations including those in this dissertation. First, methylated cytosines are hotspots of point mutation due to a methylation-dependent mutation mechanism, which has caused a deficiency of CpGs in vertebrate genomes. Second, DNA methylation in promoters is linked with transcriptional silencing of the associated genes. This dissertation presents the results of four studies in which I investigated the impacts of DNA methylation on the neutral and functional evolution of vertebrate genomes. The results of the first two studies demonstrate that DNA methylation has profound impacts on both inter- and intra-genomic neutral substitution rate variation. The third and fourth studies demonstrate that DNA methylation has played critical roles in shaping the evolution of vertebrate promoters and gene regulation.