Population dynamics and medical consequences of sex chromosome evolution

项目总结 人类基因组在DNA含量和基因表达方面存在性别偏见。人类的X和Y 染色体是推断人类人口统计学的有用工具，对我们理解人类至关重要 健康。然而，尽管进入了基因组学时代，X和Y染色体仍未得到充分利用，尤其是在 全基因组的背景。我的研究重点是整合这些染色体来构建 对人类历史的综合分析和利用进化论的方法来表征性别偏见 基因表达。利用比较基因组学，我们发现人类的Y染色体几乎丢失了 它曾经与X基因共享了90%的基因内容，但这种自然选择在人类Y基因上仍然活跃。 此外，我们还表明，只有在一起分析基因组的所有区域(常染色体，X 染色体，以及未重组和单亲遗传的Y染色体和mtDNA)，可以 推断性别偏见的人口统计学和自然选择的相对强度，作用于整个人类 基因组。此外，我们的研究支持这样一种理论，即人体通过X-射线的剂量补偿机制。 失活，在X染色体上以逐个基因特有的方式逐步进化，以响应丢失 有功能的Y连锁基因。该项目将包括利用和研究性的三管齐下的方法 人类的染色体变异。首先，我们将专注于小说的开发和广泛的测试 准确计算影响对齐和变型调用的技术变化的方法 性染色体。当前的对齐管道不考虑X和Y之间的共享同源性 染色体，导致性染色体之间的读取错误映射，并降低了变种的能力 我在打电话。我们的方法将结合性染色体生物学来改进对性别的变异呼唤 染色体。其次，我们将真正研究全基因组的变异模式(常染色体、X染色体、Y染色体 染色体和线粒体DNA)在肯尼亚的多个群体中。非洲的人口是世界上最多样化的 显然，全球人口研究中没有这种多样性的代表。在……里面 与研究文化变异的人类学家合作，我们将评估基因多样性 个体是，并使用跨性染色体和常染色体的变异模式来推断最近和 这些人口中的古老人口学。第三，我们将研究基因表达的变异(重点是 X-连锁基因表达和X-失活)在人类性别和群体之间 胎盘。胎盘是一个经常从体内排出的器官，它也提供了一个重要的接口 在开发过程中，并没有在目前的大规模组织表达项目中进行研究。与 我们将生成并全面分析特定人群的长期妊娠结局研究- 人类胎盘中的偏向。这项工作将改进研究性别连锁变异的方法学，提供 估计性别偏见的人口统计学，并阐明性别偏见在人类胎盘中的表达。

PROJECT SUMMARY Sex-bias exists in the human genome in DNA content and gene expression. The human X and Y chromosomes are useful tools for inferring human demography, and crucial for our understanding of human health. However, despite the genomics era, X and Y chromosomes are still vastly underutilized, especially in a genome-wide context. My research has focused on the integration of these chromosomes to build comprehensive analyses of human history and utilizing an evolutionary approach to characterize sex-bias in gene expression. Using comparative genomics, we have shown that the human Y chromosome has lost nearly 90% of the gene content it once shared with the X, but that natural selection is still active on the human Y. Further, we showed that, only when analyzing all regions of the genome together (autosomes, X chromosomes, and the non-recombining and uni-parentally inherited Y chromosome and mtDNA), could one infer the relative strength of sex-biased demography along with natural selection, acting across the human genome. Further, our research supports the theory that the human dosage-compensation mechanism via X- inactivation, evolved step-wise, in a gene-by-gene specific manner on the X chromosome in response to loss of functional Y-linked genes. This project will include a three-pronged approach to utilizing and studying sex chromosome variation across humans. First, we will focus on development and extensive testing of novel methodology for accurately accounting for technical variation that affects alignment and variant calling on the sex chromosomes. Current alignment pipelines do not account for the shared homology between the X and Y chromosome, resulting in mis-mapping of reads between the sex chromosomes and reduced power for variant calling. Our methodology will incorporate sex chromosome biology to improve variant calling on the sex chromosomes. Second, we will study truly genome-wide patterns of variation (autosomes, X chromosome, Y chromosome, and mtDNA) among multiple populations in Kenya. Populations in Africa are the most diverse in the world, and representation of that diversity is conspicuously absent from global population studies. In collaboration with anthropologists, who are studying, cultural variation, we will assess how genetically diverse individuals are, and use patterns of variation across the sex chromosomes and autosomes to infer recent and ancient demography in these populations. Third, we will study gene expression variation (with an emphasis on X-linked gene expression and X-inactivation) between the sexes, and between populations in the human placenta. The placenta is the one organ routinely expelled from the body that also provides a crucial interface during development, and is not studied in current large-scale tissue expression projects. In collaboration with a long-term pregnancy outcome study we will generate and comprehensively analyze population-specific sex- bias in the human placenta. This work will improve methodology for studying sex-linked variation, provide estimates of sex-biased human demography, and elucidate sex-biased expression in the human placenta.