Novel genomic effects of Y-linked polymorphisms

Y连锁多态性的新基因组效应

• 批准号: 8034816
• 负责人: Daniel L HARTL
• 金额: $ 29.64万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8034816
• 关键词: Accounting; Affect; Binding; Biological Assay; Biological Factors; Candidate Disease Gene; Chromatin; Chromosomes, Human, Y; Climate; Code; Competitive Binding; Complement; Connecticut; Culicidae; DNA; Defect; Disease; Drosophila genus; Drosophila melanogaster; Equilibrium; Evolution; Female; Fertility; Gene Expression; Gene Expression Regulation; Genes; Genetic Polymorphism; Genetic Variation; Genome; Genomics; Goals; Health; Heterochromatin; Human; Human Chromosomes; Human Genome; Infertility; Insecta; Junk DNA; Link; Maintenance; Malaria; Mediating; Minor; Mission; Modeling; Molecular; Mutation; Organism; Pathway interactions; Pheromone; Play; Population Dynamics; Population Genetics; Positioning Attribute; Production; Proteins; Recruitment Activity; Regulatory Pathway; Relative (related person); Repetitive Sequence; Research; Resources; Rice; Role; Specificity; Spermatogenesis; Structure; Testing; Testis; Theoretical model; Time; Tissue Sample; Tissues; United States National Institutes of Health; Universities; Variant; Work; X Chromosome; Y Chromosome; Y chromosome deletion; autosome; base; fitness; genetic evolution; genetic manipulation; genetic resource; human male; male; novel; programs; public health relevance; research study; sex; sperm cell; theories; trait

DESCRIPTION (provided by applicant): We propose research which is novel, hypothesis driven, transformative, and relevant to the NIH mission. The novelty emerges from our recent discovery that the Y chromosome of Drosophila melanogaster is polymorphic for sequences that differentially affect the expression of many hundreds of autosomal and X-linked genes. The quantitative effects of different Y chromosome on gene expression are termed YRV (Y-linked regulatory variation). The proposed experiments provide the first molecular approach to study the mechanism of YRV. The genes affected by YRV include all classes of genes: unbiased in expression between the sexes, female-biased, and male-biased. Many of the genes affected by YRV are related to adaptive traits (e. g., thermal tolerance) or sexual selection (e. g., pheromone reception). The discovery of YRV is potentially of great significance because it suggests that the Y chromosome in all organisms, including humans, is very special in mediating major genomic effects on gene expression through its large complement of noncoding DNA. The proposed experiments will test the hypothesis that YRV results from variation in the copy number of Y-linked sequences that compete with the autosomal and X-linked genes for binding with limiting amounts of chromatin-associated proteins that affect levels of gene expression. The proposed experiments will also test the hypothesis that YRV is mediated by regulatory pathways associated with position-effect variegation (PEV) and/or repeat- associated small interfering RNA (rasiRNA). The proposed research is therefore transformative because it may radically change our understanding of the role of Y chromosome noncoding sequences in accounting for phenotypic variation through its effects on gene regulation. Selection acting through regulatory effects may drive the rapid evolution of noncoding sequences in the Y chromosome, which are evolutionarily much more dynamic than single-copy sequences. This view challenges the current paradigm that such sequences are mere "junk" DNA evolving neutrally. The proposed experiments will also identify a set of YRV-affected candidate genes associated with thermal tolerance of spermatogenesis, a key biological factor in limiting the ecological range of many insects including the mosquitoes that transmit malaria. We will also develop theoretical models for the population dynamics of polymorphic Y chromosomes associated with YRV to determine whether a model based on competitive binding is possible with realistic values of the parameters. The relevance to the NIH mission is that our findings about the Drosophila Y chromosome are likely to be quite general among organisms with genomes rich in heterochromatin including the human genome. Hence we predict that important phenotypic variation affecting human health and disease will ultimately be traced to variation in heterochromatin in human chromosomes. The long-range goal of this research is to understand the regulatory role of the Y chromosome in genetic variation and evolution. Eventually the pericentromeric heterochromatin of the X chromosome and autosomes must also be studied, but the Drosophila Y chromosome is the place to start because of its low content of coding sequences, its high content of noncoding repetitive sequences, its relative ease of genetic manipulation, and the genetic resources available. Relevance The relevance of this research is that it investigates the molecular mechanisms and adaptive significance of newly discovered effects of the Y chromosome on gene expression, which may have widespread implications for the role of the Y chromosome in humans and other organisms. Public Health Relevance: The Y chromosome is widely considered as a gene-poor, slowly degenerating wasteland of genomic DNA whose only functions are to serve as a pairing partner for the X and to carry genes for maleness or male fertility in different species. Our preliminary findings strongly suggest that this view is false. Our novel finding is that Y chromosome polymorphisms differentially affect the level of expression of many hundreds of genes across the genome. We believe that these effects are mediated by rapidly evolving, little understood regions of the Y chromosome containing sequence repeats of noncoding DNA. The experiments proposed are transformative in challenging the current view of Y-chromosome affects on the expression of other genes, and of how the Y chromosome changes through time. We predict that important phenotypic variation affecting human health and disease will ultimately be traced to variation in sequence repeats of noncoding DNA in the human Y chromosome.

描述（由申请人提供）：我们提出的研究是新颖的，假设驱动，变革性且与NIH任务相关的研究。我们最近发现的新颖性来自于我们最近发现的，果蝇的Y染色体是多态的序列，这些序列会差异地影响数百种常染色体和X连锁基因的表达。不同Y染色体对基因表达的定量作用称为YRV（Y连锁调节变化）。提出的实验提供了研究YRV机制的第一种分子方法。受YRV影响的基因包括所有类别的基因：性别之间的表达公正，女性偏见和男性偏见。受YRV影响的许多基因与适应性性状（例如，热耐受性）或性选择（例如，信息素接受）有关。 YRV的发现可能具有重要意义，因为它表明包括人类在内的所有生物体中的Y染色体在介导基因组表达的主要基因组影响中非常特别，其非编码DNA的大量补体。提出的实验将检验以下假设：YRV是由与常染色体和X连锁基因竞争的Y连锁序列的拷贝数变化，以结合影响基因表达水平的染色质相关蛋白的限制量。提出的实验还将检验以下假设：YRV是由与位置效应变量（PEV）和/或重复相关的小型干扰RNA（Rasirna）相关的调节途径介导的。因此，提出的研究具有变革性，因为它可能从根本上改变了我们对Y染色体非编码序列在计算表型变异中对基因调节的影响的理解。通过调节作用作用的选择可能会驱动Y染色体中非编码序列的快速演变，而Y染色体的进化比单拷贝序列更具动态性。这种观点挑战了当前的范式，即这种序列仅仅是“垃圾” DNA的中立发展。提出的实验还将确定一组与YRV影响的候选基因相关的精子发生，这是限制许多昆虫的生态范围的关键生物学因素，包括传播疟疾的蚊子。我们还将为与YRV相关的多态性Y染色体的种群动力学开发理论模型，以确定与参数的现实值相关的基于竞争结合的模型。与NIH任务的相关性是，我们对果蝇染色体的发现可能在富含异染色质的基因组的生物中非常普遍，包括人类基因组。因此，我们预测影响人类健康和疾病的重要表型变异将最终可追溯到人类染色体中异染色质的变异。这项研究的远程目标是了解Y染色体在遗传变异和进化中的调节作用。最终，还必须研究X染色体和常染色体的周围质粒异染色质，但是果蝇染色体是由于其编码序列的低含量，其非编码重复序列的高含量，其相对容易的遗传操作以及可用的遗传资源，因此果蝇是起点的起点。这项研究的相关性是，它研究了Y染色体对基因表达的新发现作用的分子机制和适应性意义，这可能对Y染色体在人类和其他生物体中的作用具有广泛的影响。公共卫生相关性：Y染色体被广泛认为是基因组的基因，基因组DNA的退化荒原，其唯一的功能是作为X的配对伴侣，并携带不同物种中男性或男性生育能力的基因。我们的初步发现强烈表明这种观点是错误的。我们的新发现是，Y染色体多态性差异地影响了整个基因组中数百个基因的表达水平。我们认为，这些作用是通过快速发展而介导的，几乎没有理解的Y染色体区域包含非编码DNA的序列重复序列。提出的实验在挑战Y染色体的当前观点方面具有变革性，这会影响其他基因的表达以及Y染色体如何随着时间的流逝而变化。我们预测，影响人类健康和疾病的重要表型变异将最终可追溯到人类Y染色体中非编码DNA的序列重复序列变化。