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、假设驱动的、变革性的、与 NIH 使命相关的。我们最近发现，果蝇的 Y 染色体序列具有多态性，这些序列对数百个常染色体和 X 连锁基因的表达产生差异性影响，这一新颖性由此产生。不同Y染色体对基因表达的定量影响称为YRV（Y连锁调节变异）。所提出的实验提供了第一个研究 YRV 机制的分子方法。受 YRV 影响的基因包括所有类别的基因：性别间表达无偏差、女性偏向和男性偏向。许多受 YRV 影响的基因与适应性特征（例如耐热性）或性选择（例如信息素接收）有关。 YRV 的发现具有潜在的重要意义，因为它表明，包括人类在内的所有生物体中的 Y 染色体在通过其大量非编码 DNA 介导对基因表达的主要基因组效应方面非常特殊。拟议的实验将检验以下假设：YRV 是由 Y 连锁序列的拷贝数变化引起的，这些序列与常染色体和 X 连锁基因竞争与有限数量的染色质相关蛋白的结合，从而影响基因表达水平。拟议的实验还将检验 YRV 是由与位置效应杂色 (PEV) 和/或重复相关小干扰 RNA (rasiRNA) 相关的调节途径介导的假设。因此，这项研究具有变革性，因为它可能从根本上改变我们对 Y 染色体非编码序列通过其对基因调控的影响来解释表型变异的作用的理解。通过调控效应进行的选择可能会驱动 Y 染色体中非编码序列的快速进化，这些序列在进化上比单拷贝序列更具活力。这种观点挑战了当前的范式，即此类序列仅仅是中性进化的“垃圾”DNA。拟议的实验还将确定一组受 YRV 影响的候选基因，这些基因与精子发生的耐热性相关，这是限制许多昆虫（包括传播疟疾的蚊子）生态范围的关键生物因素。我们还将开发与 YRV 相关的多态性 Y 染色体群体动态的理论模型，以确定基于竞争性结合的模型是否可以通过实际参数值实现。与 NIH 任务相关的是，我们关于果蝇 Y 染色体的发现可能在基因组富含异染色质（包括人类基因组）的生物体中相当普遍。因此，我们预测影响人类健康和疾病的重要表型变异最终将追溯到人类染色体中异染色质的变异。这项研究的长期目标是了解 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着丝粒周围异染色质，但果蝇 Y 染色体是研究的起点，因为它的编码序列含量低，非编码重复序列含量高，遗传操作相对容易，而且遗传资源丰富。相关性 这项研究的相关性在于它调查了新发现的 Y 染色体对基因表达影响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产生广泛的影响。公共健康相关性：Y 染色体被广泛认为是基因贫乏、缓慢退化的基因组 DNA 荒地，其唯一功能是作为 X 染色体的配对伴侣，并携带不同物种的雄性或雄性生育力基因。我们的初步调查结果强烈表明这种观点是错误的。我们的新发现是，Y 染色体多态性对基因组中数百个基因的表达水平有不同的影响。我们相信，这些效应是由快速进化且鲜为人知的 Y 染色体区域介导的，其中包含非编码 DNA 的序列重复。这些实验对目前关于 Y 染色体影响其他基因表达以及 Y 染色体如何随时间变化的观点提出了革命性的挑战。我们预测，影响人类健康和疾病的重要表型变异最终将归因于人类 Y 染色体中非编码 DNA 序列重复的变异。