The molecular origin of sex-specific gene regulation

性别特异性基因调控的分子起源

• 批准号: 9325994
• 负责人: Emily Kay Delaney
• 金额: $ 5.71万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325994
• 关键词: Abdomen; Affect; Alleles; Alzheimer' s Disease; Autoimmune Diseases; Behavior; CRISPR/Cas technology; Cardiovascular Diseases; Case Study; Color; Complex; Darkness; Defect; Disease; Drosophila genus; Elements; Evolution; Family; Female; Fibrinogen; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genetic study; Genome; Gonadal Steroid Hormones; Health; Human; Intervention; Introns; Light; Maps; Medical; Modeling; Molecular; Mutation; Nature; Organism; POU Domain; POU domain factors; Parkinson Disease; Pattern; Pharmaceutical Preparations; Phenotype; Physiology; Pigmentation physiologic function; Pigments; Pituitary Dwarfism; Prevalence; Protein Isoforms; RNA Splicing; Regulation; Regulatory Element; Repression; Research; Role; Sex Bias; Specificity; System; Technology; Testing; Tissues; Transcriptional Silencer Elements; Transgenic Organisms; Untranslated RNA; Variant; Woman; Work; design; differential expression; dimorphism; experimental study; genetic variant; genome editing; genome wide association study; genotypic sex; human female; human male; improved; insight; male; malignant breast neoplasm; men; promoter; response; sex; sex determination; sexual role; trait; transcription factor

Project Summary Most traits that differ between males and females arise from differential expression of shared genes. Despite the ubiquity of sex-biased expression, we still lack an understanding of both the mechanisms that cause sex-specific gene regulation and the process by which male and female expression becomes uncoupled. These questions have fundamental health implications, as sex-biased diseases such as autoimmune disorders and drug responses show significant genotype-sex interactions. My research will establish how sex-specific gene expression originates by studying a female-limited color dimorphism (FCD) in Drosophila serrata, a species where females have two color morphs (light or dark) but males have only one color morph (only light). Identifying the female dimorphic element and how it functions will provide a useful counterpoint to studies of male-limited pigmentation, enabling me to determine if alleles evolve female- and male-specificity by the same rules. Last year, I mapped female pigmentation to a non-coding structural variant (SV) in the first intron of POU domain motif 3 (pdm3), a transcription factor that I showed represses dark pigmentation. At this variant, dark females have an allele that is radically divergent in size and sequence from the light allele, suggesting that the SV harbors a cis-regulatory element that directs female- and morph-specific pigmentation. Using transgenic experiments, I have confirmed that the sequences flanking the SV function as tissue-specific regulatory elements. In this proposal, I will (1) determine how the D. serrata SV affects pdm3 expression in a binary manner, (2) identify if this SV is regulated sex-specifically because it is controlled by doublesex (the main sex determination effector in Drosophila), and (3) test the necessity and sufficiency of this SV in the origin of FCD using genome editing. This in-depth analysis of a female-specific regulatory element in an experimentally tractable Drosophila model will improve our understanding of how sexual differences arise, and provide a framework for research in other organisms including humans. In particular, this work will inform the design of genetic studies aimed at identifying human alleles that contribute to sex-biased diseases.

项目摘要 男性和女性之间的大多数特征差异来自共享基因的差异表达。 尽管性别偏见的表达无处不在，我们仍然缺乏对这两种机制的理解 导致性别特异性基因调控和男性和女性表达成为 分离这些问题具有根本的健康影响，因为性别偏见疾病，如 自身免疫性疾病和药物应答显示出显著的基因型-性别相互作用。我的研究将 通过研究雌性限制的颜色二型性来确定性别特异性基因表达的起源 (FCD)在锯缘果蝇中，雌性有两种颜色变体（浅色或深色），而雄性有两种颜色变体 只有一种颜色变形（只有灯光）。确定雌性二型元素及其功能将 提供了一个有用的对照研究男性有限的色素沉着，使我能够确定是否等位基因 按照相同的规则进化出雌性和雄性的特异性。去年，我把女性的肤色 转录因子POU结构域基序3（pdm 3）第一内含子中的非编码结构变体（SV） 抑制了深色色素沉着。在这种变异中，深色雌性有一个等位基因， 在大小和序列上与轻等位基因不同，这表明SV具有顺式调节作用。 引导雌性和形态特异性色素沉着的元素。通过转基因实验， 证实了SV侧翼序列作为组织特异性调控元件发挥功能。在这 建议，我将（1）确定如何D。serrata SV以二元方式影响pdm 3表达，（2） 确定该SV是否受性别特异性调节，因为它受doublemex（主要性别）控制 在果蝇中的决定效应），和（3）测试这种SV在起源的必要性和充分性， 使用基因组编辑的FCD。这种对女性特异性调节元件的深入分析， 实验上易于处理的果蝇模型将提高我们对性别差异的理解 它的出现为包括人类在内的其他生物体的研究提供了一个框架。特别是这项工作 将告知遗传研究的设计，旨在确定人类等位基因，有助于性别偏见 疾病