Functional Analysis of the Anti-Müllerian Hormone as a Convergently Acquired Master Sex Determination Gene

抗苗勒氏管激素作为趋同获得性主性别决定基因的功能分析

• 批准号: 10659852
• 负责人: Michael Andrew White
• 金额: $ 31.14万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659852
• 关键词: ATAC-seq; Address; Binding; Biological Assay; Biological Models; Cells; Data; Development; Differentiated Gene; Embryonic Development; Evolution; Female; Fishes; Gasterosteidae; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Goals; Gonadal Dysgenesis; Gonadal structure; Health; Human; In Situ Hybridization; Infertility; Intersex; Knock-out; Link; Mammals; Modeling; Mutation; Nucleic Acid Regulatory Sequences; Ovary; Pattern; Phenotype; Process; Promoter Regions; Regulation; Regulatory Element; Reporter; Research; Role; Sex Chromosomes; Sex Differentiation; Signal Transduction; Surface; System; Testing; Testis; Time; Transforming Growth Factor beta; Undifferentiated; Vertebrates; Work; Y Chromosome; candidate validation; comparative; comparative genomics; genetic sex determination; genome resource; gonad development; innovation; insight; male; member; mullerian-inhibiting hormone; overexpression; paralogous gene; response; sex; sex determination; sex development disorder; single-cell RNA sequencing; transcription factor

PROJECT SUMMARY Development of separate sexes is a fundamental process throughout vertebrates. In many species, male and female differentiation is triggered early during embryogenesis by a master sex determination (MSD) gene that resides on the Y chromosome. Although sex differentiation is a remarkably conserved process among vertebrates, the MSD gene that initiates the process is incredibly variable. It remains unclear how a diverse assortment of MSD genes integrates with the canonical vertebrate sex differentiation network. A clear understanding of the genetic regulation of sex determination and differentiation is essential because disruptions in this process can lead to several disorders of sexual development. Our long-term goals are to use the diverse types of sex chromosomes among closely related species of stickleback fish to determine how anti-Müllerian hormone (Amh) has been repeatedly co-opted into a role as an MSD gene. Work in my lab has established stickleback fish as a premier vertebrate model system to understand how sex chromosomes and sex determination evolves. We have identified the independent acquisition of a Y-linked Amh (Amhy) in two species of stickleback fish that evolved through separate duplications and translocations. Our central hypothesis is that sex-linked copies of Amh (Amhy) can elicit a similar transcriptional response in the sex differentiation network across species. This occurs once duplicates have independently gained regulatory elements necessary for expression during early primordial gonad development. In this proposal we will use an innovative combination of functional genetics and comparative genomics to explore our hypothesis through three aims: (1) Determine if Amhy is necessary and sufficient for male development in threespine and brook stickleback fish, (2) Identify how Amhy is regulated during the time of sex determination, and (3) Characterize how the downstream sex differentiation regulatory network responds to the acquisition of Amhy as an MSD gene. This project will have a significant impact on the field as it will reveal the genetic mechanisms responsible for the observed plasticity in sex determination across vertebrates. This work will also lead to broader insights into the common function of Amh across vertebrates as a whole and will provide key genomic resources that will further enable stickleback fish as a leading vertebrate model system to understand how sex chromosomes evolve.

项目摘要 单独的性别的发展是整个脊椎动物的基本过程。在许多物种中，男性和 在胚胎发生期间，通过性别确定（MSD）基因触发了女性分化 位于Y染色体上。尽管性别差异是一个非常保守的过程 脊椎动物，启动该过程的MSD基因的变化极其可变。目前尚不清楚多样化 MSD基因与规范性脊椎动物性别分化网络集成。清晰 理解性别确定和分化的遗传调节是必不可少的 在此过程中，可以导致多种性发展疾病。我们的长期目标是使用潜水员 紧密相关的粘质鱼中的性染色体类型，以确定抗蛋白 马内（AMH）已反复选择作为MSD基因的角色。我的实验室工作已经建立 Stickback Fish作为主要的脊椎动物模型系统，以了解性别染色体和性别如何 决心的演变。我们已经确定了两个物种中Y连锁AMH（AMHH）的独立获取 通过单独的重复和易位演变而来的粘性鱼。我们的中心假设是 AMH（AMHY）的性别链接副本可以在性别分化网络中引起类似的转录响应 跨物种。一旦重复获得了独立的监管要素，就会发生这种情况 早期原始性腺发育期间的表达。在此提案中，我们将使用创新的组合 功能性遗传学和比较基因组学以通过三个目的探索我们的假设：（1）确定是否确定是否是否 AMHY对于三季和Brook Stickleback鱼的男性发育是必要的，足以足够，（2）确定如何 在确定性别期间对AMHY受到调节，（3）表征下游性别的方式 分化调节网络对获得AMHY作为MSD基因的响应。这个项目将有一个 对现场的重大影响，因为它将揭示导致观察到的可塑性的遗传机制 跨脊椎动物的性别决定。这项工作还将导致更广泛的见解对 整个脊椎动物的AMH将提供关键的基因组资源 鱼是一种领先的脊椎动物模型系统，以了解性别染色体的发展方式。