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 两性的分化是脊椎动物的基本过程。在许多物种中，雄性和 雌性分化在胚胎发生早期由主性别决定（MSD）基因触发， 位于Y染色体上虽然性别分化是一个非常保守的过程， 在脊椎动物中，启动这一过程的MSD基因是非常可变的。目前尚不清楚一个多样化的 MSD基因的分类与典型的脊椎动物性别分化网络整合。一个明确 了解性别决定和分化的遗传调控是至关重要的，因为 在这一过程中可能会导致几种性发育障碍。我们的长期目标是利用各种 类型的性染色体之间密切相关的物种棘鱼，以确定如何反穆勒 激素（AMH）已被反复增选为MSD基因的角色。在我的实验室里， 棘鱼作为首要的脊椎动物模型系统，以了解性染色体和性别 决心在进化。我们已经确定了独立收购的Y-连锁AMH（Amhy）在两个物种 是通过独立复制和易位进化而来的。我们的核心假设是， 性连锁的Amh拷贝（Amhy）可以在性别分化网络中引发类似的转录反应 跨越物种。一旦复制品独立获得了必要的调控元件， 在原始性腺发育早期表达。在本提案中，我们将使用以下创新组合： 功能遗传学和比较基因组学，探讨我们的假设，通过三个目标：（1）确定是否 Amhy是三刺鱼和溪刺鱼雄性发育的必要和充分条件，（2）确定Amhy是如何影响雄性发育的。 Amhy在性别决定期间受到调节，以及（3）描述下游性别如何 分化调控网络响应于作为MSD基因的Amhy的获得。该项目将有一个 对该领域的重大影响，因为它将揭示负责观察到的可塑性的遗传机制， 脊椎动物的性别决定这项工作还将使人们更深入地了解 AMH在脊椎动物中作为一个整体，并将提供关键的基因组资源，将进一步使棘鱼 鱼类作为一个领先的脊椎动物模型系统，以了解性染色体如何进化。