Mechanisms of meiotic drive and the functional consequences of rapid genome evolution in Schizosaccharomyces

裂殖酵母减数分裂驱动机制和快速基因组进化的功能后果

• 批准号: 8868546
• 负责人: Sarah Elizabeth Zanders
• 金额: $ 9万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8868546
• 关键词: Address; Alleles; Aneuploidy; Award; Beryllium; Bioinformatics; Biological Assay; Biological Models; Biology; Birth; Cell physiology; Chromosome Segregation; Chromosomes; Conflict (Psychology); Confocal Microscopy; Congenital Abnormality; Cytology; DNA Repair; DNA Sequence; DNA Transposable Elements; Diploidy; Disease; Educational process of instructing; Elements; Employee Strikes; Ensure; Essential Genes; Eukaryota; Evolution; Exhibits; Faculty; Fertility; Fission Yeast; Fred Hutchinson Cancer Research Center; Genes; Genetic; Genetic Determinism; Genome; Genomic approach; Genomics; Germ Cells; Goals; Haploidy; Health; Homozygote; Human; Hybrids; Immunity; Individual; Infertility; Inherited; Learning; Life; Location; Malignant Neoplasms; Maps; Measures; Meiosis; Meiotic Recombination; Mitosis; Molecular; Mutagenesis; Mutation; Organism; Parasites; Pathway interactions; Penetrance; Phenotype; Population; Positioning Attribute; Process; Proteins; Race; Reproduction; Reproduction spores; Research; Resources; Rest; Schizosaccharomyces; Selfish Genes; Side; Sister; Site; Stem cells; Testing; Time; Training; Treatment outcome; Variant; Virus; Work; arm; career; computer program; driving force; fitness; genome-wide; improved; innovation; insight; interdisciplinary approach; killings; novel; programs; public health relevance; transmission process

 DESCRIPTION (provided by applicant): My research focus is to understand the molecular mechanisms of meiosis and infertility. I was trained as a geneticist, but I came to the Fred Hutchinson Cancer Research Center to expand my training in the lab of Dr. Harmit Malik. Dr. Malik is teaching me how to use an evolution-guided approach to explore the molecular causes of infertility. I hypothesized that selfish genetic parasites, such as transposable elements (TEs) and meiotic drive alleles may be significant contributors to infertility within natural populations including humans. These parasites persist in genomes because they act in the germline to promote their own transmission into gametes. TEs act by inserting copies of themselves into new genomic locations. Meiotic drive alleles bias their own transmission into functional gametes by altering meiotic chromosome segregation, or by killing gametes that do not inherit them. Differences between what is best for the parasite and what is best for the host sets up an `evolutionary arms race' where each side must rapidly evolve. This rapid evolution could contribute to the natural variation underlying differential health and fertility within a populatio. To test these ideas, I use S. pombe (Sp), its closely related sister species (99.5% sequence identity) S. kambucha (Sk), and Sk/Sp hybrids. I found that TEs and meiotic drive alleles each contributed to the rapid evolution of infertility between Sp and Sk. I also discovered significant functional divergence between Sp and Sk meiosis in that Sk is less able to ensure that meiosis generates haploid, as opposed to aneuploid gametes. My proposal expands my discoveries utilizing an interdisciplinary approach. First, I will use genetics and a novel genomics approach to map and identify the molecular mechanisms by which three meiotic drive loci within Sk act. Second, I will obtain training in confocal microscopy and utilize cytology and genetics to determine the mechanism and genetic determinants of the differential propensity of Sk and Sp to generate aneuploid gametes. Finally, my proposal further probes the functional consequences of rapid genome evolution, driven by genetic parasites and other factors, by using genetics and genomics to assess how the suite of genes essential for life and sexual reproduction differs between Sk and Sp. This will require me to learn computer programming and bioinformatics. Together, these aims will expand our understanding of the causes of infertility, congenital aneuploidy, and how rapid evolution can cause the functional divergence of genes essential for life and sexual reproduction. This award will allow me to obtain the training and resources I require to complete my research objectives. This training and the innovative research program it supports will help me reach my short-term goal of obtaining a junior faculty position. The award will also help me pursue my long-term career goal of uncovering causes of infertility within natural populations, including humans.

 描述（由适用提供）：我的研究重点是了解减数分裂和不育的分子机制。我接受过遗传学家的培训，但我来到弗雷德·哈钦森癌症研究中心，以扩大我在哈米特·马利克（Harmit Malik）博士实验室的培训。 Malik博士正在教我如何使用进化引导的方法来探索不育的分子原因。我假设自私的遗传寄生虫，例如可转座元素（TES）和减数分裂驱动等位基因可能是包括人类在内的自然种群中不孕症的重要贡献者。这些寄生虫持续存在基因组，因为它们在种系中起作用以促进自己的传播到游戏中。 TES通过将自己的副本插入新的基因组位置来起作用。减数分裂驱动等位基因通过改变减数分裂染色体的隔离或杀死不继承它们的游戏的传播偏向功能性游戏。最适合寄生虫的差异与最适合主机的差异设置了一个“进化武器竞赛”，双方都必须迅速发展。这种快速的进化可能导致人口中差异健康和生育能力的自然变异。为了测试这些想法，我使用S. pombe（SP），其密切相关的姊妹物种（99.5％的序列身份）S。Kambucha（SK）和SK/SP Hybrids。我发现TES和减数分裂驱动等位基因都导致SP和SK之间不孕的快速演变。我还发现SP和SK减数分裂之间的功能差异很大，因为SK不太有能力确保减数分裂会产生单倍体，而不是非整倍性游戏。我的建议通过跨学科方法扩大了我的发现。首先，我将使用遗传学和一种新型的基因组学方法来绘制和识别SK ACT中三个减数分裂驱动基因座的分子机制。其次，我将获得共聚焦显微镜的培训，并利用细胞学和遗传学来确定SK和SP生成非整倍体游戏的差异希望的机制和遗传决定剂。最后，我的提议进一步向遗传学和基因组学来评估SK和SP之间的基因套件对基因套件以及SK和SP之间的不同之处，进一步投射了由遗传寄生虫和其他因素驱动的快速基因组进化的功能后果。这将需要我学习计算机编程和生物信息学。这些目标一起，将扩大我们对不育的原因，先天性非整倍性的理解，以及进化的快速进化会导致基因的功能差异，对生命和性繁殖必不可少。该奖项将使我能够获得完成研究目标所需的培训和资源。它支持的培训和创新研究计划将有助于我实现获得初级教师职位的短期目标。该奖项还将帮助我实现自己的长期职业目标，即在包括人类在内的自然人群中揭示了不育的原因。