Conflict-driven aneuploidy and genomic instability caused by meiotic proteins

减数分裂蛋白引起的冲突驱动的非整倍性和基因组不稳定性

• 批准号: 10199524
• 负责人: Maria Angelica Bravo Nunez
• 金额: $ 8.57万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2021-06-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10199524
• 关键词: Abnormal Karyotype; Address; Affect; Alleles; Aneuploid Cells; Aneuploidy; Antidotes; Bioinformatics; Biological Models; Biology; Cell Division Process; Cell division; Cells; Characteristics; Chromosome Segregation; Chromosome abnormality; Chromosomes; Conflict (Psychology); Confocal Microscopy; Congenital Abnormality; Cytogenetics; Cytology; DNA; Down Syndrome; Elements; Environment; Eukaryota; Evolution; Exhibits; Expression Profiling; Family; Fertility; Fission Yeast; Frequencies; Genes; Genetic; Genome; Genomic Instability; Germ Cells; Goals; Haploidy; Haplotypes; Human; Human Cell Line; Infertility; Inherited; Kinetochores; Lead; Link; Malignant Neoplasms; Meiosis; Mitosis; Mitotic; Mitotic Chromosome; Molecular; Organism; Parasites; Pattern; Phase; Poison; Population; Population Genetics; Prevalence; Process; Proteins; Research; Research Personnel; Selfish Genes; System; Techniques; Testing; Work; anticancer research; cancer cell; career; chromosome missegregation; chromosome number abnormality; driving force; genetic approach; genome integrity; insight; interdisciplinary approach; next generation; novel; segregation; transmission process; tumor progression

PROJECT SUMMARY/ ABSTRACT Chromosome segregation can fail and generate cells with too many or too few chromosomes, a condition known as aneuploidy. Aneuploidy is a driving force in cancer progression and most cancers exhibit an abnormal karyotype. Aneuploidy is also the leading cause of infertility and congenital birth defects, such as Down syndrome. Because of the prevalence of aneuploidy in cancer and infertility, it is paramount to understand the causes of inaccurate chromosome segregation. Some components of the chromosome segregation machinery are among the fastest evolving genes in the genome. This rapid evolution is paradoxical as the process of chromosome segregation is essential and largely conserved. It is thought that conflicts caused by genetic parasites, found throughout eukaryotes, could be one cause of this rapid evolution. Meiotic drivers are one such type of intragenomic parasites that selfishly promote their own transmission into gametes. The overall goal of this proposal is to identify mechanisms that cause aneuploidy and infertility. The proposed aims will address three important questions: 1) What are the molecular mechanisms utilized by meiotic drivers? 2) Do meiotic drivers promote the formation of aneuploid gametes? 3) What causes errors in chromosome segregation? My work recently identified fission yeast wtf genes as a tractable model system in which to study meiotic drive. For my thesis dissertation (Aim 1), I will test if the genetic conflict caused by these meiotic drivers could affect the chromosome segregation machinery and thus the frequency of aneuploid gametes. Additionally, I will test if a high frequency of meiotic drivers in a population could promote the evolution of low fidelity chromosome segregation. During my postdoctoral research (Aim 2), I will apply the insights gained in my thesis research to address if the meiotic components of the chromosome segregation machinery can contribute to errors in mitotic chromosome segregation in humans. In addition, I will test if the untimely expression of meiotic genes contributes to the aneuploidy seen in cancer cells. To achieve these goals, I will use interdisciplinary approaches such as genetics, theoretical evolution, confocal microscopy, and cytogenetics. The completion of these aims will expand our understanding of the causes of aneuploidy and infertility, as well as the impact that genetic conflict has on genome integrity. The proposed research represents a unique contribution to the field of chromosome segregation and cancer research.

项目概要/摘要 染色体分离可能会失败并产生染色体过多或过少的细胞，这是一种情况 称为非整倍体。非整倍体是癌症进展的驱动力，大多数癌症表现出 核型异常。非整倍体也是不孕症和先天性出生缺陷的主要原因，例如 唐氏综合症。由于癌症和不孕症中非整倍体的普遍存在，因此至关重要 了解染色体分离不准确的原因。染色体的一些组成部分 分离机制是基因组中进化最快的基因之一。这种快速的演变是 矛盾的是，染色体分离过程是必不可少的，而且在很大程度上是保守的。据认为 真核生物中普遍存在的遗传寄生虫引起的冲突可能是这种快速进化的原因之一。 减数分裂驱动因素是一种基因组内寄生虫，它们自私地促进自身传播 配子。该提案的总体目标是确定导致非整倍体和不育的机制。这 提出的目标将解决三个重要问题：1）所利用的分子机制是什么？ 减数分裂驱动因素？ 2）减数分裂驱动因素是否促进非整倍体配子的形成？ 3）什么原因导致错误 染色体分离？我的工作最近发现裂殖酵母 wtf 基因是一个易于处理的模型系统 用于研究减数分裂驱动。对于我的论文（目标 1），我将测试这些是否引起遗传冲突 减数分裂驱动因素可能影响染色体分离机制，从而影响非整倍体的频率 配子。此外，我将测试群体中高频率的减数分裂驱动因素是否可以促进 低保真度染色体分离的进化。在我的博士后研究（目标 2）期间，我将应用 在我的论文研究中获得的见解，旨在解决染色体分离的减数分裂成分 机器可能导致人类有丝分裂染色体分离错误。另外，我会测试是否 减数分裂基因的不及时表达导致癌细胞中出现非整倍性。为了实现这些 为了实现目标，我将使用跨学科的方法，例如遗传学、理论进化、共焦显微镜和 细胞遗传学。这些目标的完成将扩大我们对非整倍性和非整倍性原因的理解。 不孕症，以及遗传冲突对基因组完整性的影响。拟议的研究 代表了对染色体分离和癌症研究领域的独特贡献。

项目成果

A suppressor of a wtf poison-antidote meiotic driver acts via mimicry of the driver's antidote.

• DOI: 10.1371/journal.pgen.1007836
• 发表时间: 2018-11
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Bravo Núñez MA;Lange JJ;Zanders SE
• 通讯作者: Zanders SE

Meiosis in Quarantine discussions lead to an action plan to increase diversity and inclusion within the genetics community.

• DOI: 10.1371/journal.pgen.1009648
• 发表时间: 2021-07
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Billmyre KK;Bravo Núñez MA;Bishop DK;Cole F
• 通讯作者: Cole F

The wtf4 meiotic driver utilizes controlled protein aggregation to generate selective cell death.

• DOI: 10.7554/elife.55694
• 发表时间: 2020-10-27
• 期刊: eLife
• 影响因子: 7.7
• 作者: Nuckolls NL;Mok AC;Lange JJ;Yi K;Kandola TS;Hunn AM;McCroskey S;Snyder JL;Bravo Núñez MA;McClain M;McKinney SA;Wood C;Halfmann R;Zanders SE
• 通讯作者: Zanders SE

S. pombe wtf drivers use dual transcriptional regulation and selective protein exclusion from spores to cause meiotic drive.

• DOI: 10.1371/journal.pgen.1009847
• 发表时间: 2022-12
• 期刊: PLoS genetics
• 影响因子: 4.5