Genetic Conflict Shapes Centromeres and Heterochromatin

遗传冲突塑造着丝粒和异染色质

• 批准号: 10654557
• 负责人: HARMIT S MALIK
• 金额: $ 37.4万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10654557
• 关键词: Address; Adopted; Alleles; Amino Acid Motifs; Aneuploidy; Animals; Behavior; Binding; Biological; Biological Process; Cellular biology; Centromere; Chromatids; Chromosome Segregation; Chromosome abnormality; Chromosomes; Conflict (Psychology); Congenital Abnormality; Cytology; DNA; DNA Sequence Alteration; Defect; Deposition; Down Syndrome; Drosophila genus; Embryo; Embryonic Development; Engineering; Ensure; Epigenetic Process; Eukaryota; Evolution; Female; Foundations; Gene Duplication; Genes; Genetic; Genetic Models; Genetic study; Genome; Genome engineering; Heterochromatin; Histone H3; Histones; Infertility; Inherited; Kinetochores; Lead; Malignant Neoplasms; Mediating; Meiosis; Microtubules; Mitosis; Mitotic; Modeling; Molecular; Mus; Nematoda; Oocytes; Oogenesis; Phenotype; Plants; Process; Proteins; Proteomics; Recurrence; Rest; Role; Satellite DNA; Shapes; Site; Spermiogenesis; Testing; Transgenes; Variant; Yeasts; base; cost; developmental disease; egg; expectation; experience; fitness; fly; genetic analysis; insight; interdisciplinary approach; knock-down; neuronal cell body; paralogous gene; pleiotropism; protein protein interaction; recruit; sperm cell; tool; transmission process

PROJECT SUMMARY Chromosome segregation is an essential process. The key chromosomal sites that ensure proper segregation of chromosomes are centromeres, which bind microtubules that pull chromosomes or chromatids apart during meiosis and mitosis. Centromere function is thus essential for chromosome segregation. Defective centromeres can lead to aneuploidy, infertility, and birth defects like Down’s syndrome. Despite the conservation of the chromosome segregation process, centromeric proteins like CenH3, which bind centromeric DNA to assemble microtubule-recruiting kinetochores, evolve rapidly between closely related species. Their rapid evolution is unexpected and could imperil the fidelity of the chromosome segregation process. We previously proposed that this rapid evolution occurs due to ‘centromere-drive’, i.e., competition between chromosomes during female meiosis, in which only one of four meiotic products is chosen to be the egg pronucleus. Using an approach that combines insights from evolutionary genetics and cell biology, and state-of-the-art genome engineering tools, we propose to test this model of genetic conflict in Drosophila species. Furthermore, based on our finding of recurrent duplication of CenH3 in Drosophila species, we will test whether somatic versus germline centromeric functions have different functional constraints, which are easiest to resolve via gene duplication and specialization of CenH3 genes.

项目摘要 染色体分离是一个必不可少的过程。关键的染色体位点， 确保染色体的正确分离是结合微管的着丝粒 在减数分裂和有丝分裂过程中将染色体或染色单体拉开。着丝粒 因此，功能对于染色体分离至关重要。有缺陷的着丝粒会导致 非整倍体、不孕症和先天缺陷，如唐氏综合症。尽管 染色体分离过程的保守性，像CenH3这样的着丝粒蛋白， 结合着丝粒DNA组装微管募集动粒， 在近缘物种之间迅速传播。它们的快速进化是出乎意料的， 危及染色体分离过程的精确性。我们先前提出， 这种快速进化的发生是由于“着丝粒驱动”，即，之间的竞争 在女性减数分裂过程中，只有四个减数分裂产物中的一个是染色体， 被选为卵原核。使用的方法结合了 进化遗传学和细胞生物学，以及最先进的基因组工程工具，我们 我建议在果蝇物种中测试这种遗传冲突模型。此外，基于 在我们发现CenH3在果蝇物种中重复的基础上，我们将测试 体细胞与种系着丝粒功能是否具有不同的功能 限制，最容易通过基因复制和特化来解决 CenH3基因。

项目成果

Molecular evolution of Drosophila Cdc6, an essential DNA replication-licensing gene, suggests an adaptive choice of replication origins.

果蝇 Cdc6（一种重要的 DNA 复制许可基因）的分子进化表明复制起点的适应性选择。

• DOI: 10.4161/fly.4599
• 发表时间: 2007
• 期刊: Fly
• 影响因子: 1.2
• 作者: Wiggins,BenjaminL;Malik,HarmitS
• 通讯作者: Malik,HarmitS

Hybridization promotes asexual reproduction in Caenorhabditis nematodes.

杂交促进了线虫的无性繁殖。

• DOI: 10.1371/journal.pgen.1008520
• 发表时间: 2019
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Lamelza,Piero;Young,JanetM;Noble,LukeM;Caro,Lews;Isakharov,Arielle;Palanisamy,Meenakshi;Rockman,MatthewV;Malik,HarmitS;Ailion,Michael
• 通讯作者: Ailion,Michael

Genetics: Master Regulator or Master of Disguise?

遗传学：监管大师还是伪装大师？

• DOI: 10.1016/j.cub.2017.07.030
• 发表时间: 2017
• 期刊: Current biology : CB
• 作者: Ailion,Michael;Malik,HarmitS
• 通讯作者: Malik,HarmitS

A mitochondrial DNA hypomorph of cytochrome oxidase specifically impairs male fertility in Drosophila melanogaster.

细胞色素氧化酶的线粒体 DNA 亚型特别损害果蝇的雄性生育能力。

• DOI: 10.7554/elife.16923
• 发表时间: 2016
• 期刊: eLife
• 影响因子: 7.7
• 作者: Patel,MaulikR;Miriyala,GaneshK;Littleton,AimeeJ;Yang,Heiko;Trinh,Kien;Young,JanetM;Kennedy,ScottR;Yamashita,YukikoM;Pallanck,LeoJ;Malik,HarmitS
• 通讯作者: Malik,HarmitS

Evolution of a transcriptional regulator from a transmembrane nucleoporin.

• DOI: 10.1101/gad.280941.116
• 发表时间: 2016-05-15
• 期刊: Genes & development
• 影响因子: 10.5
• 作者: Franks TM;Benner C;Narvaiza I;Marchetto MC;Young JM;Malik HS;Gage FH;Hetzer MW
• 通讯作者: Hetzer MW