Genetic conflict shapes centromeres and heterochromatin

遗传冲突塑造着丝粒和异染色质

• 批准号: 8101936
• 负责人: HARMIT S MALIK
• 金额: $ 35.87万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101936
• 关键词: Adopted; Affect; Alleles; Aneuploidy; Beryllium; Binding; Biological; Biological Process; Cellular biology; Centromere; Chromosome Segregation; Chromosomes; Complement; Conflict (Psychology); Congenital Abnormality; DNA; DNA Sequence; Defect; Dosage Compensation (Genetics); Down Syndrome; Drosophila Proteins; Drosophila genus; Drosophila inturned protein; Elements; Ensure; Evolution; Female; Female sterility; Functional RNA; Genes; Genetic; Genetic Models; Genome; Heterochromatin; Histones; Hybrids; Infertility; Knock-out; Lead; Male Sterility; Malignant Neoplasms; Meiosis; Methods; Modeling; Molecular Evolution; Nature; Play; Population Genetics; Process; Production; Protein Binding; Proteins; Recurrence; Repetitive Sequence; Research; Role; Sex Chromosomes; Shapes; Site; System; Testing; Trisomy; X Chromosome; comparative genomics; driving force; expectation; insight; male; novel; novel strategies; parity; piRNA; preference; pressure; public health relevance; transmission process

DESCRIPTION (provided by applicant): Non-coding DNA elements serve key organizing functions in eukaryotic genomes. These essential functions range from segregating chromosomes to ensuring transcriptional parity at sex chromosomes via dosage compensation and defending the germline against transposons. Centromeric and heterochromatic DNA is required for correct chromosome segregation, defects in which can lead to infertility as well as to aneuploidy - commonly found in birth defects like trisomy (e.g. Down's syndrome) and in transitions to cancer. Defects in dosage compensation lead to male inviability in Drosophila and to a range of defects in mammalian females. The inability to defend against germline transposition can result in both male and female sterility. Despite their importance, most of these 'organizing' DNA elements have proven intractable to genetic studies owing to their highly repetitive nature (centromeres, heterochromatin), poor definition (dosage compensation entry sites) and rapid evolution. Lack of suitable traditional comparative genomics methods has impeded research into these elements. Therefore, new methods and perspectives are needed to provide insight into these important segments of our genome. My lab has adopted a "surrogate" approach to study the function and evolution of such DNA elements. By studying the selective pressures acting on the proteins that bind and, in many instances, epigenetically define the function of these elements, we obtain insight into the selective pressure on the DNA elements themselves. This approach gives unique insight into the evolutionary pressures shaping these DNA elements and the essential biological processes they carry out. This proposal aims to employ this novel approach to understand the biological forces shaping these evolutionarily and medically important components of eukaryotic genomes, using the Drosophila model genetic system. PUBLIC HEALTH RELEVANCE: Non-coding organizing DNA elements are essential for functions in chromosome segregation, dosage compensation and piRNA production. Defects in these processes can lead to infertility, inviability, birth defects and aneuploidy in transitions to cancer. My lab has adopted a "surrogate" approach to study the function and evolution of such DNA elements, providing unique insight into the evolutionary pressures shaping these DNA elements and the essential biological processes they carry out.

描述(申请人提供)：非编码DNA元件在真核基因组中起着关键的组织功能。这些基本功能从分离染色体到通过剂量补偿确保性染色体的转录奇偶性，以及保护生殖系免受转座子的侵害。着丝粒和异染色质DNA是正确的染色体分离所必需的，其中的缺陷可能导致不孕和非整倍体--通常在三体等出生缺陷(如唐氏综合症)和向癌症的过渡中发现。剂量补偿的缺陷会导致雄性果蝇丧失生存能力，并导致哺乳动物雌性的一系列缺陷。不能抵抗生殖系易位会导致男性和女性不育。尽管它们很重要，但由于它们的高度重复性(着丝粒、异染色质)、低清晰度(剂量补偿进入位点)和快速进化，这些“组织”DNA元件中的大多数已被证明对遗传学研究是困难的。缺乏合适的传统比较基因组学方法阻碍了对这些因素的研究。因此，需要新的方法和视角来洞察我们基因组的这些重要部分。我的实验室采用了一种“替代”的方法来研究这些DNA元件的功能和进化。通过研究作用于结合蛋白质的选择压力，在许多情况下，从表观上定义这些元件的功能，我们获得了对DNA元件本身的选择压力的洞察力。这种方法为形成这些DNA元素的进化压力以及它们所执行的基本生物过程提供了独特的见解。这项建议旨在利用果蝇模型遗传系统，使用这种新的方法来理解生物力量塑造这些真核生物基因组在进化和医学上的重要组成部分。 公共卫生相关性：非编码组织DNA元件对于染色体分离、剂量补偿和piRNA生产的功能至关重要。这些过程中的缺陷可能导致不育、不能生存、出生缺陷和向癌症过渡过程中的非整倍体。我的实验室采用了一种“替代”的方法来研究这些DNA元素的功能和进化，为形成这些DNA元素的进化压力以及它们执行的基本生物过程提供了独特的见解。