Genetic conflict shapes centromeres and heterochromatin

遗传冲突塑造着丝粒和异染色质

• 批准号: 8890953
• 负责人: HARMIT S MALIK
• 金额: $ 11.53万
• 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 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8890953
• 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; Health; 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; 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.

描述（由申请人提供）：非编码DNA元件在真核生物基因组中发挥关键组织功能。这些基本功能的范围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和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，其中的缺陷可以导致不育以及非整倍体-通常在出生缺陷如三体（例如唐氏综合征）和向癌症的转变中发现。剂量补偿的缺陷导致果蝇的雄性不育，并导致哺乳动物雌性的一系列缺陷。不能抵抗生殖系转座可导致雄性和雌性不育。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）、定义不佳（剂量补偿进入位点）和快速进化，大多数这些“组织”DNA元件已被证明对遗传研究来说很棘手。缺乏合适的传统比较基因组学方法阻碍了对这些元素的研究。因此，需要新的方法和观点来深入了解我们基因组的这些重要部分。我的实验室采用了“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，表观遗传学定义了这些元素的功能，我们可以深入了解DNA元素本身的选择压力。这种方法提供了独特的见解，形成这些DNA元素的进化压力和它们所进行的基本生物过程。该提案旨在利用果蝇模型遗传系统，采用这种新的方法来理解塑造真核生物基因组的这些进化和医学重要组成部分的生物力量。