Genetic conflict shapes centromeres and heterochromatin

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的组织功能。这些基本功能包括从分离染色体到通过剂量补偿确保性染色体的转录平价以及保护种系免受转座子的侵害。着丝粒和异色DNA是正确的染色体分离所必需的，染色体分离的缺陷会导致不孕症和非整倍体——常见于出生缺陷，如三体（如唐氏综合症）和向癌症的过渡。剂量补偿的缺陷导致果蝇雄性无法生存，并导致哺乳动物雌性的一系列缺陷。无法防御种系转位可导致男性和女性不育。尽管它们很重要，但由于它们高度重复的性质（着丝粒、异染色质）、定义不清（剂量补偿进入位点）和快速进化，大多数这些“组织”DNA元件已被证明难以进行遗传研究。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，需要新的方法和视角来深入了解这些重要的基因组片段。我的实验室采用了“替代”的方法来研究这些DNA元素的功能和进化。通过研究作用于蛋白质的选择压力，这些蛋白质结合并在许多情况下从表观遗传学上定义了这些元素的功能，我们对DNA元素本身的选择压力有了深入的了解。这种方法对形成这些DNA元素的进化压力和它们执行的基本生物过程提供了独特的见解。本提案旨在利用果蝇模型遗传系统，采用这种新方法来理解塑造这些进化和医学上重要的真核生物基因组组成部分的生物力量。

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.