Dosage compensation of a novel X chromosome

新型 X 染色体的剂量补偿

• 批准号: 8662560
• 负责人: Josephine Anna Reinhardt
• 金额: $ 5.33万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-22 至 2016-04-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662560
• 关键词: Accounting; Address; Aneuploidy; Antibodies; Backcrossings; Binding; Chromosome Mapping; Chromosome Structures; Chromosome abnormality; Chromosomes; Chromosomes, Human, Pair 11; Communities; Complex; Culicidae; Data; Diptera; Disease; Dosage Compensation (Genetics); Drosophila genus; Drosophila inturned protein; Drosophila melanogaster; Employee Strikes; Evolution; Eye; Family; Female; Financial compensation; Gene Dosage; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genome; Genomics; Genotype; Hereditary Disease; Human; Individual; Learning; Link; Maps; Measures; Methods; Modeling; Molecular; Organism; Pathway interactions; Population; Process; Proteins; Relative (related person); Research; Resources; Sex Chromosomes; Shotguns; Spontaneous abortion; System; Taxon; Techniques; Transcript; Work; X Chromosome; Y Chromosome; arm; autosome; comparative; coping; density; dosage; fly; fungus; insight; interest; male; novel; public health relevance; sex; sex determination; transcriptomics

DESCRIPTION (provided by applicant): Chromosomal abnormalities such as differences in chromosome number (aneuploidy) are responsible for a many genetic diseases and disorders, and are the leading cause of miscarriage in humans. Nevertheless, throughout evolution striking changes have occurred in the number, size, and organization of chromosomes. This raises the question of how changes that are typically deleterious to individuals become incorporated into the evolutionary process. In particular, what molecular mechanisms change to facilitate this process? The stalk-eyed-fly, Teleopsis dalmanni, has undergone a recent and evolutionarily unusual sex chromosome "shift," in which the ancestral X is now an autosome, and one of the autosomes (2L in Drosophila) is now the X chromosome. This shift will have radically altered the dosage (copy number) of each X-linked and formerly X- linked gene in males of this species, so provides a unique opportunity to investigate how an organism can adapt to this type of change. The proposed research will investigate whether and how gene dosage has been compensated in this species. The aims of the research are threefold. The first aim will create a high-density linkage map that will allow assignment of chromosome orthology relative to Drosophila, allowing linkage group assignment of genomic contigs and identification of the chromosome orthologous to the X in D. melanogaster (now an autosome in Teleopsis). Once orthology is established, the second aim will compare male and female expression of genes on each linkage group. If dosage compensation is complete across the chromosome, expression of T. dalmanni X linked genes should on average be equal between the sexes relative to autosomal expression. Otherwise, expression will be lower on the male X. Expression of the ancestral X may or may not differ from the autosomes - it is possible that dosage compensating mechanisms present in Drosophila may still be hyper transcribing genes on the ancestral X, leading to over-expression of genes on this chromosome in males. Finally the third aim will determine whether the same proteins that compensate dosage in Drosophila are also functioning in T. dalmanni. If the same proteins are involved, compensated chromosomes in T. dalmanni should be bound specifically by antibodies made against these proteins. In the context of the X chromosome shift, this will address the question of whether compensation is achieved by co-opting an existing molecular pathway or through the evolution of a novel mechanism. The proposed research will deepen the understanding of how organisms adapt to chromosome-wide changes in gene dosage. This is relevant to general studies of chromosome function, including studies of disease-causing chromosome abnormalities.

描述（由申请人提供）：染色体异常，例如染色体数（非整倍性）的差异是许多遗传疾病和疾病的原因，并且是人类流产的主要原因。然而，在染色体的数量，大小和组织中，都发生了整个进化的惊人变化。这就提出了一个问题，即通常对个人有害的变化如何纳入进化过程。特别是，哪些分子机制变化以促进这一过程？茎眼telepopsis dalmanni经历了最近且进化上不寻常的性爱染色体“ Shift”，其中祖先X现在是一个雌体，其中一个常染色体（果蝇中的2L）是X染色体。这种转变将从根本上改变了该物种男性中每个X连锁和以前链接的基因的剂量（拷贝数），因此提供了一个独特的机会来研究生物体如何适应这种类型的变化。拟议的研究将调查该物种中的基因剂量以及如何补偿基因剂量。研究的目的是三倍。第一个目标将创建一个高密度的连锁图，该图将允许相对于果蝇的染色体矫正学分配，从而允许基因组重叠群的连锁组分配以及鉴定D. melanogaster中X染色体的X染色体直系同源物（现在是遗传体中的自染色体）。一旦建立了矫正，第二个目标将比较每个连锁组对基因的表达。如果整个染色体上的剂量补偿是完整的，则t. dalmanni x链接基因的表达平均应等于性别相对于常染色体表达。否则，在男性X上的表达将较低。祖先X的表达可能与常染色体有所不同 - 果蝇中存在的剂量补偿机制可能仍可能是祖先X上的过度转录基因，从而导致过度转录基因男性染色体上基因的表达。最后，第三个目标将确定补偿果蝇中剂量的相同蛋白是否在t. dalmanni中也起作用。如果涉及相同的蛋白质，则在T. dalmanni中的补偿染色体应由对这些蛋白质产生的抗体特异性结合。在X染色体转移的背景下，这将解决一个问题，即是通过选择现有分子途径或通过新机制的进化来实现补偿的问题。拟议的研究将加深对生物如何适应基因剂量变化的理解。这与染色体功能的一般研究有关，包括对引起疾病的染色体异常的研究。