Organization and Function of Chromosomal Regions that ar

染色体区域的组织和功能

• 批准号: 7053897
• 负责人: james barrett
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7053897
• 关键词: biochemical evolution; breast neoplasms; cancer risk; carcinogenesis; centromere; chromosome aberrations; chromosome inversion; chromosome movement; chromosome translocation; congenital oral /facial /cranial defect; gene duplication; gene expression; genetic mapping; genetic susceptibility; human genetic material tag; loss of heterozygosity; micrencephaly; neoplasm /cancer genetics; prostate neoplasms; tissue /cell culture

We want to understand why particular chromosomal regions and genes are prone to generate genomic disorders. Relevant specialized features of the human genome, including some that are especially relevant to cancer, have increasingly become the focus of our research. Involved are 1) aspects of gene duplication and evolution; 2) specialized features of mitosis -- particularly the centromere structure and function that underlie proper chromosome segregation; and 3) genome instability. The first of these topics, gene duplication and evolution, is the basis for divergence and in some cases for the supply of variants of genes that predispose to cancer. The second topic, centromere structure and function, is directly involved in processes that when aberrant lead to aneuploidy and polyploidy. Those copy number (dosage) changes often contribute to aberrant balances of gene expression, are features of many cancers, and also provide a possible but poorly understood therapeutic target in growing cancer cells. The third topic, genome instability, is a critical feature of loss of heterozygosity, translocations, and several mutational mechanisms that underlie prominent features of many instances of carcinogenesis. Almost all the genes known so far to be affected by diversifying selection, which accelerates the alteration of gene sequences, belong to host defense genes and genes involved in sexual reproduction. Recent studies have revealed that diversifying selection (or positive natural selection) may have also acted on tumor suppressor genes. Because most tumors are formed after reproductive age, tumor promotion or suppression itself is not likely to be subject to natural selection, and selective pressures acting on the genes are most likely related to another more physiological role for these proteins, specifically in the developing embryo. The hypothesis of developmental evolution suggests that genes that form the basis of our adaptive evolution and have multiple functions may also be involved in disease predisposition.To identify new genes that have evolved under pressure of diversifying selection, we reconstructed an evolutionary history of three loci: BRCA1 encoding the breast cancer gene, ASPM encoding the microcephaly gene, and the HPCX locus containing the cluster of SPANX genes that are putative candidates for hereditary prostate cancer. Syntenic regions of these loci were isolated from a representative group of nonhuman primates and were analyzed. Our results showed that ASPM and SPANX genes have experienced positive selection in recent history. We also demonstrated that most of the BRCA1 protein sequence (not only the exon 11 sequence, as has been proposed) evolved under the pressure of positive selection in hominids. Interspecies gene homolog sequence comparisons provided a basis for the identification of conservative amino acid residues and for the prediction of missense changes that compromise BRCA1 and ASPM function. Signatures of accelerated evolution at ASPM indicate that changes in this gene controlling brain size began prior to human brain expansion in hominids. Because positive selection acts on a gene only when the organism's fitness is increased, our results indicate that ASPM may be a major genetic component underlying the evolution of the human brain. Our recent studies revealed that the expression of ASPM is not restricted to the fetal brain. ASPM transcripts were detected in many tissues, and moreover, the gene is up-regulated in a wide spectrum of cancers. Given the rapid evolution of ASPM sequences, additional studies are needed to clarify its role in carcinogenesis. Our analysis of nonhuman primate homologs resulted in the discovery of new members of the SPANX gene family at the HPCX locus and revealed that the expansion of these genes could still be an ongoing process in humans. It is intriguing that SPANX genes reside within 20-100 kb blocks, which comprise segmental chromosomal duplications (SDs) with a high level of sequence similarity. It is well documented that SDs mediate ectopic interaction of loci that can result in chromosomal rearrangements such as duplications, deletions, and inversions. These observations suggest that the predisposition to prostate cancer in some HPCX families may have resulted from genomic rearrangements mediated by SDs.

我们想了解为什么特定的染色体区域和基因容易产生基因组疾病。人类基因组的相关专门特征，包括一些与癌症特别相关的特征，日益成为我们研究的重点。涉及1）基因复制和进化的各个方面; 2）有丝分裂的特殊特征-特别是作为染色体分离基础的着丝粒结构和功能; 3）基因组不稳定性。其中第一个主题是基因复制和进化，它是分歧的基础，在某些情况下，它是提供易患癌症的基因变体的基础。第二个主题，着丝粒的结构和功能，是直接参与的过程，当异常导致非整倍体和多倍体。这些拷贝数（剂量）的变化往往导致基因表达的异常平衡，是许多癌症的特征，也提供了一个可能的，但在生长的癌细胞知之甚少的治疗靶点。第三个主题，基因组不稳定性，是杂合性丢失、易位和几种突变机制的关键特征，这些突变机制是许多致癌实例的突出特征的基础。迄今为止，几乎所有已知的受多样化选择影响的基因都属于宿主防御基因和有性生殖基因。多样化选择加速了基因序列的改变。最近的研究表明，多样化选择（或积极的自然选择）也可能对肿瘤抑制基因起作用。由于大多数肿瘤是在生育年龄后形成的，因此肿瘤促进或抑制本身不太可能受到自然选择的影响，作用于基因的选择压力很可能与这些蛋白质的另一个更生理作用有关，特别是在发育中的胚胎中。发育进化假说认为，形成我们适应性进化基础的基因，具有多种功能，也可能与疾病易感性有关。为了识别在多样化选择压力下进化的新基因，我们重建了三个位点的进化历史：编码乳腺癌基因的BRCA 1，编码小头畸形基因的ASPM，以及含有推定为遗传性前列腺癌候选者的SPAN基因簇的HPCX基因座。这些基因座的同线区域从一组有代表性的非人灵长类动物中分离出来，并进行了分析。我们的研究结果表明，ASPM和SPAN基因在最近的历史中经历了积极的选择。我们还证明了大多数BRCA 1蛋白序列（不仅仅是外显子11序列，正如已经提出的那样）在人类的正选择压力下进化。种间基因同源序列的比较提供了一个基础，为确定保守的氨基酸残基和预测的错义变化，损害BRCA 1和ASPM功能。ASPM加速进化的特征表明，这种控制大脑大小的基因的变化在人类大脑扩张之前就开始了。因为只有当生物体的适应性增加时，正选择才会作用于基因，我们的研究结果表明ASPM可能是人类大脑进化的主要遗传成分。我们最近的研究表明ASPM的表达并不局限于胎儿大脑。在许多组织中检测到ASPM转录本，此外，该基因在广泛的癌症中上调。鉴于ASPM序列的快速进化，需要更多的研究来阐明其在致癌作用中的作用。我们对非人灵长类同源物的分析导致在HPCX位点发现了新的SPAN基因家族成员，并揭示了这些基因的扩增在人类中仍然是一个持续的过程。令人感兴趣的是，SPAN X基因位于20-100 kb的区块内，其包含具有高水平序列相似性的节段性染色体重复（SD）。据文献记载，SD介导基因座的异位相互作用，可导致染色体重排，如复制、缺失和倒位。这些观察结果表明，在某些HPCX家族中，前列腺癌的易感性可能是由SD介导的基因组重排引起的。