Organization and Function of Chromosomal Regions that ar

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。人类基因组的相关特化特征，包括一些与癌症特别相关的特征，越来越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)有丝分裂的特化特征——特别是使染色体正确分离的着丝粒结构和功能；3)基因组不稳定。这些主题中的第一个，基因复制和进化，是分化的基础，在某些情况下，是提供易患癌症的基因变异的基础。第二个主题是着丝粒的结构和功能，它直接涉及异常导致非整倍体和多倍体的过程。这些拷贝数（剂量）的变化通常会导致基因表达的异常平衡，这是许多癌症的特征，也为生长中的癌细胞提供了一个可能的但鲜为人知的治疗靶点。第三个主题，基因组不稳定性，是杂合性缺失、易位和几种突变机制的关键特征，是许多癌症发生的突出特征。迄今所知的受多样性选择影响的基因，几乎都属于宿主防御基因和有性生殖相关基因。多样性选择加速了基因序列的改变。最近的研究表明，多样化选择（或正自然选择）也可能对肿瘤抑制基因起作用。因为大多数肿瘤是在生育年龄之后形成的，肿瘤的促进或抑制本身不太可能受到自然选择的影响，而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的作用有关，特别是在发育中的胚胎中。发育进化假说表明，构成我们适应性进化基础并具有多种功能的基因也可能与疾病易感性有关。为了确定在多样化选择的压力下进化的新基因，我们重建了三个位点的进化史：编码乳腺癌基因的BRCA1，编码小头畸形基因的ASPM，以及包含SPANX基因簇的HPCX位点，这些基因簇被认为是遗传性前列腺癌的候选者。从具有代表性的非人类灵长类动物群体中分离出这些基因座的同链区，并对其进行了分析。我们的结果表明，ASPM和SPANX基因在最近的历史中经历了正选择。我们还证明了大多数BRCA1蛋白序列（不仅仅是外显子11序列，正如所提出的那样）是在人类正选择的压力下进化的。种间基因同源序列比较为鉴定保守氨基酸残基和预测损害BRCA1和ASPM功能的错义变化提供了基础。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原始人大脑扩张之前就开始了。由于正选择仅在生物体的适应性增加时作用于基因，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，该基因在多种癌症中上调。鉴于ASPM序列的快速进化，需要进一步的研究来阐明其在致癌作用中的作用。我们对非人类灵长类动物同源基因的分析结果是在HPCX位点发现了SPANX基因家族的新成员，并揭示了这些基因的扩展在人类中可能仍然是一个持续的过程。有趣的是，SPANX基因位于20-100 kb的区域内，这些区域由具有高水平序列相似性的染色体片段重复（SDs）组成。有充分的证据表明，SDs介导位点的异位相互作用，可导致染色体重排，如重复、缺失和倒位。这些观察结果表明，一些HPCX家族的前列腺癌易感性可能是由SDs介导的基因组重排引起的。

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.