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我们想要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业特征，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。涉及到1)基因复制和进化的方面；2)有丝分裂的特殊特征--特别是构成适当染色体分离的着丝粒结构和功能；以及3)基因组的不稳定性。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体的基础。第二个主题，着丝粒结构和功能，直接涉及当异常导致非整倍体和多倍体的过程。这些拷贝数(剂量)的变化经常导致基因表达的异常平衡，是许多癌症的特征，也为生长中的癌细胞提供了一个可能但鲜为人知的治疗靶点。第三个主题，基因组不稳定，是杂合性丧失、易位和几个突变机制的关键特征，这些突变机制是许多癌症发生的突出特征的基础。到目前为止，已知的受多样性选择影响的基因几乎都属于寄主防御基因和参与有性繁殖的基因，这些基因加速了基因序列的改变。最近的研究表明，多样化的选择(或积极的自然选择)可能也对肿瘤抑制基因起作用。由于大多数肿瘤是在生殖年龄之后形成的，肿瘤的促进或抑制本身不太可能受到自然选择的影响，作用于基因的选择压力很可能与这些蛋白质的另一个更具生理性的作用有关，特别是在发育中的胚胎中。发育进化假说表明，构成人类适应性进化基础和具有多种功能的基因也可能参与疾病易感性。为了确定在多样化选择的压力下进化的新基因，我们重建了三个基因座的进化史：编码乳腺癌基因的BRCA1，编码小头症基因的ASPM，以及包含可能的遗传性前列腺癌候选基因SPANX基因簇的HPCX基因座。从一组具有代表性的非人灵长类动物中分离出这些基因座的共线区，并进行了分析。我们的结果表明ASPM和SPANX基因在近代史上经历了正向选择。我们还证明了大多数BRCA1蛋白序列(不仅仅是外显子11序列)是在原始人的正选择压力下进化的。种间基因同源序列比较为鉴定保守的氨基酸残基和预测影响BRCA1和ASPM功能的错义变化提供了基础。ASPM加速进化的迹象表明，控制大脑大小的这个基因的变化早于人类大脑在原始人中的扩张。因为正向选择只在有机体的适合度增加时才对基因起作用，我们的结果表明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。在许多组织中都检测到了ASPM转录本，而且，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癌症发生中的作用。我们对非人类灵长类同源物的分析导致在HPCX基因座发现了span x基因家族的新成员，并揭示了这些基因的扩展在人类中仍可能是一个持续的过程。耐人寻味的是，SPANX基因位于20-100kb的区块内，这些区块包括具有高度序列相似性的节段性染色体复制(SDS)。已有文献证明，十二烷基硫酸钠可介导基因座之间的异位相互作用，从而导致染色体重排，如重复、缺失和倒位。这些观察表明，在一些HPCX家族中，前列腺癌的易感性可能是由十二烷基硫酸钠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.