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.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010413-04
Application #
7053897
Study Section
(LBC)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2004
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Kouprina, Natalay; Earnshaw, William C; Masumoto, Hiroshi et al. (2013) A new generation of human artificial chromosomes for functional genomics and gene therapy. Cell Mol Life Sci 70:1135-48
Kouprina, Natalay; Lee, Nicholas C O; Pavlicek, Adam et al. (2012) Exclusion of the 750-kb genetically unstable region at Xq27 as a candidate locus for prostate malignancy in HPCX1-linked families. Genes Chromosomes Cancer 51:933-48
Kouprina, Natalay; Larionov, Vladimir (2008) Selective isolation of genomic loci from complex genomes by transformation-associated recombination cloning in the yeast Saccharomyces cerevisiae. Nat Protoc 3:371-7
Nakano, Megumi; Cardinale, Stefano; Noskov, Vladimir N et al. (2008) Inactivation of a human kinetochore by specific targeting of chromatin modifiers. Dev Cell 14:507-22
Leem, S-H; Yoon, Y-H; Kim, S I et al. (2008) Purification of circular YACs from yeast cells for DNA sequencing. Genome 51:155-8
Kouprina, Natalay; Noskov, Vladimir N; Pavlicek, Adam et al. (2007) Evolutionary diversification of SPANX-N sperm protein gene structure and expression. PLoS ONE 2:e359
Okamoto, Yasuhide; Nakano, Megumi; Ohzeki, Jun-ichirou et al. (2007) A minimal CENP-A core is required for nucleation and maintenance of a functional human centromere. EMBO J 26:1279-91
Kouprina, Natalay; Noskov, Vladimir N; Solomon, Greg et al. (2007) Mutational analysis of SPANX genes in families with X-linked prostate cancer. Prostate 67:820-8
Kouprina, Natalay; Noskov, Vladimir N; Koriabine, Maxim et al. (2004) Exploring transformation-associated recombination cloning for selective isolation of genomic regions. Methods Mol Biol 255:69-89
Kouprina, Natalay; Pavlicek, Adam; Mochida, Ganeshwaran H et al. (2004) Accelerated evolution of the ASPM gene controlling brain size begins prior to human brain expansion. PLoS Biol 2:E126

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