Inimese DNA koopiaarvu variatsioonid: nende tekkemehhanismid ja ...

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Human copy number variations: mechanisms of formation and methods of detection. Olga Tšuiko Summary During the recent years our knowledge regarding to human copy number variants has greatly increased due to completion of Human Genome Sequencing project and establishing of HapMap project. Nowadays, numerous databases for describing CNV-s have been created, according to which, it is now clear that CNV distribution among human genome is rather wide and a major part of CNV-s might be involved in the development of an abnormal phenotype. CNV-s were shown to cause sporadic diseases and mendelian or complex traits, by affecting gene dosage, disruption of the gene or by causing the positional effect. The use of microarrays has made it possible to establish that in about of 10-20% of clinical cases, the reason for developmental delay lies in the submicroscopic DNA aberrations. Despite the fact, that SNP-s are considered to be the main factor in the determination of human variability, it was proposed that CNV-s are responsible for most of genetic and phenotypic variation. Thanks to accelerated development of methods for studying copy number changes, three main mechanisms were proposed for the formation of CNV-s: recombination-based Non-Allelic Homologous Recombination and Non-Homologous End Joining, and a relatively new replication-based mechanism – Fork Stalling and Template Switching/Microhomology Mediated Break Induced Replication. Detailed CNV maps offer a great deal of interest for researches involved in the study of evolution as well. It is thought that CNV may be a leading force in the human evolution via gene duplication and exon shuffling. However, a lot of CNV regions are yet to be discovered, especially those that cover only a couple of dozens of base pairs. Thus, further studies in the improving of methods of CNV detection and increasing resolution may give an opportunity to examine CNV mechanisms of formation in greater detail and to give the picture of how genomic rearrangements affect genes and their regulatory elements. Understanding of the molecular basis for CNV formation will provide the opportunity to find more regions, susceptible to genomic rearrangements, thus being a very promising tool in clinical molecular diagnostic development and proper assessment of medical methods. 30
Kirjanduse loetelu A) Ajakirjad Armour, J. A., Sismani, C., Patsalis, P. C., and Cross, G. (2000). Measurement of locus copy number by hybridisation with amplifiable probes. Nucleic Acids Res 28(2), 605-9. Aula, P., Kääriäinen, H., and Palotie, A. (2010). "Pärilikkusmeditsiin." Carter, N. P. (2007). Methods and strategies for analyzing copy number variation using DNA microarrays. Nat Genet 39(7 Suppl), S16-21. Conrad, D. F., and Hurles, M. E. (2007). The population genetics of structural variation. Nat Genet 39(7 Suppl), S30-6. Conrad, D. F., Pinto, D., Redon, R., Feuk, L., Gokcumen, O., Zhang, Y., Aerts, J., Andrews, T. D., Barnes, C., Campbell, P., Fitzgerald, T., Hu, M., Ihm, C. H., Kristiansson, K., Macarthur, D. G., Macdonald, J. R., Onyiah, I., Pang, A. W., Robson, S., Stirrups, K., Valsesia, A., Walter, K., Wei, J., Tyler-Smith, C., Carter, N. P., Lee, C., Scherer, S. W., and Hurles, M. E. (2009). Origins and functional impact of copy number variation in the human genome. Nature 464(7289), 704-12. de Cid, R., Riveira-Munoz, E., Zeeuwen, P. L., Robarge, J., Liao, W., Dannhauser, E. N., Giardina, E., Stuart, P. E., Nair, R., Helms, C., Escaramis, G., Ballana, E., Martin- Ezquerra, G., den Heijer, M., Kamsteeg, M., Joosten, I., Eichler, E. E., Lazaro, C., Pujol, R. M., Armengol, L., Abecasis, G., Elder, J. T., Novelli, G., Armour, J. A., Kwok, P. Y., Bowcock, A., Schalkwijk, J., and Estivill, X. (2009). Deletion of the late cornified envelope LCE3B and LCE3C genes as a susceptibility factor for psoriasis. Nat Genet 41(2), 211-5. Feuk, L. (2010). Inversion variants in the human genome: role in disease and genome architecture. Genome Med 2(2), 11. Freeman, J. L., Perry, G. H., Feuk, L., Redon, R., McCarroll, S. A., Altshuler, D. M., Aburatani, H., Jones, K. W., Tyler-Smith, C., Hurles, M. E., Carter, N. P., Scherer, S. W., and Lee, C. (2006). Copy number variation: new insights in genome diversity. Genome Res 16(8), 949-61. Gu, W., Zhang, F., and Lupski, J. R. (2008). Mechanisms for human genomic rearrangements. Pathogenetics 1(1), 4. Hastings, P. J., Ira, G., and Lupski, J. R. (2009a). A microhomology-mediated break-induced replication model for the origin of human copy number variation. PLoS Genet 5(1), e1000327. Hastings, P. J., Lupski, J. R., Rosenberg, S. M., and Ira, G. (2009b). Mechanisms of change in gene copy number. Nat Rev Genet 10(8), 551-64. Iafrate, A. J., Feuk, L., Rivera, M. N., Listewnik, M. L., Donahoe, P. K., Qi, Y., Scherer, S. W., and Lee, C. (2004). Detection of large-scale variation in the human genome. Nat Genet 36(9), 949-51. 31
Page 1 and 2: TARTU ÜLIKOOL LOODUS- JA TEHNOLOOG
Page 3 and 4: Sissejuhatus Inimese genoomi lõpli
Page 5 and 6: 1. Koopiaarvu variatsioonid: fenome
Page 7 and 8: valikule ja geneetilise triivile. K
Page 9 and 10: Joonis 1. Genoomsete ümberkorraldu
Page 11 and 12: ka olla aluseks sellistele erinevus
Page 13 and 14: Esimesena pakkusid mittehomoloogset
Page 15 and 16: mehhanism - replikatsioonikahvli pe
Page 17 and 18: MMBIR võib põhjustada erinevate s
Page 19 and 20: 3.1. Genotüüp-fenotüüp suhe Fen
Page 21 and 22: inversioon vanemate kromosoomis soo
Page 23 and 24: meetod, mille lahutusvõime on prae
Page 25 and 26: mõnede indiviidide puhul sõltub t
Page 27 and 28: 4.2.2. Multipleks ligeeritavate pro
Page 29: Kokkuvõte Viimaste aastate jooksul
Page 33 and 34: Nobile, C., Toffolatti, L., Rizzi,

Inimese DNA koopiaarvu variatsioonid: nende tekkemehhanismid ja ...

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