Dmytruk I. The genes alleles polymorphisms involved in the processes of DNA methylation in patient with high risk of de novo mutations.

The thesis is devoted to analysis of associations between different combinations of gene's allelic variants involved in methylation system and the appearance of de novo mutations in somatic and generative cells among individuals with high risk of spontaneous mutations (parents of children with achondro/hypochondroplasia, leukemia/lymphoma and breast cancer patients). It was established the prevalence of FGFR3 gene mutations c.1138G>A, c.1138G>C, c.1620C>A and c.1620C>G in patients with achondroplasia and hypochondroplasia in Ukraine. De novo mutations of FGFR3 gene were revealed in 93% of patients. It was first shown that TYMS alelle of the high expression (3RG) increased the risk of de novo mutations in germ cells, causing hereditary diseases, such as achondroplasia or hypochondroplasia. It was found that MTHFR 677C>T, MTR 2756A>G, TYMS 3R2R and TYMS 3RG>C genes polymorphisms act as modulating factors for breast cancer and leukemias/lymphomas occurrence, possibly causing de novo mutations in somatic cells. According to our data, the propensity to breast cancer and leukaemia in West Ukrainians was associated with the combination of few genotypes, namely: MTHFR 677СС / MTR 2756AG / TYMS 2R2R, 3RC2R, 3RC3RC and MTHFR 677СT / TYMS 3RG2R, 3RG3RC. It was established that the combination of genotypes MTHFR 677CC / MTR 2756AA / TYMS 3RG2R, 3RG3RC and MTR 2756AA / TYMS 3RG2R, 3RG3RC increased the risk of having a child with achondro- /hypochondroplasia. It is shown that frequencies of alleles and genotypes of polymorphic loci DNMT3B 579G>T, DNMT3B 149C>T, MTR 2756A>G, TYMS 3R2R and TYMS 3RG>C among the population of Western Ukraine, identified in the study, coincide with the generalized data among the Europeans (according to 1000 Genome Project).