Evolutionarily conserved genomic regions are parts of the genome whose sequences have remained largely unchanged among different species throughout evolution, suggesting that they have important biological roles. The aim of this master’s thesis was to analyse selected conserved genomic regions in humans, identify the genes located within these regions, and evaluate their biological functions and associations with monogenic diseases or other phenotypes affecting development, survival, or fundamental biological processes. The analysis included 20 selected constrained elements (CE), comprising ten of the longest elements and ten with the highest values of evolutionary conservation, measured using GERP (genomic evolutionary rate profiling). Using the Ensembl, NCBI, and STRING tools, we identified the genes containing CE regions and characterized their biological functions, while associations with monogenic diseases were investigated using the OMIM and ClinVar databases. For causal variants associated with monogenic diseases, GERP values were also examined, and for selected variants, multiple sequence alignments of genomes from 92 mammalian species were additionally performed. Information on gene function and their association with lethality was obtained from the MGD database. The analysed CE regions are located within 17 genes that are primarily involved in nervous and muscular system function, organismal development, regulation of gene expression, and cellular processes such as intracellular transport and signalling. Causal variants associated with various monogenic diseases were identified in the genes VPS13D, TTN, MYORG, KMT2A, SACS and EXT1. Nucleotide sequence alignments of selected variants showed a high degree of sequence conservation among mammalian species. Previous studies have demonstrated lethality in mice for 12 of the 17 analysed genes. The results indicate that the analysed CE regions overlap with genes involved in various fundamental biological processes, with associations with disease and organismal survival also identified for some genes. These findings may contribute to a better understanding of the functional significance of CE regions and facilitate the identification of potentially important genes and variants in future research.
|
