engleski

Computational Analysis of Sequence Variants Found In 5' And 3' Untranslated Regions of BRCA1 and BRCA2 Genes

Untranslated regions (UTRs) are parts of the mature mRNA located before the start codon (5' UTR) and after the stop codon (3' UTR). They are transcribed with the coding region but they are not translated. Several regulatory roles have been assigned to the untranslated regions, including mRNA's localization and stability, and translational efficiency. These functions depend both on the sequence and structure of the UTRs. BRCA1 and BRCA2 are the major hereditary breast/ovarian cancer predisposing genes and their mutations increase the risk of developing cancer. Interpretation of sequence variants found in genetic testing is the major concern for BRCA genes, especially for risk assessment in genetic counseling. In general, for sequence variants found within the coding region of the genes it is much easier to predict their potential effects on the structure and function of the protein. Sequence variants that are found within untranslated and other regulatory genomic regions are much harder for interpretation. As it is known that the function of non-coding RNAs (ncRNAs) greatly depends on their secondary structure, we analyzed how sequence variants found in 5’ and 3’ UTRs of BRCA1 and BRCA2 genes could have impact on predicted consensus secondary structures of these UTRs. To extract sequences of 5’ and 3’ UTRs we used mRNA sequences of BRCA1 and BRCA2 genes from different organisms (from sea urchin to human). We then used different algorithms (RNAalifold, RNAforester…) to predict consensus secondary structures of UTRs and to find out if there are substructures that have been conserved by evolution, as it is far more likely that conserved structures are functionally important. From different public databases (BIC, kConFab, SNPdb…) we collected BRCA1 and BRCA2 5' and 3' UTRs variants and examine their potential functional significance that could be expressed by disrupting the consensus secondary structure. By analyzing potential changes in predicted secondary structures of the 5' and 3' UTRs from the patients with breast/ovarian cancer we tried to find out if this in silico approach could be used for evaluation of sequence variants of unknown clinical significance in cancer etiology.

BRCA1; BRCA2; 5' i 3' UTRovi; sekundarna struktura RNA; rak dojke

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