Assessing cell-specific effects of genetic variations using tRNA microarrays
Background: By definition, effect of synonymous single-nucleotide variants (SNVs) on protein folding and function are neutral, as they alter the codon and not the encoded amino acid. Recent examples indicate tissue-specific and transfer RNA (tRNA)-dependent effects of some genetic variations arguing against neutrality of synonymous SNVs for protein biogenesis. Results: We performed systematic analysis of tRNA abunandance across in various models used in cystic fibrosis (CF) research and drug development, including Fischer rat thyroid (FRT) cells, patient-derived primary human bronchial epithelia (HBE) from lung biopsies, primary human nasal epithelia (HNE) from nasal curettage, intestinal organoids, and airway progenitor-directed differentiation of human induced pluripotent stem cells (iPSCs). These were compared to an immortalized CF bronchial cell model (CFBE41o-) and two widely used laboratory cell lines, HeLa and HEK293. We discovered that specific synonymous SNVs exhibited differential effects which correlated with variable concentrations of cognate tRNAs. Conclusions: Our results highlight ways in which the presence of synonymous SNVs may alter local kinetics of mRNA translation; and thus, impact protein biogenesis and function. This effect is likely to influence results from mechansistic analysis and/or drug screeining efforts, and establishes importance of cereful model system selection based on genetic variation profile.
|Keywords||Cystic fibrosis, Nucleotide variants, Protein translation, Synonymous single nucleotide polymorphisms, tRNA|
|Persistent URL||dx.doi.org/10.1186/s12864-019-5864-1, hdl.handle.net/1765/118385|
Polte, C. (Christine), Wedemeyer, D. (Daniel), Oliver, K.E. (Kathryn E.), Wagner, J. (Johannes), Bijvelds, M.J.C, Mahoney, J. (John), … Ignatova, Z. (Zoya). (2019). Assessing cell-specific effects of genetic variations using tRNA microarrays. BMC Genomics, 20. doi:10.1186/s12864-019-5864-1