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- Title
Assessing cell-specific effects of genetic variations using tRNA microarrays.
- Authors
Polte, Christine; Wedemeyer, Daniel; Oliver, Kathryn E.; Wagner, Johannes; Bijvelds, Marcel J. C.; Mahoney, John; de Jonge, Hugo R.; Sorscher, Eric J.; Ignatova, Zoya
- Abstract
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.
- Subjects
PLURIPOTENT stem cells; TRANSFER RNA; INDUCED pluripotent stem cells; PROTEIN folding; CYSTIC fibrosis
- Publication
BMC Genomics, 2019, Vol 20, Issue 8, pN.PAG
- ISSN
1471-2164
- Publication type
Article
- DOI
10.1186/s12864-019-5864-1