Author(s): Michael J. Molumby, Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, United States; Michael J. Molumby, Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, United States; Mridu Kapur, Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, United States; Susan L. Ackerman, Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, United States //

ABSTRACT: Many genetic loci contribute to complex polygenic disease etiology. Genome-wide association studies have established that most complex disease risk loci reside in non-coding regions containing single nucleotide polymorphisms (SNPs) within regulatory elements. Sequence variation at these non-coding risk loci may contribute to complex disease manifestation via epistatic interactions with other risk loci to alter gene expression of coding and non-coding genes. Transfer RNAs (tRNAs) are highly conserved non-coding adapter molecules critical for protein synthesis and maintenance of cellular homeostasis. Strong purifying selection acts on mutations that occur within the mature tRNA sequence, however, the regions flanking highly expressed tRNA genes exhibit elevated mutation rates as a result of transcription-associated mutagenesis. To date, the impact of sequence changes in these regions on tRNA expression and function is unknown. Here, we present evidence that SNPs upstream of a tRNA gene differentially alter its expression by regulating RNA Polymerase III recruitment. These regulatory SNPs were identified during a forward genetic screen that utilized mouse inbred lines to identify a locus which modified neurodegeneration in mice lacking the ribosome rescue factor, GTPBP2.  Interestingly, neurodegeneration can be exacerbated or attenuated depending on the SNP profile. Our results demonstrate that impact of SNPs upstream of tRNA genes may emerge through epistasis to impact human health.

Source of Funding: NINDS F32NS111857, NINDS R01NS094637, Howard Hughes Medical Institute