Functional variants within the 5UTR support reduced exon usage as a molecular mechanism underlying the quantitative trait gene Hnrnph1 for reduced methamphetamine sensitivity

Ruan, Q. T.; Yazdani, N.; Reed, E. R.; Beierle, J. A.; Peterson, L. P.; Luttik, K. P.; Szumlinski, K. K.; Johnson, W. E.; Ash, P. E. A.; Wolozin, B.; Bryant, C. D.

doi:10.1101/2020.01.11.902908

bioRxiv · 10.1101/2020.01.11.902908

Functional variants within the 5UTR support reduced exon usage as a molecular mechanism underlying the quantitative trait gene Hnrnph1 for reduced methamphetamine sensitivity

Ruan, Q. T.·Yazdani, N.·Reed, E. R.·Beierle, J. A.·Peterson, L. P.·Luttik, K. P.·Szumlinski, K. K.·Johnson, W. E.·Ash, P. E. A.·Wolozin, B.·Bryant, C. D.

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Abstract

We previously identified a 210 kb region on chromosome 11 (50.37-50.58 Mb, mm10) containing two protein-coding genes (Hnrnph1, Rufy1) that was necessary for reduced methamphetamine-induced locomotor activity in C57BL/6J congenic mice harboring DBA/2J polymorphisms. Gene editing of a small deletion in the first coding exon supported Hnrnph1 as a quantitative trait gene. We have since shown that Hnrnph1 mutants also exhibit reduced methamphetamine-induced reward, reinforcement, and dopamine release. However, the quantitative trait variants (QTVs) that modulate Hnrnph1 function at the molecular level are not known. Nine single nucleotide polymorphisms and seven indels distinguish C57BL/6J from DBA/2J within Hnrnph1, including four variants within the 5 untranslated region (UTR). Here, we show that a 114 kb introgressed region containing Hnrnph1 and Rufy1 was sufficient to cause a decrease in MA-induced locomotor activity. Gene-level transcriptome analysis of striatal tissue from 114 kb congenics versus Hnrnph1 mutants identified a nearly perfect correlation of fold-change in expression for those differentially expressed genes that were common to both mouse lines, indicating functionally similar effects on the transcriptome and behavior. Exon-level analysis (including noncoding exons) revealed decreased 5 UTR usage of Hnrnph1 and immunoblot analysis identified a corresponding decrease in hnRNP H protein in 114 kb congenic mice. Molecular cloning of the Hnrnph1 5 UTR containing all four variants (but none of them individually) upstream of a reporter induced a decrease in reporter signal in both HEK293 and N2a cells, thus identifying a set of QTVs underlying molecular regulation of Hnrnph1.

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Ruan, Q. T., Yazdani, N., Reed, E. R., Beierle, J. A., Peterson, L. P., Luttik, K. P., Szumlinski, K. K., Johnson, W. E., Ash, P. E. A., Wolozin, B., Bryant, C. D.. 2020-01-13. Functional variants within the 5UTR support reduced exon usage as a molecular mechanism underlying the quantitative trait gene Hnrnph1 for reduced methamphetamine sensitivity. https://doi.org/10.1101/2020.01.11.902908

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