Hypothalamic transcriptomes of 99 mouse strains reveal trans eQTL hotspots, splicing QTLs and novel non-coding genes.

Yehudit Hasin-Brumshtein,Farhad Hormozdiari,Paul D Piehowski,Richard D Smith,Desmond J Smith,Arshad H Khan,Xinshu Xiao,Anneke Brümmer,Aldons J Lusis,Eleazar Eskin,Brian W Parks,Matteo Pellegrini,Calvin Pan,Vladislav A Petyuk

doi:10.7554/elife.15614

Yehudit Hasin-Brumshtein, Farhad Hormozdiari + Show 12 more

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https://doi.org/10.7554/elife.15614

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Abstract

Previous studies had shown that the integration of genome wide expression profiles, in metabolic tissues, with genetic and phenotypic variance, provided valuable insight into the underlying molecular mechanisms. We used RNA-Seq to characterize hypothalamic transcriptome in 99 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP), a reference resource population for cardiovascular and metabolic traits. We report numerous novel transcripts supported by proteomic analyses, as well as novel non coding RNAs. High resolution genetic mapping of transcript levels in HMDP, reveals both local and trans expression Quantitative Trait Loci (eQTLs) demonstrating 2 trans eQTL 'hotspots' associated with expression of hundreds of genes. We also report thousands of alternative splicing events regulated by genetic variants. Finally, comparison with about 150 metabolic and cardiovascular traits revealed many highly significant associations. Our data provide a rich resource for understanding the many physiologic functions mediated by the hypothalamus and their genetic regulation.

Highlights

The regulation of body weight and appetite are complex processes, in which hypothalamic nuclei play a pivotal role
We explored the transcriptional landscape of mouse hypothalamus using RNAseq from 282 mice, representing 99 inbred and recombinant inbred strains from the Hybrid Mouse Diversity Panel (HMDP)
In this work we present a comprehensive picture of the transcriptome of the mouse hypothalamus and its genetic variation and regulation

Summary

Introduction

The regulation of body weight and appetite are complex processes, in which hypothalamic nuclei play a pivotal role. Genome wide association studies have shown that DNA sequence variants significantly contribute to variation in metabolic traits both in humans and mice. In most cases the connection between genetic variant and final phenotype remains unknown (Suhre et al, 2011; Teslovich et al, 2010; Lappalainen et al, 2013). In an effort to better understand how genetic variation results in phenotypic differences, many projects in the last decade have focused on genome

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