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

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

doi:10.7554/eLife.15614

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

Elife. 2016 Sep 13:5:e15614. doi: 10.7554/eLife.15614.

Authors

Yehudit Hasin-Brumshtein^{1

2

3

4}, Arshad H Khan⁵, Farhad Hormozdiari⁶, Calvin Pan^{1

2}, Brian W Parks^{1

2

3

4}, Vladislav A Petyuk⁷, Paul D Piehowski⁷, Anneke Brümmer⁸, Matteo Pellegrini⁹, Xinshu Xiao⁸, Eleazar Eskin⁶, Richard D Smith⁷, Aldons J Lusis^{1

2

3

4}, Desmond J Smith⁵

Affiliations

¹ Department of Human Genetics, University of California, Los Angeles, Los Angeles, United States.
² David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
³ Department of Microbiology, University of California, Los Angeles, Los Angeles, United states.
⁴ Department of Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, United States.
⁵ Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States.
⁶ Department of Computer Science, University of California, Los Angeles, Los Angeles, United States.
⁷ Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States.
⁸ Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, United States.
⁹ Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, United States.

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.

Keywords: RNA-Seq; eQTL; evolutionary biology; genomics; high fat diet; hypothalamus; mouse; neuroscience; obesity; trans-eQTL.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Alternative Splicing
Animals
Cardiovascular Diseases / genetics
Chromosome Mapping
Genetic Association Studies
Hypothalamus / physiology*
Metabolic Diseases / genetics
Mice
Proteome / analysis
Quantitative Trait Loci*
RNA, Untranslated / analysis
Sequence Analysis, RNA
Transcriptome*

Substances

Proteome
RNA, Untranslated

Abstract

Publication types

MeSH terms

Substances

Grants and funding