Whole genome sequence analysis of the TALLYHO/Jng mouse

Abstract

BackgroundThe TALLYHO/Jng (TH) mouse is a polygenic model for obesity and type 2 diabetes first described in the literature in 2001. The origin of the TH strain is an outbred colony of the Theiler Original strain and mice derived from this source were selectively bred for male hyperglycemia establishing an inbred strain at The Jackson Laboratory. TH mice manifest many of the disease phenotypes observed in human obesity and type 2 diabetes.ResultsWe sequenced the whole genome of TH mice maintained at Marshall University to a depth of approximately 64.8X coverage using data from three next generation sequencing runs. Genome-wide, we found approximately 4.31 million homozygous single nucleotide polymorphisms (SNPs) and 1.10 million homozygous small insertions and deletions (indels) of which 98,899 SNPs and 163,720 indels were unique to the TH strain compared to 28 previously sequenced inbred mouse strains. In order to identify potentially clinically-relevant genes, we intersected our list of SNP and indel variants with human orthologous genes in which variants were associated in GWAS studies with obesity, diabetes, and metabolic syndrome, and with genes previously shown to confer a monogenic obesity phenotype in humans, and found several candidate variants that could be functionally tested using TH mice. Further, we filtered our list of variants to those occurring in an obesity quantitative trait locus, tabw2, identified in TH mice and found a missense polymorphism in the Cidec gene and characterized this variant’s effect on protein function.ConclusionsWe generated a complete catalog of variants in TH mice using the data from whole genome sequencing. Our findings will facilitate the identification of causal variants that underlie metabolic diseases in TH mice and will enable identification of candidate susceptibility genes for complex human obesity and type 2 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3245-6) contains supplementary material, which is available to authorized users.

Chronic Insulin Infusion Down-Regulates Circulating and Urinary Nitric Oxide (NO) Levels Despite Molecular Changes in the Kidney Predicting Greater Endothelial NO Synthase Activity in Mice

“…We infused TALLYHO/Jng (TH) mice with insulin (50 U/kg·bw/d) for two weeks. TH mice were developed by Jackson Laboratory by selectively inbreeding mice of the Theiler Original colony for hyperglycemia [ 16 ]. Several multiple quantitative trait loci have been identified in these mice that are linked to adiposity, hyperglycemia, insulin resistance, and type 2 diabetes [ 16 ].…”

“…TH mice were developed by Jackson Laboratory by selectively inbreeding mice of the Theiler Original colony for hyperglycemia [ 16 ]. Several multiple quantitative trait loci have been identified in these mice that are linked to adiposity, hyperglycemia, insulin resistance, and type 2 diabetes [ 16 ]. Although female TH mice are obese, they are much more resistant to developing type 2 diabetes; thus we chose to study only males in this particular study.…”

Congenic mice demonstrate the presence of QTLs conferring obesity and hypercholesterolemia on chromosome 1 in the TALLYHO mouse

“…We previously conducted a whole genome sequencing analysis for the TH mouse and generated a complete catalog of variants (relative to the B6 strain) (Denvir et al 2016). We used this catalog to search potential candidates in the distal region of Chr 1.…”

“…We used a previously published catalog of sequence variants in the TH mouse (relative to the B6 strain) (Denvir et al 2016) to list all variants lying between the markers D1Mit498 (position 135,687,493 bp on Chr 1 in the GRCm38 genome build) and D1Mit361 (186,261,999 bp on Chr 1). We restricted these to variants with the potential to alter the protein sequence: namely those with sequence ontology terms “frameshift_variant”, “inframe_deletion”, “inframe_insertion”, “missense_variant”, “stop_gained”, “stop_lost”, “initiator_codon_variant”, “splice_region_variant”, “splice_acceptor_variant”, or “splice_donor_variant”.…”

Drosophila melanogasteras a Model for Diabetes Type 2 Progression

“…In addition, there are also a variety of different polygenic models of obesity that include the KK-AY mice [ 135 ], New Zealand obese (NZO) mice [ 136 ], the TALLYHO/Jng mice [ 137 ], and the OLETF rats [ 127 ], besides diet-induced models of obesity [ 30 ]. These models also lead to diabetic states.…”