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Identification of a Putative Quantitative Trait Gene for Resistance to Obesity in Mice Using Transcriptome Analysis and Causal Inference Tests.

ABSTRACT: It is still challenging to identify causal genes governing obesity. Pbwg1.5, a quantitative trait locus (QTL) for resistance to obesity, was previously discovered from wild Mus musculus castaneus mice and was fine-mapped to a 2.1-Mb genomic region of mouse chromosome 2, where no known gene with an effect on white adipose tissue (WAT) has been reported. The aim of this study was to identify a strong candidate gene for Pbwg1.5 by an integration approach of transcriptome analysis (RNA-sequencing followed by real-time PCR analysis) and the causal inference test (CIT), a statistical method to infer causal relationships between diplotypes, gene expression and trait values. Body weight, body composition and biochemical traits were measured in F2 mice obtained from an intercross between the C57BL/6JJcl strain and a congenic strain carrying Pbwg1.5 on the C57BL/6JJcl background. The F2 mice showed significant diplotype differences in 12 traits including body weight, WAT weight and serum cholesterol/triglyceride levels. The transcriptome analysis revealed that Ly75, Pla2r1, Fap and Gca genes were differentially expressed in the liver and that Fap, Ifih1 and Grb14 were differentially expressed in WAT. However, CITs indicated statistical evidence that only the liver Ly75 gene mediated between genotype and WAT. Ly75 expression was negatively associated with WAT weight. The results suggested that Ly75 is a putative quantitative trait gene for the obesity-resistant Pbwg1.5 QTL discovered from the wild M. m. castaneus mouse. The finding provides a novel insight into a better understanding of the genetic basis for prevention of obesity.

SUBMITTER: Ishikawa A

PROVIDER: S-EPMC5256930 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Identification of a Putative Quantitative Trait Gene for Resistance to Obesity in Mice Using Transcriptome Analysis and Causal Inference Tests.

Ishikawa Akira A

PloS one 20170123 1

It is still challenging to identify causal genes governing obesity. Pbwg1.5, a quantitative trait locus (QTL) for resistance to obesity, was previously discovered from wild Mus musculus castaneus mice and was fine-mapped to a 2.1-Mb genomic region of mouse chromosome 2, where no known gene with an effect on white adipose tissue (WAT) has been reported. The aim of this study was to identify a strong candidate gene for Pbwg1.5 by an integration approach of transcriptome analysis (RNA-sequencing fo ...[more]

PMID: 28114323

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Project description:BackgroundBreeding of fire blight resistant scions and rootstocks is a goal of several international apple breeding programs, as options are limited for management of this destructive disease caused by the bacterial pathogen Erwinia amylovora. A broad, large-effect quantitative trait locus (QTL) for fire blight resistance has been reported on linkage group 3 of Malus 'Robusta 5'. In this study we identified markers derived from putative fire blight resistance genes associated with the QTL by integrating further genetic mapping studies with bioinformatics analysis of transcript profiling data and genome sequence databases.ResultsWhen several defined E.amylovora strains were used to inoculate three progenies from international breeding programs, all with 'Robusta 5' as a common parent, two distinct QTLs were detected on linkage group 3, where only one had previously been mapped. In the New Zealand 'Malling 9' X 'Robusta 5' population inoculated with E. amylovora ICMP11176, the proximal QTL co-located with SNP markers derived from a leucine-rich repeat, receptor-like protein (MxdRLP1) and a closely linked class 3 peroxidase gene. While the QTL detected in the German 'Idared' X 'Robusta 5' population inoculated with E. amylovora strains Ea222_JKI or ICMP11176 was approximately 6 cM distal to this, directly below a SNP marker derived from a heat shock 90 family protein gene (HSP90). In the US 'Otawa3' X 'Robusta5' population inoculated with E. amylovora strains Ea273 or E2002a, the position of the LOD score peak on linkage group 3 was dependent upon the pathogen strains used for inoculation. One of the five MxdRLP1 alleles identified in fire blight resistant and susceptible cultivars was genetically associated with resistance and used to develop a high resolution melting PCR marker. A resistance QTL detected on linkage group 7 of the US population co-located with another HSP90 gene-family member and a WRKY transcription factor previously associated with fire blight resistance. However, this QTL was not observed in the New Zealand or German populations.ConclusionsThe results suggest that the upper region of 'Robusta 5' linkage group 3 contains multiple genes contributing to fire blight resistance and that their contributions to resistance can vary depending upon pathogen virulence and other factors. Mapping markers derived from putative fire blight resistance genes has proved a useful aid in defining these QTLs and developing markers for marker-assisted breeding of fire blight resistance.

Project description:Temporal analysis of genome-wide data can provide insights into the underlying mechanism of the biological processes in two ways. First, grouping the temporal data provides a richer, more robust representation of the underlying processes that are co-regulated. The net result is a significant dimensional reduction of the genome-wide array data into a smaller set of vocabularies for bioinformatics analysis. Second, the computed set of time-course vocabularies can be interrogated for a potential causal network that can shed light on the underlying interactions. The method is coupled with an experiment for investigating responses to high doses of ionizing radiation with and without a small priming dose. From a computational perspective, inference of a causal network can rapidly become computationally intractable with the increasing number of variables. Additionally, from a bioinformatics perspective, larger networks always hinder interpretation. Therefore, our method focuses on inferring the simplest network that is computationally tractable and interpretable. The method first reduces the number of temporal variables through consensus clustering to reveal a small set of temporal templates. It then enforces simplicity in the network configuration through the sparsity constraint, which is further regularized by requiring continuity between consecutive time points. We present intermediate results for each computational step, and apply our method to a time-course transcriptome dataset for a cell line receiving a challenge dose of ionizing radiation with and without a prior priming dose. Our analyses indicate that (i) the priming dose increases the diversity of the computed templates (e.g., diversity of transcriptome signatures); thus, increasing the network complexity; (ii) as a result of the priming dose, there are a number of unique templates with delayed and oscillatory profiles; and (iii) radiation-induced stress responses are enriched through pathway and subnetwork studies.

Project description:Tyrosylprotein sulfotransferase 2 (TPST2) is one of the enzymes responsible for tyrosine O-sulfation and catalyzes the sulfation of the specific tyrosine residue of thyroid stimulating hormone receptor (TSHR). Since this modification is indispensable for the activation of TSH signaling, a non-functional TPST2 mutation (Tpst2(grt)) in DW/J-grt mice leads to congenital hypothyroidism (CH) characterized by severe thyroid hypoplasia and dwarfism related to TSH hyporesponsiveness. Previous studies indicated that the genetic background of the 129(+Ter)/SvJcl (129) mouse strain ameliorates Tpst2(grt)-induced CH. To identify loci responsible for CH resistance in 129 mice, we performed quantitative trait locus (QTL) analysis using backcross progenies from susceptible DW/J and resistant 129 mice. We used the first principal component calculated from body weights at 5, 8 and 10 weeks as an indicator of CH, and QTL analysis mapped a major QTL showing a highly significant linkage to the distal portion of chromosome (Chr) 2; between D2Mit62 and D2Mit304, particularly close to D2Mit255. In addition, two male-specific QTLs showing statistically suggestive linkage were also detected on Chrs 4 and 18, respectively. All QTL alleles derived from the 129 strain increased resistance to growth retardation. There was also a positive correlation between recovery from thyroid hypoplasia and the presence of the 129 allele at D2Mit255 in male progenies. These results suggested that the major QTL on Chr 2 is involved in thyroid development. Moreover, since DW/J congenic strain mice carrying both a Tpst2(grt) mutation and 129 alleles in the major QTL show resistance to dwarfism and thyroid hypoplasia, we confirmed the presence of the resistant gene in this region, and that it is involved in thyroid development. Further genetical analysis should lead to identification of genes for CH tolerance and, from a better understanding of thyroid organogenesis and function, the subsequent development of new treatments for thyroid disorders.

Dataset Information

Identification of a Putative Quantitative Trait Gene for Resistance to Obesity in Mice Using Transcriptome Analysis and Causal Inference Tests.

Publications

Identification of a Putative Quantitative Trait Gene for Resistance to Obesity in Mice Using Transcriptome Analysis and Causal Inference Tests.

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