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Genetic identification of Ly75 as a novel quantitative trait gene for resistance to obesity in mice.

ABSTRACT: Identification of causal quantitative trait genes (QTGs) governing obesity is challenging. We previously revealed that the lymphocyte antigen 75 (Ly75) gene with an immune function is a putative QTG for Pbwg1.5, a quantitative trait locus (QTL) for resistance to obesity found from wild mice (Mus musculus castaneus). The objective of this study was to identify a true QTG for Pbwg1.5 by a combined approach of a quantitative complementation test, qualitative phenotypic analyses and causal analysis using segregating populations. In a four-way cross population among an Ly75 knockout strain, a subcongenic strain carrying Pbwg1.5 and their background strains, the quantitative complementation test showed genetic evidence that the Ly75 locus is identical to Pbwg1.5. Qualitative phenotypic analyses in two intercross populations between knockout and background strains and between subcongenic and background strains suggested that Ly75 may have pleiotropic effects on weights of white fat pads and organs. Causal analysis in the intercross population between knockout and background strains revealed that only variation in fat pad weight is caused by the genotypic difference via the difference in liver Ly75 expression. The results showed that Ly75 is a true Pbwg1.5 QTG for resistance to obesity. The finding provides a novel insight for obesity biology.

SUBMITTER: Makino K

PROVIDER: S-EPMC6281609 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Genetic identification of Ly75 as a novel quantitative trait gene for resistance to obesity in mice.

Makino Keita K Ishikawa Akira A

Scientific reports 20181205 1

Identification of causal quantitative trait genes (QTGs) governing obesity is challenging. We previously revealed that the lymphocyte antigen 75 (Ly75) gene with an immune function is a putative QTG for Pbwg1.5, a quantitative trait locus (QTL) for resistance to obesity found from wild mice (Mus musculus castaneus). The objective of this study was to identify a true QTG for Pbwg1.5 by a combined approach of a quantitative complementation test, qualitative phenotypic analyses and causal analysis ...[more]

PMID: 30518881

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Project description:Trauma- and stress-related disorders are clinically heterogeneous and associated with substantial genetic risk. Understanding the biological origins of heterogeneity of key intermediate phenotypes such as cognition and emotion can provide novel mechanistic insights into disorder pathogenesis. Performing quantitative genetics in animal models is a tractable strategy for examining both the genetic basis of intermediate phenotypes and functional testing of candidate quantitative traits genes (QTGs). Here, existing and newly collected data were used for collaborative genome-wide mapping of cued fear acquisition and expression in 65 mouse strains from the BXD genetic reference panel. For fear acquisition, we identified a significant locus on chromosome (Chr) 10 and eight suggestive loci on Chr 2, 4, 5, 11, 13, and 15. For fear expression, we identified one significant and another highly suggestive locus on Chr 13, as well as four suggestive loci on Chr 10, 11, and X. Across these loci, 60 putative QTGs were identified. The quantitative trait locus on distal Chr 13 contained a single, highly promising gene at the location of the peak likelihood ratio statistic score. The gene, hyperpolarization-activated cyclic nucleotide-gated channel 1 (Hcn1), regulates neuronal excitability. Validation experiments using behavioral pharmacology revealed that functional Hcn channels in the basolateral amygdala are necessary for conditioned fear acquisition and expression. Hcn1, together with the other candidate QTGs, thus provide new targets for neurobiological and treatment studies of fear learning and trauma- and stress-related disorders.There is a knowledge gap in understanding the genetic contributions to behavioral heterogeneity in typical and atypical populations. Mouse genetic reference panels (GRPs) provide one approach for identifying genetic sources of variation. Here, we identified three loci for conditioned fear acquisition and expression in a mouse GRP. Each locus contained candidate quantitative trait genes (QTGs). One locus had a single QTG, Hcn1 (hyperpolarization-activated cyclic nucleotide-gated channel 1), which has been implicated in neuronal excitability and learning. This discovery was validated using behavioral pharmacology, revealing that Hcn channels in the basolateral amygdala are required for fear acquisition and expression. The study thus identifies novel candidate QTGs that may contribute to variation in emotional learning and highlight the utility of mouse GRPs for the identification of genes underlying complex traits.

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

Genetic identification of Ly75 as a novel quantitative trait gene for resistance to obesity in mice.

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Genetic identification of Ly75 as a novel quantitative trait gene for resistance to obesity in mice.

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