Subcongenic analysis of a quantitative trait locus affecting body weight and glucose metabolism in zinc transporter 7 (znt7)-knockout mice

Authors: Huang, Liping; TEPAAMORNDECH, SURAPUN - National Center For Genetic Engineering And Biotechnology (BIOTEC); Kirschke, Catherine; CAI, YIMENG - University Of California, Davis; ZHAO, JUNLI - Nanjing Xiaozhuang University; CAO, XIAOHAN - University Of California, Davis; RAO, ANDREW - University Of California, Davis

Submitted to: BioMed Central (BMC) Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/11/2018
Publication Date: 2/18/2019
Citation: Huang, L., Tepaamorndech, S., Kirschke, C.P., Cai, Y., Zhao, J., Cao, X., Rao, A. 2019. Subcongenic analysis of a quantitative trait locus affecting body weight and glucose metabolism in zinc transporter 7 (znt7)-knockout mice. BioMed Central (BMC) Genetics. 20:19. https://doi.org/10.1186/s12863-019-0715-2.
DOI: https://doi.org/10.1186/s12863-019-0715-2

Interpretive Summary: A genome-wide mapping study, a tool to identify new genes and their function linking to a defined phenotype, such as growth or weight gain, using male znt7-KO mice (these animals lack a zinc transporter 7 in their genome) in a mixed 129P1/ReJ (129P1) and C57BL/6J (B6) genetic background. We previously identified a quantitative trait locus (QTL) on mouse chromosome 7, which had a synergistic effect on weight gain and fat depot with the znt7-null mutation. In this study, the genetic segment on mouse chromosome 7 was investigated by newly created subcongenic znt7-KO mouse strains carrying different lengths of genomic fragments of chromosome 7 from the 129P1 donor strain in the B6 recipient background. We demonstrated that the sub-QTL for weight gain was located in the proximal region of the previously mapped QTL, ranging from 47.4 to 64.4 megabases (Mb) on chromosome 7. The 129P1 donor allele conferred lower weight gain and better glucose handling during intraperitoneal glucose challenge than the B6 allele control. We identified four candidate genes, including Htatip2, E030018B13Rik, Nipa1, and Atp10a, in this sub-QTL using quantitative RT-PCR (a method to quantify gene expression) and cSNP detection (single nucleotide polymorphisms in the protein coding region; a tool to predict functional or structural consequences of a given protein due to an amino acid change in the protein sequence).This study dissected the genetic basis of determinate of body weight and glucose metabolism in znt7-KO mice. The study demonstrates that a 17-Mb long 129P1 genomic region on mouse chromosome 7 confers reduction in weight gain and an improved glucose tolerance in znt7-KO male mice. Among the four candidate genes identified, Htatip2 is the most likely candidate gene involved in control of body weight based on its function in regulation of lipid metabolism. The candidate genes discovered in this study laid a foundation for future studies of their roles in development of metabolic diseases, such as obesity and type 2 diabetes.

Technical Abstract: A genome-wide mapping study using male F2 znt7-KO mice and their wild type littermates in a mixed 129P1/ReJ (129P1) and C57BL/6J (B6) background identified a quantitative trait locus (QTL) on chromosome 7, which had a synergistic effect on body weight gain and fat depot with the znt7-null mutation. The genetic segment for body weight on mouse chromosome 7 was investigated by newly created subcongenic znt7-KO mouse strains carrying different lengths of genomic fragments of chromosome 7 from the 129P1 donor strain in the B6 background. We demonstrated that the sub-QTL for body weight was located in the proximal region of the previously mapped QTL, ranging from 47.4 to 64.4 megabases (Mb) on chromosome 7. The 129P1 donor allele conferred lower body weight gain and better glucose handling during intraperitoneal glucose challenge than the B6 allele control. We identified four candidate genes, including Htatip2, E030018B13Rik, Nipa1, and Atp10a, in this sub-QTL using quantitative RT-PCR and cSNP detection (single nucleotide polymorphisms in the protein coding region).This study dissected the genetic basis of determinate of body weight and glucose metabolism in znt7-KO mice. The study demonstrates that a 17-Mb long 129P1 genomic region on mouse chromosome 7 confers reduction in weight gain and an improved glucose tolerance in znt7-KO male mice. Among the four candidate genes identified, Htatip2 is the most likely candidate gene involved in control of body weight based on its function in regulation of lipid metabolism. The candidate genes discovered in this study laid a foundation for future studies of their roles in development of metabolic diseases, such as obesity and type 2 diabetes.