Prioritization of candidate genes for the effect of Fob3b1 QTL on chromosome 15 in mouse models for polygenic obesity and leanness using integrative genomics

Šimon, Martin (author), Kunej, Tanja (author), Morton, Nicholas M. (author), Horvat, Simon (author)

The accumulation of excess fat affects meat quality, fertility, productivity, and whole-body metabolism in farm animals. The mouse model presents an efficient tool for investigating these traits. Previous QTL analyses of the unique mouse selection lines for polygenic obesity (Fat line) and leanness (Lean line) have revealed four major obesity QTLs: Fob1, Fob2, Fob3, and Fob4. Fob3, located on chromosome 15, was later subdivided into Fob3a and Fob3b, which additionally split into Fob3b1 and Fob3b2. Of the 158 genes annotated in Fob3b1, 16 candidate genes have been previously proposed for the QTL effects. However, genomic variability between the Fat and Lean lines at this locus has not been fully investigated. The present study aimed to validate previously identified candidates and to identify novel candidate genes potentially responsible for the Fob3b1 effect. Data from whole-genome sequencing and transcriptome analyses of Fat and Lean mouse lines were integrated with obesity QTLs in cattle and pigs from Animal QTLdb and phenotypes obtained from the International Mouse Phenotyping Consortium (IMPC) and the Mouse Genome Database (MGD). Out of 158 genes located in the Fob3b1 interval we prioritized 17 candidate genes, including six previously proposed (Adgrb1, Col22a1, Cyp11b1, Dgat1, Gpibp1 and Ly6a) and 11 novel candidates: 9030619P08Rik, Eppk1, Kcnk9, Ly6c1, Ly6d, Ly6h, Ly6i, Ly6m, Ptk2, Trappc9, and a strong candidate Ly6e that deserve further functional analyses. Biological function and literature screening for candidate genes suggest that the Fob3b1's impact on obesity may operate through triglyceride metabolism (Dgat1 and Gpihbp1) and cytoskeletal and extracellular matrix remodelling (Ly6a, Ly6e and Eppk1). Further fine mapping, genetic and "omic" studies should clarify whether the Fob3b1 effect is due to a causal genetic variant in one of the candidates or possibly due to an additive effect of a combination of these positional candidates. The applied bioinformatics approach in determining the priority of candidate genes for obesity can also serve as a model for other traits in veterinary and livestock sciences.

• Language: English
• Keywords: data integration, gene expression, gene prioritisation, mouse models, obesity, QTL, single nucleotide polymorphism
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: BF - Biotechnical Faculty
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: Str. 127-136
• Numbering: Vol. 61, iss. 2
• PID: 20.500.12556/RUL-158787
• UDC: 575
• ISSN on article: 1580-4003
• DOI: 10.26873/SVR-1972-2024
• COBISS.SI-ID: 199456259
• Publication date in RUL: 20.06.2024

Record is a part of a journal

• Title: Slovenian veterinary research. ǂthe ǂscientific journal of the Veterinary Faculty University of Ljubljana
• Shortened title: Slov. vet. res.
• Publisher: Veterinarska fakulteta, Veterinarska fakulteta, Založba Univerze v Ljubljani
• ISSN: 1580-4003
• COBISS.SI-ID: 108028416

Licences

• License: CC BY-SA 4.0, Creative Commons Attribution-ShareAlike 4.0 International
• Link: http://creativecommons.org/licenses/by-sa/4.0/
• Description: This Creative Commons license is very similar to the regular Attribution license, but requires the release of all derivative works under this same license.

Secondary language

• Language: Slovenian
• Title: oločanje prioritetnih kandidatnih genov znotraj intervala Fob3b1 QTL na kromosomu 15 pri mišjih modelih za poligensko debelost in vitkost z uporabo integrativne genomike
• Keywords: genetika, kandidatni geni, genomika, debelost, vitkost, mišji modeli

Projects

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: P4-0220
• Name: Primerjalna genomika in genomska biodiverziteta

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: J4-2548
• Name: Vpliv RNA variant na fenotipsko raznolikost pri živalskih modelih