PRIORITIZATION OF CANDIDATE GENES FOR THE EFFECT OF Fob3b1 QTL ON CHROMOSOME 15 IN MOUSE MODELS FOR POLYGENIC OBESITY AND LEANNESS USING INTEGRATIVE GENOMICS
DOI:
https://doi.org/10.26873/SVR-1972-2024Keywords:
data integration, gene expression, gene prioritisation, mouse models, obesity, QTL, single nucleotide polymorphismAbstract
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. Out of 158 genes located in the Fob3b1 interval we prioritized 17 candidate genes, including six previously proposed (Adgrb1, Col22a1, Cyp11b1, Dgat1, Gpihbp1 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.
Določanje prioritetnih kandidatnih genov znotraj intervala Fob3b1 QTL na kromosomu 15 pri mišjih modelih za poligensko debelost in vitkost z uporabo integrativne genomike
Izvleček: Kopičenje odvečne maščobe vpliva na kakovost mesa, plodnost, proizvodnost in presnovo pri rejnih živalih. Mišji modeli predstavljajo učinkovito orodje za raziskovanje genetske osnove teh lastnosti. Predhodne analize QTL-ov edinstvenih mišjih selekcijskih linij za poligensko debelost (debela linija) in vitkost (vitka linija) so razkrile štiri glavne QTL-e za debelost: Fob1, Fob2, Fob3 in Fob4. Fob3, ki se nahaja na kromosomu 15, je bil kasneje razdeljen na Fob3a in Fob3b, zadnji pa se dodatno razdeli na Fob3b1 in Fob3b2. Od 158 genov, anotiranih v Fob3b1, je bilo v prejšnjih študijah predlaganih 16 kandidatnih genov. Vendar pa genomska variabilnost med debelo in vitko linijo na tem lokusu ni bila v celoti raziskana. Namen te študije je bil potrditi predhodno identificirane kandidate in identificirati nove kandidatne gene, ki bi lahko bili odgovorni za učinek Fob3b1. Podatki iz celotnega genoma sekvenciranja in transkriptomskih analiz debelih in vitkih mišjih linij so bili vključeni v primerjalno analizo s QTL-i za debelost pri govedu in prašičih iz Animal QTLdb ter fenotipi, pridobljenimi iz Mednarodnega konzorcija za fenotipizacijo miši (IMPC) in podatkovne zbirke mišjega genoma (MGD). Izmed 158 genov, lociranih v Fob3b1, smo prednostno obravnavali 17 kandidatnih genov, vključno s šestimi predhodno predlaganimi (Adgrb1, Col22a1, Cyp11b1, Dgat1, Gpihbp1 in Ly6a) in 11 novimi kandidati: 9030619P08Rik, Eppk1, Kcnk9, Ly6c1, Ly6d, Ly6h, Ly6i, Ly6m, Ptk2, Trappc9 in Ly6e. Biološka funkcija in pregled literature za kandidatne gene nakazujeta, da lahko učinek Fob3b1 na debelost deluje preko metabolizma trigliceridov (Dgat1 in Gpihbp1) ter preoblikovanja citoskeleta in zunajceličnega matriksa (Ly6a, Ly6e in Eppk1). Nadaljnje natančno kartiranje, genetske in »omske« študije bodo pojasnili, ali je učinek Fob3b1 posledica vzročnega učinka ene same genetske različice ali morda aditivnega učinka kombinacije večjega števila teh pozicijskih kandidatov. Uporabljeni bioinformacijski pristop pri določanju prednostne liste kandidatnih genov za debelost lahko služi tudi kot model za preučevanje drugih lastnosti v veterinarskih in živinorejskih znanostih.
Ključne besede: povezovanje podatkov; izražanje genov; razvrstitev genov po pomembnosti; mišji modeli; debelost; QTL; posamezni nukleotid; polimorfizem
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