Primerjava regulatornih regij genov HIF pri debeli in vitki liniji miši

Rečnik, Matevž (author), Kunej, Tanja (mentor), Horvat, Simon (co-mentor)

Povišana raven nalaganja maščob pri debelosti ima večfaktorsko etiologijo. V zelo redkih primerih je rezultat ene same mutacije z velikim učinkom (monogena oblika) ali pa je posledica številnih genetskih različic z majhnimi učinki, vpliv katerih se sešteva v poligensko obliko debelosti. Slednjo obliko je težje diagnosticirati, ker je kvantitativni in kvalitativni doprinos različnih genov k bolezni v veliki meri še nepoznan, znano je le, da so učinki zelo majhni. Genska družina HIF je primer takšne skupine metabolno pomembnih genov, ki so aktivni tudi v maščobnem tkivu debelih posameznikov. Povezali so jih s kroničnimi vnetji, ki so eden izmed vzrokov za razvoj sladkorne bolezni tipa 2 in drugih metabolnih bolezni. Njihova morebitna vloga pri razvoju poligenske debelosti je še nepoznana. Namen te raziskave je bil odkriti razlike v regulatornih regijah genske družine Hif (Hif1, Epas1 in Hif3a) med selekcioniranima skupinama laboratorijskih miši. Po 60 generacijah selekcije med njima obstaja več kot petkratna razlika v masi telesnega maščevja. Odkrite različice smo umestili v referenčno zaporedje iz zbirke Ensembl in SwissRegulon, prikazali pa smo jih v programu GenomeBrowse. Rezultati bioinformacijske analize so pokazali, da je med linijama znotraj teh genov 418 razlik v zaporedju, večina v genu Hif1a debele linije. Od vseh odkritih različic se jih 24 nahaja v poznanih regulatornih zaporedjih. Glede na lokacijo različic v genih in vrednost GERP smo iz širokega nabora podatkov izbrali 28 različic nukleotidnega zaporedja, ki predstavljajo obetavne kandidate za nadaljnje raziskovanje in oceno njihove morebitne kavzalne vloge pri razvoju debelosti.

• Language: Slovenian
• Keywords: geni Hif, hipoksija maščobnega tkiva, miši, poligenska debelost, regulatorne regije
• Work type: Master's thesis/paper
• Typology: 2.09 - Master's Thesis
• Organization: BF - Biotechnical Faculty
• Year: 2023
• PID: 20.500.12556/RUL-144050
• COBISS.SI-ID: 139933187
• Publication date in RUL: 29.01.2023

Secondary language

• Language: English
• Title: Comparison of regulatory regions in HIF genes between fat and lean mouse lines

Abstract

The elevated rate of fat accumulation in obese individuals has a multifactorial etiology. In extremely rare cases, it can develop as a result of a single mutation with large effect (monogenic form), or as a combined effect of a multitude of less impactful genetic variants representing a polygenic form of obesity. This form is harder to diagnose since the effect size of different genes is very small and the type of action is still largely unknown. HIF gene family is an example of metabolically relevant genes, which are also active in the fat tissue of obese individuals. They have been linked with chronic inflammation, which is one of the causes ort he development of type 2 diabetes and other metabolic diseases. Their possible role in the onset of polygenic obesity has not yet been recognized. The goal of this study was to find differences in regulatory regions of the Hif gene family (Hif1, Epas1 in Hif3a) between two groups of selectively breed laboratory mice. After 60 generations of selection there is more than a five-fold difference in body fat percentage between them. All discovered variations were positioned in the reference sequence from the Ensembl and SwissRegulon databases, and visualized in the GenomeBrowse program. Results showed that there are 418 sequence differences between the lines, most of which are located in the Hif1a gene of the fat line. Out of all detected variants, 24 of them are located within regulatory regions. We have selected 28 of the most promising sequence variants based on their location and GERP value, that represent viable candidates for future studies aimed at identifying their causal role in the obesity development.

• Keywords: Hif genes, hipoxia of fat tissue, mice, polygenic obesity, regulatory regions