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      An F2 Pig Resource Population as a Model for Genetic Studies of Obesity and Obesity-Related Diseases in Humans: Design and Genetic Parameters

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          Abstract

          Obesity is a rising worldwide public health problem. Difficulties to precisely measure various obesity traits and the genetic heterogeneity in human have been major impediments to completely disentangle genetic factors causing obesity. The pig is a relevant model for studying human obesity and obesity-related (OOR) traits. Using founder breeds divergent with respect to obesity traits we have created an F2 pig resource population (454 pigs), which has been intensively phenotyped for 36 OOR traits. The main rationale for our study is to characterize the genetic architecture of OOR traits in the F2 pig design, by estimating heritabilities, genetic, and phenotypic correlations using mixed- and multi-trait BLUP animal models. Our analyses revealed high coefficients of variation (15–42%) and moderate to high heritabilities (0.22–0.81) in fatness traits, showing large phenotypic and genetic variation in the F2 population, respectively. This fulfills the purpose of creating a resource population divergent for OOR traits. Strong genetic correlations were found between weight and lean mass at dual-energy x-ray absorptiometry scanning (0.56–0.97). Weight and conformation also showed strong genetic correlations with slaughter traits (e.g., r g between abdominal circumference and leaf fat at slaughtering: 0.66). Genetic correlations between fat-related traits and the glucose level vary between 0.35 and 0.74 and show a strong correlation between adipose tissue and impaired glucose metabolism. Our power calculations showed a minimum of 80% power for QTL detection for all phenotypes. We revealed genetic correlations at population level, for the first time, for several difficult to measure and novel OOR traits and diseases. The results underpin the potential of the established F2 pig resource population for further genomic, systems genetics, and functional investigations to unravel the genetic background of OOR traits.

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          A genome-wide association study identifies novel risk loci for type 2 diabetes.

          Robert Sladek, Ghislain Rocheleau, Johan Rung … (2007)
          Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants was recently made possible by the development of high-density arrays that permit the genotyping of hundreds of thousands of polymorphisms. We tested 392,935 single-nucleotide polymorphisms in a French case-control cohort. Markers with the most significant difference in genotype frequencies between cases of type 2 diabetes and controls were fast-tracked for testing in a second cohort. This identified four loci containing variants that confer type 2 diabetes risk, in addition to confirming the known association with the TCF7L2 gene. These loci include a non-synonymous polymorphism in the zinc transporter SLC30A8, which is expressed exclusively in insulin-producing beta-cells, and two linkage disequilibrium blocks that contain genes potentially involved in beta-cell development or function (IDE-KIF11-HHEX and EXT2-ALX4). These associations explain a substantial portion of disease risk and constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.
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            The development of porcine models of obesity and the metabolic syndrome.

            Michael Spurlock, Nicholas K. Gabler (2008)
            Despite aggressive research aimed at understanding the myriad biochemical factors that are integrated to balance energy intake and expenditure to maintain normal body weight, obesity is increasing at an alarming rate, and the long-term success of prevention and intervention strategies is minimal. Because much of the scientific literature addressing obesity has originated with rodent models, there is considerable interest among researchers and funding agencies in the development of comparative animal models. Furthermore, numerous disparate results between rodent models and humans (i.e., adipsin, leptin, resistin, tumor necrosis factor-alpha, and other adipokines) have hindered the translation of rodent data into actionable technologies for humans. The pig is an exceptional restenosis model, and is emerging rapidly as a biomedical model for energy metabolism and obesity in humans because it is devoid of brown fat postnatally and because of their similar metabolic features, cardiovascular systems, and proportional organ sizes. This article highlights the current literature devoted to the development of porcine models for obesity and the metabolic syndrome, with a particular emphasis on the role of adipose tissue and adipokines in the regulation of energy balance and the inflammation associated with obesity.
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              Genome-Wide Association Study Identifies Loci for Body Composition and Structural Soundness Traits in Pigs

              Bin Fan, Suneel Onteru, Zhi-Qiang Du … (2011)
              Background The recent completion of the swine genome sequencing project and development of a high density porcine SNP array has made genome-wide association (GWA) studies feasible in pigs. Methodology/Principal Findings Using Illumina's PorcineSNP60 BeadChip, we performed a pilot GWA study in 820 commercial female pigs phenotyped for backfat, loin muscle area, body conformation in addition to feet and leg (FL) structural soundness traits. A total of 51,385 SNPs were jointly fitted using Bayesian techniques as random effects in a mixture model that assumed a known large proportion (99.5%) of SNPs had zero effect. SNP annotations were implemented through the Sus scrofa Build 9 available from pig Ensembl. We discovered a number of candidate chromosomal regions, and some of them corresponded to QTL regions previously reported. We not only have identified some well-known candidate genes for the traits of interest, such as MC4R (for backfat) and IGF2 (for loin muscle area), but also obtained novel promising genes, including CHCHD3 (for backfat), BMP2 (for loin muscle area, body size and several FL structure traits), and some HOXA family genes (for overall leg action). The candidate regions responsible for body conformation and FL structure soundness did not overlap greatly which implied that these traits were controlled by different genes. Functional clustering analyses classified the genes into categories related to bone and cartilage development, muscle growth and development or the insulin pathway suggesting the traits are regulated by common pathways or gene networks that exert roles at different spatial and temporal stages. Conclusions/Significance This study is one of the earliest GWA reports on important quantitative traits in pigs, and the findings will contribute to the further biological function analysis of the identified candidate genes and potential utilization of them in marker assisted selection.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Front Genet
                Journal ID (iso-abbrev): Front Genet
                Journal ID (publisher-id): Front. Genet.
                Title: Frontiers in Genetics
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 1664-8021
                Publication date (Electronic): 18 March 2013
                Publication date Collection: 2013
                Volume: 4
                Electronic Location Identifier: 29
                Affiliations
                [1] 1Department of Veterinary Clinical and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen Copenhagen, Denmark
                Author notes

                Edited by: Tad S. Sonstegard, United States Department of Agriculture, USA

                Reviewed by: Luca Fontanesi, University of Bologna, Italy; Jeffrey O’Connell, University of Maryland School of Medicine, USA

                *Correspondence: Merete Fredholm, Faculty of Health and Medical Sciences, University of Copenhagen, Grønnegårdsvej 3, 1870 Frederiksberg C, Copenhagen, Denmark. e-mail: mf@ 123456sund.ku.dk

                This article was submitted to Frontiers in Livestock Genomics, a specialty of Frontiers in Genetics.

                Article
                DOI: 10.3389/fgene.2013.00029
                PMC ID: 3600696
                PubMed ID: 23515185
                SO-VID: ed0fb075-e8ae-4451-9929-a2f2597136af
                Copyright © Copyright © 2013 Kogelman, Kadarmideen, Mark, Karlskov-Mortensen, Bruun, Cirera, Jacobsen, Jørgensen and Fredholm.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

                History
                Date received : 07 December 2012
                Date accepted : 22 February 2013
                Page count
                Figures: 4, Tables: 6, Equations: 6, References: 57, Pages: 14, Words: 10357
                Categories
                Subject: Genetics
                Subject: Original Research

                ScienceOpen disciplines: Genetics
                Keywords: animal model,diabetes,f2 design,genetic correlations,genetic predictions,heritabilities,obesity
                Data availability:
                ScienceOpen disciplines: Genetics
                Keywords: animal model, diabetes, f2 design, genetic correlations, genetic predictions, heritabilities, obesity

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