Combined QTL and selective sweep mappings with coding SNP annotation and cis-eQTL analysis revealed PARK2 and JAG2 as new candidate genes for adiposity regulation.
Bottom Line: Using new haplotype-based statistics exploiting the very high SNP density generated through whole-genome resequencing, we found 129 significant selective sweeps.We then focused on two of these QTL/sweeps.This study shows for the first time the interest of combining selective sweeps mapping, coding SNP annotation and cis-eQTL analyses for identifying causative genes for a complex trait, in the context of divergent lines selected for this specific trait.
Affiliation: INRA, UMR1348 Pegase, Saint-Gilles, 35590, France Agrocampus Ouest, UMR1348 Pegase, Rennes, 35000, France Université Européenne de Bretagne, France.Show MeSH
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Mentions: To further question the implication of JAG2 in adiposity, we studied its expression in liver and white adipose of two independent mice models contrasted for adiposity: B6.V-Lepob/J mice (n = 8), which are KO for the gene encoding leptin and have severe obesity compared with mice from the same genetic background C57BL6/J (n = 8), and the Hybrid Mouse Diversity Panel (Bennett et al. 2010; Ghazalpour et al. 2012), which includes a population of 96 inbred mouse strains variable for obesity-related phenotypes, including total body fat mass. JAG2 is lowly expressed in liver, contrarily to WAT in these two models. In WAT, no differential expression was observed between B6.V-Lepob/J mice and C57BL6/J mice, whereas we identified a significant negative correlation between body fat mass and JAG2 expression in WAT (Figure 4A; r = −0.4, P = 3 × 10−8, Pearson correlation test) in HMDP fed a chow diet. In addition, the difference of JAG2 expression between chow and high-fat/high-sucrose diet was negatively correlated to the difference of fat mass between those diets (Figure 4B), highlighting a negative correlation between JAG2 expression in WAT and adiposity induced by diet. HMDP mice fed a high-fat/high-sucrose diet are fatter than those maintained on a chow diet (top of Figure 4B), whereas JAG2 expression in WAT is higher in chow diet compared with the high-fat/high-sucrose diet (bottom of Figure 4B). These results strengthen that JAG2 is a negative regulator of adiposity. Therefore, because the JAG2 haplotype was fixed under selection in the LL and not in the FL (Figure 4C), and because JAG2 appears as a negative regulator of adiposity in mouse models, this selected haplotype should correspond to a “gain-of-function” mutation in JAG2. This result is also consistent with the direction of allele effects in the QTL mapping study reported by Lagarrigue et al. (2006), in which the microsatellite allele of the QTL associated with a decrease of adiposity came from the F0 lean line. To further explore the causal link between JAG2 and adiposity, we performed a genetics association for JAG2 expression and body fat mass in the HMDP design. As shown in Figure 4D, this analysis revealed a cis-eQTL for JAG2 expression in adipose tissue that colocalized with a QTL for body fat mass gain (during the first weeks of high-fat diet). These results suggest that a mutation acting in cis on JAG2 expression could be the causal mutation responsible for adiposity variation in this mice panel.
Affiliation: INRA, UMR1348 Pegase, Saint-Gilles, 35590, France Agrocampus Ouest, UMR1348 Pegase, Rennes, 35000, France Université Européenne de Bretagne, France.