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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.

Roux PF, Boitard S, Blum Y, Parks B, Montagner A, Mouisel E, Djari A, Esquerré D, Désert C, Boutin M, Leroux S, Lecerf F, Le Bihan-Duval E, Klopp C, Servin B, Pitel F, Duclos MJ, Guillou H, Lusis AJ, Demeure O, Lagarrigue S - G3 (Bethesda) (2015)

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.

View Article: PubMed Central - PubMed

Affiliation: INRA, UMR1348 Pegase, Saint-Gilles, 35590, France Agrocampus Ouest, UMR1348 Pegase, Rennes, 35000, France Université Européenne de Bretagne, France.

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Expression of JAG2 in mice HMDP. (A) Correlation between JAG2 expression in white adipose tissue (WAT) and body fat mass (%) in HMDP of 86 mice fed a chow diet. (B) Body fat mass in % of body weight (top) and WAT expression (bottom) in HMDP panel of 86 mice fed chow diet (in grey) and high-fat/high-sucrose diet (in black). For each graph, values are centered on the mean of the whole values. (C) Haplotype cluster frequencies for both chicken lines for the PARK2 selective sweep. The difference in color along the Y-axis gives the frequencies of each haplotype cluster. The difference in color along the X-axis has no meaning. The almost fixed haplotype is colored red in the lean line. (D) Genetic association (top) for body fat mass gain between the second and the fourth week of high-fat diet in the HMDP and (bottom) for JAG2 expression in WAT. Gene positions as given in Ensembl 77 for GRCm38 mouse genome assembly .
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fig4: Expression of JAG2 in mice HMDP. (A) Correlation between JAG2 expression in white adipose tissue (WAT) and body fat mass (%) in HMDP of 86 mice fed a chow diet. (B) Body fat mass in % of body weight (top) and WAT expression (bottom) in HMDP panel of 86 mice fed chow diet (in grey) and high-fat/high-sucrose diet (in black). For each graph, values are centered on the mean of the whole values. (C) Haplotype cluster frequencies for both chicken lines for the PARK2 selective sweep. The difference in color along the Y-axis gives the frequencies of each haplotype cluster. The difference in color along the X-axis has no meaning. The almost fixed haplotype is colored red in the lean line. (D) Genetic association (top) for body fat mass gain between the second and the fourth week of high-fat diet in the HMDP and (bottom) for JAG2 expression in WAT. Gene positions as given in Ensembl 77 for GRCm38 mouse genome assembly .

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.


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.

Roux PF, Boitard S, Blum Y, Parks B, Montagner A, Mouisel E, Djari A, Esquerré D, Désert C, Boutin M, Leroux S, Lecerf F, Le Bihan-Duval E, Klopp C, Servin B, Pitel F, Duclos MJ, Guillou H, Lusis AJ, Demeure O, Lagarrigue S - G3 (Bethesda) (2015)

Expression of JAG2 in mice HMDP. (A) Correlation between JAG2 expression in white adipose tissue (WAT) and body fat mass (%) in HMDP of 86 mice fed a chow diet. (B) Body fat mass in % of body weight (top) and WAT expression (bottom) in HMDP panel of 86 mice fed chow diet (in grey) and high-fat/high-sucrose diet (in black). For each graph, values are centered on the mean of the whole values. (C) Haplotype cluster frequencies for both chicken lines for the PARK2 selective sweep. The difference in color along the Y-axis gives the frequencies of each haplotype cluster. The difference in color along the X-axis has no meaning. The almost fixed haplotype is colored red in the lean line. (D) Genetic association (top) for body fat mass gain between the second and the fourth week of high-fat diet in the HMDP and (bottom) for JAG2 expression in WAT. Gene positions as given in Ensembl 77 for GRCm38 mouse genome assembly .
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4390568&req=5

fig4: Expression of JAG2 in mice HMDP. (A) Correlation between JAG2 expression in white adipose tissue (WAT) and body fat mass (%) in HMDP of 86 mice fed a chow diet. (B) Body fat mass in % of body weight (top) and WAT expression (bottom) in HMDP panel of 86 mice fed chow diet (in grey) and high-fat/high-sucrose diet (in black). For each graph, values are centered on the mean of the whole values. (C) Haplotype cluster frequencies for both chicken lines for the PARK2 selective sweep. The difference in color along the Y-axis gives the frequencies of each haplotype cluster. The difference in color along the X-axis has no meaning. The almost fixed haplotype is colored red in the lean line. (D) Genetic association (top) for body fat mass gain between the second and the fourth week of high-fat diet in the HMDP and (bottom) for JAG2 expression in WAT. Gene positions as given in Ensembl 77 for GRCm38 mouse genome assembly .
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.

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.

View Article: PubMed Central - PubMed

Affiliation: INRA, UMR1348 Pegase, Saint-Gilles, 35590, France Agrocampus Ouest, UMR1348 Pegase, Rennes, 35000, France Université Européenne de Bretagne, France.

Show MeSH
Related in: MedlinePlus