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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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HapFLK statistics profile inside each AF QTL region. The associated name of each QTL region is given at the top of each graph. Statistics are written as the -log10 of the p-value of the HapFLK test; for each sweep, the number of genes it contained is indicated in an orange box. Some QTL (AF3.I and AF3.II) colocalized with several selective sweeps, whereas others (AF5, AF7, and BMWT1) colocalized with a single selective sweep. The number of genes included in a sweep ranges from 0 to 6.
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fig2: HapFLK statistics profile inside each AF QTL region. The associated name of each QTL region is given at the top of each graph. Statistics are written as the -log10 of the p-value of the HapFLK test; for each sweep, the number of genes it contained is indicated in an orange box. Some QTL (AF3.I and AF3.II) colocalized with several selective sweeps, whereas others (AF5, AF7, and BMWT1) colocalized with a single selective sweep. The number of genes included in a sweep ranges from 0 to 6.

Mentions: In previous genetic studies of the LL and FL lines, we reported two QTL (P < 0.05) and four suggestive QTL (P < 0.1) for AF weight on chromosomes 1, 3, 5, and 7 using a F0-F1-F2 design generated by crossing the FL and LL lines (Lagarrigue et al. 2006). The design was composed of 5 F1 sire families with a total of 585 F2 offspring. The five F1 sires were included in the 20 animals we sequenced in this study at the whole-genome scale. Because it usually happens when using linkage analysis methods, QTL were resolved to a rather large genomic region, with a size ranging from 7.5 Mb to 18.1 Mb (Table 2). Four out of these six QTL colocalized with at least one selective sweep (Table 2). We also showed two-fold highly significant enrichment in selective sweeps within QTL compared with the genome level: 1.36% of the whole-genome against 2.48% of the total QTL intervals were covered by selective sweeps (P < 10−16, χ2 test). This clearly indicates that the relatively large number of sweeps detected genome-wide are not due to an excess of false positives, but rather to other factors related to trait architecture. As shown in Figure 2, sweep analysis revealed the genetic complexity underlying some QTL. The two QTL, AF3.I and AF3.II, on chromosome 3 colocalized with five and three selective sweeps, respectively. Conversely, the two QTL, AF5 and AF7, on chromosomes 5 and 7, respectively, had a simpler genetic profile and contained only one sweep with one and two genes, respectively (Figure 2 and Table 2). This approach combining selective sweep analysis and QTL mapping allowed a reduction in the size of the four QTL regions from, on average, 12 Mb to 100 kb, with some of these regions now containing one gene, therefore standing as strong causal positional candidate. Thus, this broad reduction of QTL size provided a great advance for the identification of causal genes. Subsequently, we set out to explore in greater depth two QTL to identify candidate causal underlying genes. With this aim, different data and approaches were combined.


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)

HapFLK statistics profile inside each AF QTL region. The associated name of each QTL region is given at the top of each graph. Statistics are written as the -log10 of the p-value of the HapFLK test; for each sweep, the number of genes it contained is indicated in an orange box. Some QTL (AF3.I and AF3.II) colocalized with several selective sweeps, whereas others (AF5, AF7, and BMWT1) colocalized with a single selective sweep. The number of genes included in a sweep ranges from 0 to 6.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390568&req=5

fig2: HapFLK statistics profile inside each AF QTL region. The associated name of each QTL region is given at the top of each graph. Statistics are written as the -log10 of the p-value of the HapFLK test; for each sweep, the number of genes it contained is indicated in an orange box. Some QTL (AF3.I and AF3.II) colocalized with several selective sweeps, whereas others (AF5, AF7, and BMWT1) colocalized with a single selective sweep. The number of genes included in a sweep ranges from 0 to 6.
Mentions: In previous genetic studies of the LL and FL lines, we reported two QTL (P < 0.05) and four suggestive QTL (P < 0.1) for AF weight on chromosomes 1, 3, 5, and 7 using a F0-F1-F2 design generated by crossing the FL and LL lines (Lagarrigue et al. 2006). The design was composed of 5 F1 sire families with a total of 585 F2 offspring. The five F1 sires were included in the 20 animals we sequenced in this study at the whole-genome scale. Because it usually happens when using linkage analysis methods, QTL were resolved to a rather large genomic region, with a size ranging from 7.5 Mb to 18.1 Mb (Table 2). Four out of these six QTL colocalized with at least one selective sweep (Table 2). We also showed two-fold highly significant enrichment in selective sweeps within QTL compared with the genome level: 1.36% of the whole-genome against 2.48% of the total QTL intervals were covered by selective sweeps (P < 10−16, χ2 test). This clearly indicates that the relatively large number of sweeps detected genome-wide are not due to an excess of false positives, but rather to other factors related to trait architecture. As shown in Figure 2, sweep analysis revealed the genetic complexity underlying some QTL. The two QTL, AF3.I and AF3.II, on chromosome 3 colocalized with five and three selective sweeps, respectively. Conversely, the two QTL, AF5 and AF7, on chromosomes 5 and 7, respectively, had a simpler genetic profile and contained only one sweep with one and two genes, respectively (Figure 2 and Table 2). This approach combining selective sweep analysis and QTL mapping allowed a reduction in the size of the four QTL regions from, on average, 12 Mb to 100 kb, with some of these regions now containing one gene, therefore standing as strong causal positional candidate. Thus, this broad reduction of QTL size provided a great advance for the identification of causal genes. Subsequently, we set out to explore in greater depth two QTL to identify candidate causal underlying genes. With this aim, different data and approaches were combined.

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