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Using regulatory and epistatic networks to extend the findings of a genome scan: identifying the gene drivers of pigmentation in merino sheep.

García-Gámez E, Reverter A, Whan V, McWilliam SM, Arranz JJ, International Sheep Genomics ConsortiumKijas J - PLoS ONE (2011)

Bottom Line: We combined these results with gene expression data from five tissue types analysed with a skin-specific microarray.Likewise, by testing two-loci models derived from all pair-wise comparisons across piebald-associated SNP, we generated an epistatic network.Further, we report a number of differentially expressed genes in regions containing highly associated SNP including ATRN, DOCK7, FGFR1OP, GLI3, SILV and TBX15.

View Article: PubMed Central - PubMed

Affiliation: Livestock Industries, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Brisbane, Queensland, Australia.

ABSTRACT
Extending genome wide association analysis by the inclusion of gene expression data may assist in the dissection of complex traits. We examined piebald, a pigmentation phenotype in both human and Merino sheep, by analysing multiple data types using a systems approach. First, a case control analysis of 49,034 ovine SNP was performed which confirmed a multigenic basis for the condition. We combined these results with gene expression data from five tissue types analysed with a skin-specific microarray. Promoter sequence analysis of differentially expressed genes allowed us to reverse-engineer a regulatory network. Likewise, by testing two-loci models derived from all pair-wise comparisons across piebald-associated SNP, we generated an epistatic network. At the intersection of both networks, we identified thirteen genes with insulin-like growth factor binding protein 7 (IGFBP7), platelet-derived growth factor alpha (PDGFRA) and the tetraspanin platelet activator CD9 at the kernel of the intersection. Further, we report a number of differentially expressed genes in regions containing highly associated SNP including ATRN, DOCK7, FGFR1OP, GLI3, SILV and TBX15. The application of network theory facilitated co-analysis of genetic variation with gene expression, recapitulated aspects of the known molecular biology of skin pigmentation and provided insights into the transcription regulation and epistatic interactions involved in piebald Merino sheep.

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Genome wide association for piebald.(A) A piebald lamb is pictured with its non-pigmented mother (left hand side). The asymmetrical presentation of pigmentation (the lamb has one pigmented and one white forelimb) characterises this colour morph from Recessive Black (right hand side) which arises through action of the Agouti locus [39]. (B) The genetic relationship between 24 piebald animals and 72 non-pigmented controls. Allele sharing, or genetic similarity, was calculated between each pair-wise combination of animal using 48,686 SNP. Increasing values of allele sharing are represented using darker colour. Unsupervised hierarchical clustering distributed the piebald cases (indicated with a dot) across the matrix, reflecting the sampling strategy used to select controls which were as closely related to cases as possible. (C) Unsupervised hierarchical clustering of the 226 associated SNP (P<0.001) successfully distinguished all piebald animals as genetically distinct from the controls. Animals are arranged into columns and annotated above the matrix using either red (piebald) or black lines (controls). The 226 associated SNP are arranged into rows and each cell indicates the observed genotypic outcome as follows: homozygote (bright red), heterozygote (dark red), alternate homozygote (black).
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pone-0021158-g001: Genome wide association for piebald.(A) A piebald lamb is pictured with its non-pigmented mother (left hand side). The asymmetrical presentation of pigmentation (the lamb has one pigmented and one white forelimb) characterises this colour morph from Recessive Black (right hand side) which arises through action of the Agouti locus [39]. (B) The genetic relationship between 24 piebald animals and 72 non-pigmented controls. Allele sharing, or genetic similarity, was calculated between each pair-wise combination of animal using 48,686 SNP. Increasing values of allele sharing are represented using darker colour. Unsupervised hierarchical clustering distributed the piebald cases (indicated with a dot) across the matrix, reflecting the sampling strategy used to select controls which were as closely related to cases as possible. (C) Unsupervised hierarchical clustering of the 226 associated SNP (P<0.001) successfully distinguished all piebald animals as genetically distinct from the controls. Animals are arranged into columns and annotated above the matrix using either red (piebald) or black lines (controls). The 226 associated SNP are arranged into rows and each cell indicates the observed genotypic outcome as follows: homozygote (bright red), heterozygote (dark red), alternate homozygote (black).

Mentions: We collected DNA from 24 piebald Merinos characterised by the appearance of pigmentation spots (Figure 1A). To minimise unrelated genetic variability, we then selected 72 genetically similar but non-pigmented Merinos from a wider population sample using allele sharing calculated from 49,034 SNP. The resulting relationship matrix linking all 96 animals is shown in Figure 1B. Comparing allele frequency differences between piebald and non-pigmented animals revealed 226 loci were highly associated (p<0.001) and collectively distinguished piebald from non-pigmented animals (Figure 1C). The highest association (p = 8.45×10−7) was observed for SNP s49104 located in the region containing IGFBP7 (OAR 6 Mb 78.9), however the absence of a single and strong association peak confirmed a multigenic basis for ovine piebald (Figure S1).


Using regulatory and epistatic networks to extend the findings of a genome scan: identifying the gene drivers of pigmentation in merino sheep.

García-Gámez E, Reverter A, Whan V, McWilliam SM, Arranz JJ, International Sheep Genomics ConsortiumKijas J - PLoS ONE (2011)

Genome wide association for piebald.(A) A piebald lamb is pictured with its non-pigmented mother (left hand side). The asymmetrical presentation of pigmentation (the lamb has one pigmented and one white forelimb) characterises this colour morph from Recessive Black (right hand side) which arises through action of the Agouti locus [39]. (B) The genetic relationship between 24 piebald animals and 72 non-pigmented controls. Allele sharing, or genetic similarity, was calculated between each pair-wise combination of animal using 48,686 SNP. Increasing values of allele sharing are represented using darker colour. Unsupervised hierarchical clustering distributed the piebald cases (indicated with a dot) across the matrix, reflecting the sampling strategy used to select controls which were as closely related to cases as possible. (C) Unsupervised hierarchical clustering of the 226 associated SNP (P<0.001) successfully distinguished all piebald animals as genetically distinct from the controls. Animals are arranged into columns and annotated above the matrix using either red (piebald) or black lines (controls). The 226 associated SNP are arranged into rows and each cell indicates the observed genotypic outcome as follows: homozygote (bright red), heterozygote (dark red), alternate homozygote (black).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3119053&req=5

pone-0021158-g001: Genome wide association for piebald.(A) A piebald lamb is pictured with its non-pigmented mother (left hand side). The asymmetrical presentation of pigmentation (the lamb has one pigmented and one white forelimb) characterises this colour morph from Recessive Black (right hand side) which arises through action of the Agouti locus [39]. (B) The genetic relationship between 24 piebald animals and 72 non-pigmented controls. Allele sharing, or genetic similarity, was calculated between each pair-wise combination of animal using 48,686 SNP. Increasing values of allele sharing are represented using darker colour. Unsupervised hierarchical clustering distributed the piebald cases (indicated with a dot) across the matrix, reflecting the sampling strategy used to select controls which were as closely related to cases as possible. (C) Unsupervised hierarchical clustering of the 226 associated SNP (P<0.001) successfully distinguished all piebald animals as genetically distinct from the controls. Animals are arranged into columns and annotated above the matrix using either red (piebald) or black lines (controls). The 226 associated SNP are arranged into rows and each cell indicates the observed genotypic outcome as follows: homozygote (bright red), heterozygote (dark red), alternate homozygote (black).
Mentions: We collected DNA from 24 piebald Merinos characterised by the appearance of pigmentation spots (Figure 1A). To minimise unrelated genetic variability, we then selected 72 genetically similar but non-pigmented Merinos from a wider population sample using allele sharing calculated from 49,034 SNP. The resulting relationship matrix linking all 96 animals is shown in Figure 1B. Comparing allele frequency differences between piebald and non-pigmented animals revealed 226 loci were highly associated (p<0.001) and collectively distinguished piebald from non-pigmented animals (Figure 1C). The highest association (p = 8.45×10−7) was observed for SNP s49104 located in the region containing IGFBP7 (OAR 6 Mb 78.9), however the absence of a single and strong association peak confirmed a multigenic basis for ovine piebald (Figure S1).

Bottom Line: We combined these results with gene expression data from five tissue types analysed with a skin-specific microarray.Likewise, by testing two-loci models derived from all pair-wise comparisons across piebald-associated SNP, we generated an epistatic network.Further, we report a number of differentially expressed genes in regions containing highly associated SNP including ATRN, DOCK7, FGFR1OP, GLI3, SILV and TBX15.

View Article: PubMed Central - PubMed

Affiliation: Livestock Industries, Commonwealth Scientific and Industrial Research Organisation (CSIRO), Brisbane, Queensland, Australia.

ABSTRACT
Extending genome wide association analysis by the inclusion of gene expression data may assist in the dissection of complex traits. We examined piebald, a pigmentation phenotype in both human and Merino sheep, by analysing multiple data types using a systems approach. First, a case control analysis of 49,034 ovine SNP was performed which confirmed a multigenic basis for the condition. We combined these results with gene expression data from five tissue types analysed with a skin-specific microarray. Promoter sequence analysis of differentially expressed genes allowed us to reverse-engineer a regulatory network. Likewise, by testing two-loci models derived from all pair-wise comparisons across piebald-associated SNP, we generated an epistatic network. At the intersection of both networks, we identified thirteen genes with insulin-like growth factor binding protein 7 (IGFBP7), platelet-derived growth factor alpha (PDGFRA) and the tetraspanin platelet activator CD9 at the kernel of the intersection. Further, we report a number of differentially expressed genes in regions containing highly associated SNP including ATRN, DOCK7, FGFR1OP, GLI3, SILV and TBX15. The application of network theory facilitated co-analysis of genetic variation with gene expression, recapitulated aspects of the known molecular biology of skin pigmentation and provided insights into the transcription regulation and epistatic interactions involved in piebald Merino sheep.

Show MeSH
Related in: MedlinePlus