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Association and haplotype analyses of positional candidate genes in five genomic regions linked to scrotal hernia in commercial pig lines.

Du ZQ, Zhao X, Vukasinovic N, Rodriguez F, Clutter AC, Rothschild MF - PLoS ONE (2009)

Bottom Line: In total, 151 out of 416 SNPs discovered were genotyped successfully.The SNPs around the ELF5 region were in high linkage disequilibrium with each other, and a haplotype containing SNPs from ELF5 and CAT was highly significantly associated with hernia development.Extensive re-sequencing work focused on the KIF18A gene did not detect any further SNPs with extensive association signals.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Science and Center for Integrated Animal Genomics, Iowa State University, Ames, IA, USA.

ABSTRACT
Scrotal hernia in pigs is a complex trait likely affected by genetic and environmental factors. A large-scale association analysis of positional and functional candidate genes was conducted in four previously identified genomic regions linked to hernia susceptibility on Sus scrofa chromosomes 2 and 12, as well as the fifth region around 67 cM on chromosome 2, respectively. In total, 151 out of 416 SNPs discovered were genotyped successfully. Using a family-based analysis we found that four regions surrounding ELF5, KIF18A, COL23A1 on chromosome 2, and NPTX1 on chromosome 12, respectively, may contain the genetic variants important for the development of the scrotal hernia in pigs. These findings were replicated in another case-control dataset. The SNPs around the ELF5 region were in high linkage disequilibrium with each other, and a haplotype containing SNPs from ELF5 and CAT was highly significantly associated with hernia development. Extensive re-sequencing work focused on the KIF18A gene did not detect any further SNPs with extensive association signals. These genes may be involved in the estrogen receptor signaling pathway (KIF18A and NPTX1), the epithelial-mesenchymal transition (ELF5) and the collagen metabolism pathway (COL23A1), which are associated with the important molecular characteristics of hernia pathophysiology. Further investigation on the molecular mechanisms of these genes may provide more molecular clues on hernia development in pigs.

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Extensive positional candidate gene analyses of four porcine genomic regions for hernia development on SSC2.A, Hernia QTL on SSC2. Genomic region around 48 cM was significantly linked to risk of hernia development. Three regions (I, at 3 cM; II at 42 cM; III, at 66 cM) and a fourth region (IV at 70 cM) could be potentially linked to scrotal hernia. These regions were indicated by the blue frames. B, The gene map was built based on the latest porcine physical FPC (fingerprint contigs) map (Sanger Porcine Genome Sequencing Project) (Table S1). Genes in contigs 1, 3, 5 and 8 on SSC2 were selected to cover the four regions, respectively. Contigs 6 and 7 were also used to search for candidate genes. C, Single marker association analyses. SNPs of genes located in region II were significantly associated with pig hernia in Pietrain-based line. The small red box includes SNPs in ELF5 significantly associated with scrotal hernia. D, LD heatmap was constructed by Haploview. Genes in region II were found to be in high LD with each other. The red box indicates the common haplotype formed by ELF5-1, ELF5-3, ELF5-5, ELF5-8 and EHF1 was significantly associated with scrotal hernia. E, 26 new SNP markers were added into the region II region (blue arrowhead), with focus on the 1 MB region including EHF-ELF5-CAT, and the 6 MB region covering KIF18A. Re-sequencing work on KIF18A did not detect any further association signal. The red box defines the haplotype composed of ELF5-1, ELF5-3, ELF5-5, ELF5-8, CAT-E11-1, CAT-5U-5 and CAT-5U-1 to be highly significantly associated with scrotal hernia.
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pone-0004837-g001: Extensive positional candidate gene analyses of four porcine genomic regions for hernia development on SSC2.A, Hernia QTL on SSC2. Genomic region around 48 cM was significantly linked to risk of hernia development. Three regions (I, at 3 cM; II at 42 cM; III, at 66 cM) and a fourth region (IV at 70 cM) could be potentially linked to scrotal hernia. These regions were indicated by the blue frames. B, The gene map was built based on the latest porcine physical FPC (fingerprint contigs) map (Sanger Porcine Genome Sequencing Project) (Table S1). Genes in contigs 1, 3, 5 and 8 on SSC2 were selected to cover the four regions, respectively. Contigs 6 and 7 were also used to search for candidate genes. C, Single marker association analyses. SNPs of genes located in region II were significantly associated with pig hernia in Pietrain-based line. The small red box includes SNPs in ELF5 significantly associated with scrotal hernia. D, LD heatmap was constructed by Haploview. Genes in region II were found to be in high LD with each other. The red box indicates the common haplotype formed by ELF5-1, ELF5-3, ELF5-5, ELF5-8 and EHF1 was significantly associated with scrotal hernia. E, 26 new SNP markers were added into the region II region (blue arrowhead), with focus on the 1 MB region including EHF-ELF5-CAT, and the 6 MB region covering KIF18A. Re-sequencing work on KIF18A did not detect any further association signal. The red box defines the haplotype composed of ELF5-1, ELF5-3, ELF5-5, ELF5-8, CAT-E11-1, CAT-5U-5 and CAT-5U-1 to be highly significantly associated with scrotal hernia.

Mentions: Based on the nucleotide sequence information provided by the markers in the three regions associated with scrotal hernia on SSC2 at approximately 3, 42 and 65 cM, which existed in genomic DNA sequences (NCBI accession numbers: BH021488, DQ648562 and CL352219), we blasted them against the NCBI nucleotide database, and selected a first set of four important candidate genes distributed in the three specific sub-regions, i.e. the homeodomain interacting protein kinase 3 (HIPK3) and the complement regulatory protein CD59 molecule (CD59) in region II, the cathepsin F (CTSF) in region I, and the mitochondrial lon peptidase 1 (LONP1) (Figure S1). Then new candidate genes were selected on both ends of the first set of genes, combining the comparative genomic information between human and pig (Table S1), and the information from the constructed gene networks, too (Figure S2). This further enabled us to select additional positional candidate genes from HSA5q35 potentially involved in human inguinal hernia [35], e.g. the collagen type XXIII, alpha 1 (COL23A1) and the ADAM metallopeptidase with thrombospondin type 1 motif, 2 (ADAMTS2), which likely map to the region surrounding 67 cM on SSC2 potentially linked to hernia susceptibility (Figure 1).


Association and haplotype analyses of positional candidate genes in five genomic regions linked to scrotal hernia in commercial pig lines.

Du ZQ, Zhao X, Vukasinovic N, Rodriguez F, Clutter AC, Rothschild MF - PLoS ONE (2009)

Extensive positional candidate gene analyses of four porcine genomic regions for hernia development on SSC2.A, Hernia QTL on SSC2. Genomic region around 48 cM was significantly linked to risk of hernia development. Three regions (I, at 3 cM; II at 42 cM; III, at 66 cM) and a fourth region (IV at 70 cM) could be potentially linked to scrotal hernia. These regions were indicated by the blue frames. B, The gene map was built based on the latest porcine physical FPC (fingerprint contigs) map (Sanger Porcine Genome Sequencing Project) (Table S1). Genes in contigs 1, 3, 5 and 8 on SSC2 were selected to cover the four regions, respectively. Contigs 6 and 7 were also used to search for candidate genes. C, Single marker association analyses. SNPs of genes located in region II were significantly associated with pig hernia in Pietrain-based line. The small red box includes SNPs in ELF5 significantly associated with scrotal hernia. D, LD heatmap was constructed by Haploview. Genes in region II were found to be in high LD with each other. The red box indicates the common haplotype formed by ELF5-1, ELF5-3, ELF5-5, ELF5-8 and EHF1 was significantly associated with scrotal hernia. E, 26 new SNP markers were added into the region II region (blue arrowhead), with focus on the 1 MB region including EHF-ELF5-CAT, and the 6 MB region covering KIF18A. Re-sequencing work on KIF18A did not detect any further association signal. The red box defines the haplotype composed of ELF5-1, ELF5-3, ELF5-5, ELF5-8, CAT-E11-1, CAT-5U-5 and CAT-5U-1 to be highly significantly associated with scrotal hernia.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654076&req=5

pone-0004837-g001: Extensive positional candidate gene analyses of four porcine genomic regions for hernia development on SSC2.A, Hernia QTL on SSC2. Genomic region around 48 cM was significantly linked to risk of hernia development. Three regions (I, at 3 cM; II at 42 cM; III, at 66 cM) and a fourth region (IV at 70 cM) could be potentially linked to scrotal hernia. These regions were indicated by the blue frames. B, The gene map was built based on the latest porcine physical FPC (fingerprint contigs) map (Sanger Porcine Genome Sequencing Project) (Table S1). Genes in contigs 1, 3, 5 and 8 on SSC2 were selected to cover the four regions, respectively. Contigs 6 and 7 were also used to search for candidate genes. C, Single marker association analyses. SNPs of genes located in region II were significantly associated with pig hernia in Pietrain-based line. The small red box includes SNPs in ELF5 significantly associated with scrotal hernia. D, LD heatmap was constructed by Haploview. Genes in region II were found to be in high LD with each other. The red box indicates the common haplotype formed by ELF5-1, ELF5-3, ELF5-5, ELF5-8 and EHF1 was significantly associated with scrotal hernia. E, 26 new SNP markers were added into the region II region (blue arrowhead), with focus on the 1 MB region including EHF-ELF5-CAT, and the 6 MB region covering KIF18A. Re-sequencing work on KIF18A did not detect any further association signal. The red box defines the haplotype composed of ELF5-1, ELF5-3, ELF5-5, ELF5-8, CAT-E11-1, CAT-5U-5 and CAT-5U-1 to be highly significantly associated with scrotal hernia.
Mentions: Based on the nucleotide sequence information provided by the markers in the three regions associated with scrotal hernia on SSC2 at approximately 3, 42 and 65 cM, which existed in genomic DNA sequences (NCBI accession numbers: BH021488, DQ648562 and CL352219), we blasted them against the NCBI nucleotide database, and selected a first set of four important candidate genes distributed in the three specific sub-regions, i.e. the homeodomain interacting protein kinase 3 (HIPK3) and the complement regulatory protein CD59 molecule (CD59) in region II, the cathepsin F (CTSF) in region I, and the mitochondrial lon peptidase 1 (LONP1) (Figure S1). Then new candidate genes were selected on both ends of the first set of genes, combining the comparative genomic information between human and pig (Table S1), and the information from the constructed gene networks, too (Figure S2). This further enabled us to select additional positional candidate genes from HSA5q35 potentially involved in human inguinal hernia [35], e.g. the collagen type XXIII, alpha 1 (COL23A1) and the ADAM metallopeptidase with thrombospondin type 1 motif, 2 (ADAMTS2), which likely map to the region surrounding 67 cM on SSC2 potentially linked to hernia susceptibility (Figure 1).

Bottom Line: In total, 151 out of 416 SNPs discovered were genotyped successfully.The SNPs around the ELF5 region were in high linkage disequilibrium with each other, and a haplotype containing SNPs from ELF5 and CAT was highly significantly associated with hernia development.Extensive re-sequencing work focused on the KIF18A gene did not detect any further SNPs with extensive association signals.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Science and Center for Integrated Animal Genomics, Iowa State University, Ames, IA, USA.

ABSTRACT
Scrotal hernia in pigs is a complex trait likely affected by genetic and environmental factors. A large-scale association analysis of positional and functional candidate genes was conducted in four previously identified genomic regions linked to hernia susceptibility on Sus scrofa chromosomes 2 and 12, as well as the fifth region around 67 cM on chromosome 2, respectively. In total, 151 out of 416 SNPs discovered were genotyped successfully. Using a family-based analysis we found that four regions surrounding ELF5, KIF18A, COL23A1 on chromosome 2, and NPTX1 on chromosome 12, respectively, may contain the genetic variants important for the development of the scrotal hernia in pigs. These findings were replicated in another case-control dataset. The SNPs around the ELF5 region were in high linkage disequilibrium with each other, and a haplotype containing SNPs from ELF5 and CAT was highly significantly associated with hernia development. Extensive re-sequencing work focused on the KIF18A gene did not detect any further SNPs with extensive association signals. These genes may be involved in the estrogen receptor signaling pathway (KIF18A and NPTX1), the epithelial-mesenchymal transition (ELF5) and the collagen metabolism pathway (COL23A1), which are associated with the important molecular characteristics of hernia pathophysiology. Further investigation on the molecular mechanisms of these genes may provide more molecular clues on hernia development in pigs.

Show MeSH
Related in: MedlinePlus