Limits...
Non-synonymous FGD3 Variant as Positional Candidate for Disproportional Tall Stature Accounting for a Carcass Weight QTL (CW-3) and Skeletal Dysplasia in Japanese Black Cattle.

Takasuga A, Sato K, Nakamura R, Saito Y, Sasaki S, Tsuji T, Suzuki A, Kobayashi H, Matsuhashi T, Setoguchi K, Okabe H, Ootsubo T, Tabuchi I, Fujita T, Watanabe N, Hirano T, Nishimura S, Watanabe T, Hayakawa M, Sugimoto Y, Kojima T - PLoS Genet. (2015)

Bottom Line: The risk allele was on the same chromosome as the Q allele that increases carcass weight.Phenotypic characterization revealed that the risk allele causes disproportional tall stature and bone size that increases carcass weight in heterozygous individuals but causes disproportionately narrow chest width in homozygotes.Thus, loss of FDG3 activity may lead to subsequent loss of Cdc42 function.

View Article: PubMed Central - PubMed

Affiliation: National Livestock Breeding Center, Odakura, Nishigo, Fukushima, Japan; Shirakawa Institute of Animal Genetics, Japan Livestock Technology Association, Odakura, Nishigo, Fukushima, Japan.

ABSTRACT
Recessive skeletal dysplasia, characterized by joint- and/or hip bone-enlargement, was mapped within the critical region for a major quantitative trait locus (QTL) influencing carcass weight; previously named CW-3 in Japanese Black cattle. The risk allele was on the same chromosome as the Q allele that increases carcass weight. Phenotypic characterization revealed that the risk allele causes disproportional tall stature and bone size that increases carcass weight in heterozygous individuals but causes disproportionately narrow chest width in homozygotes. A non-synonymous variant of FGD3 was identified as a positional candidate quantitative trait nucleotide (QTN) and the corresponding mutant protein showed reduced activity as a guanine nucleotide exchange factor for Cdc42. FGD3 is expressed in the growth plate cartilage of femurs from bovine and mouse. Thus, loss of FDG3 activity may lead to subsequent loss of Cdc42 function. This would be consistent with the columnar disorganization of proliferating chondrocytes in chondrocyte-specific inactivated Cdc42 mutant mice. This is the first report showing association of FGD3 with skeletal dysplasia.

No MeSH data available.


Related in: MedlinePlus

Association analyses using imputed BovineHD genotypes (A), segments of the identical-by-descent (IBD) Q haplotype (B), and candidate causative variations (C).Association with carcass weight was analyzed by a variance component approach using EMMAX software [39] with adjustments for age, slaughterhouse, and year as covariates and fixed effects. (A) Red and blue dots represent p values of imputed BovineHD genotypes in–log10 scale before and after conditioning, respectively. A conditioned analysis was performed by including an imputed genotype of BovineHD0800025437 as a covariate in the model. (B) Light blue and black lines represent p values of approximately 1-Mb and 500-kb Q haplotypes in–log10 scale, respectively. (C) Brown dots, a red triangle, and blue squares represent p values of Bovine50K genotypes, experimentally validated BovineHD0800025437 genotype, and the genotypes of candidate causative variations in–log10 scale, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4549114&req=5

pgen.1005433.g002: Association analyses using imputed BovineHD genotypes (A), segments of the identical-by-descent (IBD) Q haplotype (B), and candidate causative variations (C).Association with carcass weight was analyzed by a variance component approach using EMMAX software [39] with adjustments for age, slaughterhouse, and year as covariates and fixed effects. (A) Red and blue dots represent p values of imputed BovineHD genotypes in–log10 scale before and after conditioning, respectively. A conditioned analysis was performed by including an imputed genotype of BovineHD0800025437 as a covariate in the model. (B) Light blue and black lines represent p values of approximately 1-Mb and 500-kb Q haplotypes in–log10 scale, respectively. (C) Brown dots, a red triangle, and blue squares represent p values of Bovine50K genotypes, experimentally validated BovineHD0800025437 genotype, and the genotypes of candidate causative variations in–log10 scale, respectively.

Mentions: A GWAS using BovineSNP50 genotypes from 1156 Japanese Black steers also detected CW-3 [7]. The QTL was represented by a haplotype consisting of two single nucleotide polymorphisms (SNPs) but not by any single SNP [7]. To explore an SNP marker tagging the QTL, the BovineSNP50 genotypes were imputed to BovineHD genotypes using 651 steers as a reference population, followed by an examination for association. Twenty-two SNPs between 85.7 and 85.8 Mb were strongly associated with carcass weight (p < 3.1 × 10–15), of which the genotype of BovineHD0800025437 was experimentally validated to show 99.2% concordance (18 inconsistent alleles among 2312 alleles). Inclusion of BovineHD0800025437 genotype in the statistical model as a covariate resulted in the loss of all significant associations on BTA 8, indicating that the SNP is in strong linkage disequilibrium with the causative variation for CW-3 (Fig 2A).


Non-synonymous FGD3 Variant as Positional Candidate for Disproportional Tall Stature Accounting for a Carcass Weight QTL (CW-3) and Skeletal Dysplasia in Japanese Black Cattle.

Takasuga A, Sato K, Nakamura R, Saito Y, Sasaki S, Tsuji T, Suzuki A, Kobayashi H, Matsuhashi T, Setoguchi K, Okabe H, Ootsubo T, Tabuchi I, Fujita T, Watanabe N, Hirano T, Nishimura S, Watanabe T, Hayakawa M, Sugimoto Y, Kojima T - PLoS Genet. (2015)

Association analyses using imputed BovineHD genotypes (A), segments of the identical-by-descent (IBD) Q haplotype (B), and candidate causative variations (C).Association with carcass weight was analyzed by a variance component approach using EMMAX software [39] with adjustments for age, slaughterhouse, and year as covariates and fixed effects. (A) Red and blue dots represent p values of imputed BovineHD genotypes in–log10 scale before and after conditioning, respectively. A conditioned analysis was performed by including an imputed genotype of BovineHD0800025437 as a covariate in the model. (B) Light blue and black lines represent p values of approximately 1-Mb and 500-kb Q haplotypes in–log10 scale, respectively. (C) Brown dots, a red triangle, and blue squares represent p values of Bovine50K genotypes, experimentally validated BovineHD0800025437 genotype, and the genotypes of candidate causative variations in–log10 scale, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4549114&req=5

pgen.1005433.g002: Association analyses using imputed BovineHD genotypes (A), segments of the identical-by-descent (IBD) Q haplotype (B), and candidate causative variations (C).Association with carcass weight was analyzed by a variance component approach using EMMAX software [39] with adjustments for age, slaughterhouse, and year as covariates and fixed effects. (A) Red and blue dots represent p values of imputed BovineHD genotypes in–log10 scale before and after conditioning, respectively. A conditioned analysis was performed by including an imputed genotype of BovineHD0800025437 as a covariate in the model. (B) Light blue and black lines represent p values of approximately 1-Mb and 500-kb Q haplotypes in–log10 scale, respectively. (C) Brown dots, a red triangle, and blue squares represent p values of Bovine50K genotypes, experimentally validated BovineHD0800025437 genotype, and the genotypes of candidate causative variations in–log10 scale, respectively.
Mentions: A GWAS using BovineSNP50 genotypes from 1156 Japanese Black steers also detected CW-3 [7]. The QTL was represented by a haplotype consisting of two single nucleotide polymorphisms (SNPs) but not by any single SNP [7]. To explore an SNP marker tagging the QTL, the BovineSNP50 genotypes were imputed to BovineHD genotypes using 651 steers as a reference population, followed by an examination for association. Twenty-two SNPs between 85.7 and 85.8 Mb were strongly associated with carcass weight (p < 3.1 × 10–15), of which the genotype of BovineHD0800025437 was experimentally validated to show 99.2% concordance (18 inconsistent alleles among 2312 alleles). Inclusion of BovineHD0800025437 genotype in the statistical model as a covariate resulted in the loss of all significant associations on BTA 8, indicating that the SNP is in strong linkage disequilibrium with the causative variation for CW-3 (Fig 2A).

Bottom Line: The risk allele was on the same chromosome as the Q allele that increases carcass weight.Phenotypic characterization revealed that the risk allele causes disproportional tall stature and bone size that increases carcass weight in heterozygous individuals but causes disproportionately narrow chest width in homozygotes.Thus, loss of FDG3 activity may lead to subsequent loss of Cdc42 function.

View Article: PubMed Central - PubMed

Affiliation: National Livestock Breeding Center, Odakura, Nishigo, Fukushima, Japan; Shirakawa Institute of Animal Genetics, Japan Livestock Technology Association, Odakura, Nishigo, Fukushima, Japan.

ABSTRACT
Recessive skeletal dysplasia, characterized by joint- and/or hip bone-enlargement, was mapped within the critical region for a major quantitative trait locus (QTL) influencing carcass weight; previously named CW-3 in Japanese Black cattle. The risk allele was on the same chromosome as the Q allele that increases carcass weight. Phenotypic characterization revealed that the risk allele causes disproportional tall stature and bone size that increases carcass weight in heterozygous individuals but causes disproportionately narrow chest width in homozygotes. A non-synonymous variant of FGD3 was identified as a positional candidate quantitative trait nucleotide (QTN) and the corresponding mutant protein showed reduced activity as a guanine nucleotide exchange factor for Cdc42. FGD3 is expressed in the growth plate cartilage of femurs from bovine and mouse. Thus, loss of FDG3 activity may lead to subsequent loss of Cdc42 function. This would be consistent with the columnar disorganization of proliferating chondrocytes in chondrocyte-specific inactivated Cdc42 mutant mice. This is the first report showing association of FGD3 with skeletal dysplasia.

No MeSH data available.


Related in: MedlinePlus