Identification of the Causative Gene for Simmental Arachnomelia Syndrome Using a Network-Based Disease Gene Prioritization Approach

Abstract

Arachnomelia syndrome (AS), mainly found in Brown Swiss and Simmental cattle, is a congenital lethal genetic malformation of the skeletal system. In this study, a network-based disease gene prioritization approach was implemented to rank genes in the previously reported ∼7 Mb region on chromosome 23 associated with AS in Simmental cattle. The top 6 ranked candidate genes were sequenced in four German Simmental bulls, one known AS-carrier ROMEL and a pooled sample of three known non-carriers (BOSSAG, RIFURT and HIRMER). Two suspicious mutations located in coding regions, a mis-sense mutation c.1303G>A in the bystin-like (BYSL) gene and a 2-bp deletion mutation c.1224_1225delCA in the molybdenum cofactor synthesis step 1 (MOCS1) gene were detected. Bioinformatic analysis revealed that the mutation in MOCS1 was more likely to be the causative mutation. Screening the c.1224_1225delCA site in 383 individuals from 12 cattle breeds/lines, we found that only the bull ROMEL and his 12 confirmed progeny carried the mutation. Thus, our results confirm the conclusion of Buitkamp et al. that the 2-bp deletion mutation c.1224_1225delCA in exon 11 of the MOCS1 gene is causative for AS in Simmental cattle. Furthermore, a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was developed to detect the causative mutation.

Multiple congenital ocular abnormalities including microphthalmia, microphakia and aphakia in a Simmental cross bull

“…Genetic mutations causing congenital multiple ocular abnormalities have previously been described in cattle17 18 and cannot be ruled out in this case, as their presence was not assessed. A number of genetic mutations are described in beef cattle19 and for some of these, rapid and accessible techniques such as PCR have been developed to aid diagnosis 20 21. In Japanese Black cattle, mutations of the WFDC1 gene have been identified as a cause of multiple congenital ocular abnormalities17 18; however, in the Holstein breed, a different gene mutation (in the MITF gene) has been associated with congenital microphthalmia,7 a mutation also associated with multiple congenital abnormalities (including some ocular abnormalities) has been reported in the German Fleckvieh breed 22.…”

Selection and implementation of SNP markers for parentage analysis in a Chinese crossbred cattle population

“…As a cost and time-effective design, pooling DNA has been used in many kinds of research, such as, detecting SNP [21], estimating allele frequencies [22], QTL mapping [23], as well as genome association scan [24]. In the present study, direct sequencing of pooled DNA was chosen for evaluating SNP heterozygosity, and finally, 59 markers with high information were determined.…”

Selection and implementation of SNP markers for parentage analysis in a Chinese crossbred cattle population

“…As a cost and time-effective design, pooling DNA has been used in many kinds of research, such as, detecting SNP [16], estimating allele frequencies [17], QTL mapping [18], as well as genome association scan [19]. In the present study, the pooled DNA was chosen for evaluating SNP heterozygosity, and nally, 59 markers were determined and selected from 269 candidates.…”