A deletion mutation in bovine SLC4A2 is associated with osteopetrosis in Red Angus cattle

Abstract

BackgroundOsteopetrosis is a skeletal disorder of humans and animals characterized by the formation of overly dense bones, resulting from a deficiency in the number and/or function of bone-resorbing osteoclast cells. In cattle, osteopetrosis can either be induced during gestation by viral infection of the dam, or inherited as a recessive defect. Genetically affected calves are typically aborted late in gestation, display skull deformities and exhibit a marked reduction of osteoclasts. Although mutations in several genes are associated with osteopetrosis in humans and mice, the genetic basis of the cattle disorder was previously unknown.ResultsWe have conducted a whole-genome association analysis to identify the mutation responsible for inherited osteopetrosis in Red Angus cattle. Analysis of >54,000 SNP genotypes for each of seven affected calves and nine control animals localized the defective gene to the telomeric end of bovine chromosome 4 (BTA4). Homozygosity analysis refined the interval to a 3.4-Mb region containing the SLC4A2 gene, encoding an anion exchanger protein necessary for proper osteoclast function. Examination of SLC4A2 from normal and affected animals revealed a ~2.8-kb deletion mutation in affected calves that encompasses exon 2 and nearly half of exon 3, predicted to prevent normal protein function. Analysis of RNA from a proven heterozygous individual confirmed the presence of transcripts lacking exons 2 and 3, in addition to normal transcripts. Genotyping of additional animals demonstrated complete concordance of the homozygous deletion genotype with the osteopetrosis phenotype. Histological examination of affected tissues revealed scarce, morphologically abnormal osteoclasts displaying evidence of apoptosis.ConclusionsThese results indicate that a deletion mutation within bovine SLC4A2 is associated with osteopetrosis in Red Angus cattle. Loss of SLC4A2 function appears to induce premature cell death, and likely results in cytoplasmic alkalinization of osteoclasts which, in turn, may disrupt acidification of resorption lacunae.

Genome-wide association study for calving traits in Holstein–Friesian dairy cattle

“…Associations existed on 16 different chromosomes, some of which have previously been documented to be associated with calving traits (i.e. ss86324977), whereas others are novel previously unreported associations but have been reported to be associated with growth, skeletal development, birth weight and stature (Cole et al, 2009;McClure et al, 2010;Meyers et al, 2010). QTL regions that were solely associated with one trait were also identified facilitating direct genomic selection for these regions thereby possibly aiding in resolving known genetic antagonisms between the calving performance traits (Luo et al, 1999;Steinbock et al, 2003).…”

“…Two of these genes, SLC26A7 and TMEM64 have been documented to be associated with cartilage and bone development in humans (Lohi et al, 2002;Kim et al, 2013) suggesting that these genes may be responsible for the many morphological abnormalities associated with perinatal mortality. In cattle, a deletion in a similar gene (SLC4A2) has been shown to be associated with osteoporosis in Red Angus cattle (Meyers et al, 2010). Osteoporosis is a bone disorder observed in humans and many other animals and can be inherited as a recessive defect.…”

“…Osteoporosis is a bone disorder observed in humans and many other animals and can be inherited as a recessive defect. Loss of SLC4A2 function induces premature cell death and cytoplasmic alkalinization of osteoclasts (Meyers et al, 2010). The death of osteoclasts, which are large multinucleated cells that reabsorb bone, can result in the formation of extremely dense fragile bones and affected calves are typically born stillborn, slightly premature and morphologically small with a flat skull (Meyers et al, 2010).…”

“…Loss of SLC4A2 function induces premature cell death and cytoplasmic alkalinization of osteoclasts (Meyers et al, 2010). The death of osteoclasts, which are large multinucleated cells that reabsorb bone, can result in the formation of extremely dense fragile bones and affected calves are typically born stillborn, slightly premature and morphologically small with a flat skull (Meyers et al, 2010). Selecting on the causative mutation tagged by the ss86296129 SNP could aid in reducing both direct calving difficulty and perinatal mortality; a moderate MAF exists for this SNP signifying scope for selection.…”

Genome-wide detection of copy-number variations in local cattle breeds

“…The coat colours of horse, pig and sheep are partly determined by CNVs (Clop et al 2012), and milk production (Xu et al 2014), female fertility failure (Kadri et al 2014), osteoporosis (Meyers et al 2010), abortions and stillbirth in cattle have been shown to be influenced by CNVs. CNVs have been identified in different cattle breeds, including African, Indicine and Taurine breeds (Matukumalli et al 2009), andBae et al (2010) and Fadista et al (2010) created two CNV maps of the bovine genome using SNP genotyping and CGH arrays.…”