Breeding experiments and genome-wide association analysis elucidate two genetically different forms of non-syndromic congenital cleft lip and jaw in Vorderwald × Montbéliarde cattle.

Abstract

Non-syndromic congenital cleft lip and jaw (CLJ) is a condition reported in Vorderwald×Montbéliarde cattle. The objective of the present study was to perform a genome-wide association study (GWAS) for 10 CLJ-affected and 50 unaffected Vorderwald×Montbéliarde cattle using the bovine Illumina high density bead chip to identify loci for this condition. Phenotypic classification of CLJ was based on a detailed recording of orofacial structures using computed tomography. A breeding experiment among CLJ-affected Vorderwald×Montbéliarde cattle and CLJ-affected Vorderwald×Montbéliarde cattle with unaffected Holsteins confirmed recessive inheritance and different loci for bilateral or left-sided versus right-sided CLJ. The GWAS for the five cases with right-sided CLJ gave a genome-wide signal on bovine chromosome (BTA) 29 at 16Mb. For the four left-sided and one bilateral CLJ case, a genome-wide significant association was identified on BTA4 at 32Mb. Two different loci are very likely to be involved in CLJ in Vorderwald×Montbéliarde cattle because experimental matings among affected cows and bulls with different types of CLJ did not result in CLJ-affected progeny, and in addition, two different loci were also found through GWAS and mapped on two different bovine chromosomes. Validation in 346 Vorderwald×Montbéliarde cattle for the highly associated SNPs on BTA4 and 29 gave ratios of 33/346 (0.095, BTA4) and 6/346 (0.017, BTA29) homozygous mutant genotypes. Further studies should elucidate the responsible mutations underlying the different types of CLJ in Vorderwald×Montbéliarde cattle.