Candidate lethal haplotypes and causal mutations in Angus cattle

Abstract

BackgroundIf unmanaged, high rates of inbreeding in livestock populations adversely impact their reproductive fitness. In beef cattle, historical selection strategies have increased the frequency of several segregating fatal autosomal recessive polymorphisms. Selective breeding has also decreased the extent of haplotypic diversity genome-wide. By identifying haplotypes for which homozygotes are not observed but would be expected based on their frequency, candidates for developmentally lethal recessive loci can be localized. This analysis comes without the need for observation of the loss-associated phenotype (e.g., failure to implant, first trimester abortion, deformity at birth). In this study, haplotypes were estimated for 3961 registered Angus individuals using 52,545 SNP loci using findhap v2, which exploited the complex pedigree among the individuals in this population.ResultsSeven loci were detected to possess haplotypes that were not observed in homozygous form despite a sufficiently high frequency and pedigree-based expectation of homozygote occurrence. These haplotypes were identified as candidates for harboring autosomal recessive lethal alleles. Of the genotyped individuals, 109 were resequenced to an average 27X depth of coverage to identify putative loss-of-function alleles genome-wide and had variants called using a custom in-house developed pipeline. For the candidate lethal-harboring haplotypes present in these bulls, sequence-called genotypes were used to identify concordant variants. In addition, whole-genome sequence imputation of variants was performed into the set of 3961 genotyped animals using the 109 resequenced animals to identify candidate lethal recessive variants at the seven loci. Following the imputation, no variants were identified that were fully concordant with the marker-based diplotypes.ConclusionsSelective breeding programs could utilize the predicted lethal haplotypes associated with SNP genotypes. Sequencing and other methods for identifying the causal variants underlying these haplotypes can allow for more efficient methods of management such as gene editing. These two methods in total will reduce the negative impacts of inbreeding on fertility and maximize overall genetic gains.

Balancing selection on a recessive lethal deletion with pleiotropic effects on two neighboring genes in the porcine genome

“…Inherited defects usually derive from unique “founder” mutations [ 2 ]. Especially in cattle breeds, several high frequency lethal alleles have been described [ 3 , 4 ] reaching carrier frequencies up to 32% [ 5 ], that can be traced back to prime bulls that were used extensively in the past decades. However, the effect of individual sires on the population depends on the breeding goal and the structure of the breeding program.…”

Gene Regulation in Ruminants: A Nutritional Perspective

“…However, not all mutations have beneficial effects on the productivity of meat-producing animals. There are also mutations that are considered lethal, affecting, for example, the reproductive performance of females through early embryonic loss [81], or mutations that produce genetic disorders in beef cattle [82]. The Arachnomelia syndrome in Simmental cattle [83] that produce malformations of the skeleton mainly affecting the legs, the spinal column, and the skull is an example of these genetic disorders.…”

Implementation of Bayesian methods to identify SNP and haplotype regions with transmission ratio distortion across the whole genome: TRDscan v.1.0

“…However, the non-Mendelian segregation remains ambiguous (Nadeau, 2017) and current knowledge about its prevalence and possible causes in livestock species is still scarce. The link to impaired fer-Implementation of Bayesian methods to identify SNP and haplotype regions with transmission ratio distortion across the whole genome: TRDscan v.1.0 tility (Silver, 1989) and differential offspring survival at different stages (Dean et al, 2006;Eversley et al, 2010) emphasizes the relevance of TRD, which could be an outstanding alternative to search for genomic regions that may contain potential causative mutations directly affecting reproductive traits, as illustrated by the success of previous methods targeting a particular type of TRD based on the absence of homozygous haplotypes (e.g., VanRaden et al, 2011;Hoff et al, 2017).…”