bioRxiv2020
Recessive lethal variants often segregate at low frequencies in animal populations, such that two randomly selected individuals are unlikely to carry the same mutation. However, the likelihood of an individual inheriting two copies of a recessive lethal mutation is dramatically increased by inbreeding events. Such occurrences are particularly common in domestic animal populations, which are often characterised by high rates of inbreeding and low effective population sizes. To date there have been no published investigations into the presence of specific variants at high frequencies in domestic horse populations. This study aimed to identify potential recessive lethal haplotypes in the Thoroughbred horse breed, a closed population that has been selectively bred for racing performance. In this study, we scanned genotype data from Thoroughbred horses (n = 526) for adjacent single nucleotide polymorphisms (SNPs) at high heterozygote frequencies, but with a complete absence of homozygotes. Two SNPs that matched these criteria were mapped to an intronic region in the LY49B gene, indicating that a closely linked mutation may cause lethality in homozygous state. Despite a complete absence of homozygotes, almost 35% of Thoroughbreds included in these analyses were heterozygous for both SNPs. A similar loss or absence of homozygotes was observed in genotype data from other domestic horse breeds (n = 2030). Variant analysis of whole-genome sequence data (n = 90) identified two SNPs in the 3UTR region of the LY49B gene that may result in loss of function. Analysis of transcriptomic data from equine embryonic tissue revealed that LY49B is expressed in the trophoblast during placentation stage of development. In this study, a region in the LY49B gene was identified as a strong candidate for harbouring a variant causing lethality in homozygous state. These findings suggest that LY49B may have an essential, but as yet unknown function in the implantation stage of equine development. Further investigation of this region may allow for the development of a genetic test to improve fertility rates in horse populations. Identification of other lethal variants could assist in improving natural levels of fertility in horse populations. Author SummaryRecessive lethal mutations may reach high frequencies in livestock populations due to selective breeding practices, resulting in reduced fertility rates. In this study, we characterise recessive lethal mutations at high frequencies in the Thoroughbred horse population, a breed with high rates of inbreeding and low genetic diversity. We identified a haplotype in the LY49B gene that shows strong evidence of being homozygous lethal, despite having high frequencies of heterozygotes in Thoroughbreds and other domestic horse breeds. Two 3UTR variants were identified as most likely to cause loss of function in the LY49B gene, resulting in lethality. This finding provides novel insights into the potential importance of LY49B in equine development. Additionally, this study may assist with breeding strategies to improve fertility rates in the Thoroughbred and other domestic horse breeds.