A genome-wide scan for candidate lethal variants in Thoroughbred horses

Abstract

2Recessive lethal variants often segregate at low frequencies in animal populations, such that two 3 randomly selected individuals are unlikely to carry the same mutation. However, the likelihood 4 of an individual inheriting two copies of a recessive lethal mutation is dramatically increased by 5 inbreeding events. Such occurrences are particularly common in domestic animal populations, 6 which are often characterised by high rates of inbreeding and low effective population sizes. To 7 date there have been no published investigations into the presence of specific variants at high 8 frequencies in domestic horse populations. This study aimed to identify potential recessive lethal 9 haplotypes in the Thoroughbred horse breed, a closed population that has been selectively bred 10 for racing performance. 11In this study, we scanned genotype data from Thoroughbred horses (n = 526) for adjacent single 12 nucleotide polymorphisms (SNPs) at high heterozygote frequencies, but with a complete absence 13 of homozygotes. Two SNPs that matched these criteria were mapped to an intronic region in the 14 LY49B gene, indicating that a closely linked mutation may cause lethality in homozygous state. 15 Despite a complete absence of homozygotes, almost 35% of Thoroughbreds included in these 16 analyses were heterozygous for both SNPs. A similar loss or absence of homozygotes was 17 observed in genotype data from other domestic horse breeds (n = 2030). Variant analysis of 18 whole-genome sequence data (n = 90) identified two SNPs in the 3UTR region of the LY49B 19 gene that may result in loss of function. Analysis of transcriptomic data from equine embryonic 20 tissue revealed that LY49B is expressed in the trophoblast during placentation stage of 21 development. 23 variant causing lethality in homozygous state. These findings suggest that LY49B may have an 24 essential, but as yet unknown function in the implantation stage of equine development. Further 25 investigation of this region may allow for the development of a genetic test to improve fertility 26 rates in horse populations. Identification of other lethal variants could assist in improving natural 27 levels of fertility in horse populations. 28 Author Summary 29Recessive lethal mutations may reach high frequencies in livestock populations due to selective 30 breeding practices, resulting in reduced fertility rates. In this study, we characterise recessive 31 lethal mutations at high frequencies in the Thoroughbred horse population, a breed with high 32 rates of inbreeding and low genetic diversity. We identified a haplotype in the LY49B gene that 33 shows strong evidence of being homozygous lethal, despite having high frequencies of 34 heterozygotes in Thoroughbreds and other domestic horse breeds. Two 3'UTR variants were 35 identified as most likely to cause loss of function in the LY49B gene, resulting in lethality. This 36 finding provides novel insights into the potential importance of LY49B in equine development. 37Additionally, this study may assist with...

Development and validation of a horse reference panel for genotype imputation

“…In cattle, several potentially deleterious haplotypes have been discovered based on the principle of missing homozygosity [31][32][33][34]. On the contrary, in horses, this approach to detect lethal variants has only been used to a limited extent [37][38][39]. A major shortcoming of such analyses is that, especially for variants with a low frequency, a large sample size is necessary to statistically prove missing homozygosity.…”

“…They detected a couple of variants that potentially influenced stallion fertility, including a splice-site disruption variant in the NOTCH1 gene [37]. Furthermore, a haplotype in the LY49B gene was detected from genotype data on Thoroughbreds that showed a deficiency of homozygotes, and it represents a strong candidate for containing a recessive lethal mutation [38].…”

“…The detection of lethal variants can also aid in diminishing the prevalence of genetic disorders and in the optimisation of fertility rates in horses [38,39]. Therefore, we applied an approach based on missing homozygosity to identify putative lethal mutations.…”