The Thoroughbred horse has played an important role in both sporting and economic aspects of society since the establishment of the breed in the 1700s. The extensive pedigree and phenotypic information available for the Thoroughbred horse population provides a unique opportunity to examine the effects of 300 years of selective breeding on genetic load. By analysing the relationship between inbreeding and racing performance of 135,572 individuals, we found that selective breeding has not efficiently alleviated the Australian Thoroughbred population of its genetic load. However, we found evidence for purging in the population that might have improved racing performance over time. Over 80% of inbreeding in the contemporary population is accounted for by a small number of ancestors from the foundation of the breed. Inbreeding to these ancestors has variable effects on fitness, demonstrating that an understanding of the distribution of genetic load is important in improving the phenotypic value of a population in the future. Our findings hold value not only for Thoroughbred and other domestic breeds, but also for small and endangered populations where such comprehensive information is not available.

Endometriosis is a common complex inflammatory condition characterised by the presence of endometrium-like tissue outside the uterus, mainly in the pelvic area. It is associated with chronic pelvic pain and infertility, and its pathogenesis remains poorly understood. The disease is typically classified according to the revised American Fertility Society (rAFS) 4-stage surgical assessment system, although stage does not correlate well with symptomatology or prognosis. Previously identified genetic variants mainly are associated with stage III/IV disease, highlighting the need for further phenotype-stratified analysis that requires larger datasets. We conducted a meta-analysis of 15 genome-wide association studies (GWAS) and a replication analysis, including 58,115 cases and 733,480 controls in total, and sub-phenotype analyses of stage I/II, stage III/IV and infertility-associated endometriosis cases. This revealed 27 genetic loci associated with endometriosis at the genome-wide p-value threshold (P<5×10−8), 13 of which are novel and an additional 8 novel genes identified from gene-based association analyses. Of the 27 loci, 21 (78%) had greater effect sizes in stage III/IV disease compared to stage I/II, 1 (4%) had greater effect size in stage I/II compared to stage III/IV and 17 (63%) had greater effect sizes when restricted to infertility-associated endometriosis cases compared to overall endometriosis. These results suggest that specific variants may confer risk for different sub-types of endometriosis through distinct pathways. Analyses of genetic variants underlying different pain symptoms reported in the UK Biobank showed that 7/9 had positive significant (p<1.28×103) positive genetic correlations with endometriosis, suggesting a genetic basis for sensitivity to pain in general. Additional conditions with significant positive genetic correlations with endometriosis included uterine fibroids, excessive and irregular menstrual bleeding, osteoarthritis, diabetes as well as menstrual cycle length and age at menarche. These results provide a basis for fine-mapping of the causal variants at these 27 loci, and for functional follow-up to understand their contribution to endometriosis and its potential subtypes.

Background: Horses produce only one foal from an eleven-month gestation period, making the maintenance of high reproductive rates essential. Genetic bottlenecks and inbreeding can increase the frequency of deleterious variants, resulting in reduced reproductive levels in a population. In this study we examined the influence of inbreeding levels on foaling rate, gestation length and secondary sex ratio in Australian Thoroughbred mares. We also investigated the genetic change in these traits throughout the history of the breed. Phenotypic data were obtained from 27,262 breeding records of Thoroughbred mares provided by three Australian stud farms. Inbreeding was estimated using the pedigree of each individual dating back to the foundation of the breed in the eighteenth century. Results: While both gestation length and foaling rate were heritable, no measurable effect of inbreeding on either trait was found. However, we did find that the genetic value for both traits had decreased within recent generations. A number of environmental factors also had significant effects on foaling rate and gestation length. Secondary sex ratio had only an extremely small paternal heritable effect and was not susceptible to environmental influences. Conclusions: In contrast to racing performance, inbreeding had no measurable effect on foaling rate or gestation length in Australian Thoroughbred horses. This could be because the level of inbreeding in the population examined is not high enough to show a discernible effect on reproductive traits. Populations that experience higher levels of inbreeding due to use of artificial reproductive technologies or extremely small population sizes may show a more pronounced reduction in natural foaling rate or gestation length. It is also possible that the intensive management techniques used in the Thoroughbred population masks any negative effects of inbreeding. The decrease in the genetic value of foaling rate is likely to be because horses with unfavourable genetic potential have not yet been selected out of the population. The change in genetic value of gestation length may be due to selective breeding favouring horses with shorter pregnancies. We also found that prioritising the mating of older mares, and avoiding out of season mating could lead to an increased breeding success.

Domestic animal populations are often characterised by high rates of inbreeding and low effective population sizes due to selective breeding practices. These practices can result in otherwise rare recessive deleterious alleles drifting to high frequencies, resulting in reduced fertility rates. 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 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. Variant analysis of whole-genome sequence data identified two SNPs in the 3′UTR 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. 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.

Donkeys transformed human history as essential beasts of burden for long-distance movement, especially across semi-arid and upland environments. They remain insufficiently studied despite globally expanding and providing key support to low- to middle-income communities. To elucidate their domestication history, we constructed a comprehensive genome panel of 207 modern and 31 ancient donkeys, as well as 15 wild equids. We found a strong phylogeographic structure in modern donkeys that supports a single domestication in Africa ~5000 BCE, followed by further expansions in this continent and Eurasia and ultimately returning to Africa. We uncover a previously unknown genetic lineage in the Levant ~200 BCE, which contributed increasing ancestry toward Asia. Donkey management involved inbreeding and the production of giant bloodlines at a time when mules were essential to the Roman economy and military.

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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...

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