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The genomic sequence of the horse has been available since 2009, providing critical resources for discovering important genomic variants regarding both animal health and population structures. However, to fully understand the functional implications of these variants, detailed annotation of the horse genome is required. Due to the limited availability of functional data for the equine genome, as well as the technical limitations of short-read RNA-seq, existing annotation of the equine genome contains limited information about important aspects of gene regulation, such as alternate isoforms and regulatory elements, which are either not transcribed or transcribed at a very low level. To solve above problems, the Functional Annotation of the Animal Genomes (FAANG) project proposed a systemic approach to tissue collection, phenotyping, and data generation, adopting the blueprint laid out by the Encyclopedia of DNA Elements (ENCODE) project. Here we detail the first comprehensive overview of gene expression and regulation in the horse, presenting 39,625 novel transcripts, 84,613 candidate cis-regulatory elements (CRE) and their target genes, 332,115 open chromatin regions genome wide across a diverse set of tissues. We showed substantial concordance between chromatin accessibility, chromatin states in different genic features and gene expression. This comprehensive and expanded set of genomics resources will provide the equine research community ample opportunities for studies of complex traits in the horse.

The role of histone modifications in transcription remains incompletely understood. Here, we examine the relationship between histone modifications and transcription using experimental perturbations combined with sensitive machine-learning tools. Transcription predicted the variation in active histone marks and complex chromatin states, like bivalent promoters, down to single-nucleosome resolution and at an accuracy that rivaled the correspondence between independent ChIP-seq experiments. Blocking transcription rapidly removed two punctate marks, H3K4me3 and H3K27ac, from chromatin indicating that transcription is required for active histone modifications. Transcription was also required for maintenance of H3K27me3, consistent with a role for RNA in recruiting PRC2. A subset of DNase-I-hypersensitive sites were refractory to prediction, precluding models where transcription initiates pervasively at any open chromatin. Our results, in combination with past literature, support a model in which active histone modifications serve a supportive, rather than an essential regulatory, role in transcription. A machine-learning tool can predict the distribution of histone post-translational modifications using nascent transcription data. Inhibiting transcription impacts H3K4me3, H3K27ac and H3K27me3 dynamics.

Cytosine methylation patterns have not yet been thoroughly studied in horses. Here, we profile n  = 333 samples from 42 horse tissue types at loci that are highly conserved between mammalian species using a custom array (HorvathMammalMethylChip40). Using the blood and liver tissues from horses, we develop five epigenetic aging clocks: a multi-tissue clock, a blood clock, a liver clock and two dual-species clocks that apply to both horses and humans. In addition, using blood methylation data from three additional equid species (plains zebra, Grevy’s zebras and Somali asses), we develop another clock that applies across all equid species. Castration does not significantly impact the epigenetic aging rate of blood or liver samples from horses. Methylation and RNA data from the same tissues define the relationship between methylation and RNA expression across horse tissues. We expect that the multi-tissue atlas will become a valuable resource. Methylation levels of specific sites in the genome is correlated with aging. Here the authors develop a human-horse clock which could assist in translating anti-aging interventions from humans to horses and vice versa.

Whole genome sequences (WGS) of 185 North American Thoroughbred horses were compared to quantify the number and frequency of variants, diversity of mitotypes, and autosomal runs of homozygosity (ROH). Of the samples, 82 horses were born between 1965 and 1986 (Group 1); the remaining 103, selected to maximize pedigree diversity, were born between 2000 and 2020 (Group 2). Over 14.3 million autosomal variants were identified with 4.5–5.0 million found per horse. Mitochondrial sequences associated the North American Thoroughbreds with 9 of 17 clades previously identified among diverse breeds. Individual coefficients of inbreeding, estimated from ROH, averaged 0.266 (Group 1) and 0.283 (Group 2). When SNP arrays were simulated using subsets of WGS markers, the arrays over-estimated lengths of ROH. WGS-based estimates of inbreeding were highly correlated (r > 0.98) with SNP array-based estimates, but only moderately correlated (r = 0.40) with inbreeding based on 5-generation pedigrees. On average, Group 1 horses had more heterozygous variants ( P  < 0.001), more total variants ( P  < 0.001), and lower individual inbreeding (F ROH ; P  < 0.001) than horses in Group 2. However, the distribution of numbers of variants, allele frequency, and extent of ROH overlapped among all horses such that it was not possible to identify the group of origin of any single horse using these measures. Consequently, the Thoroughbred population would be better monitored by investigating changes in specific variants, rather than relying on broad measures of diversity. The WGS for these 185 horses is publicly available for comparison to other populations and as a foundation for modeling changes in population structure, breeding practices, or the appearance of deleterious variants.

A premature stop codon in the DMRT3 gene has a major effect on the pattern of locomotion in horses, and the Dmrt3 transcription factor is critical in the development of a coordinated locomotor network in mice, suggesting that it has an important role in configuring the spinal circuits that control stride. Gait keeper: a single mutation gives horses pace Some horses — notably the harness-racing American Standardbred and the all-terrain Icelandic breed — have the ability to perform extra gaits. All horses can walk, trot, canter and gallop, but some can also 'pace' — moving the two legs on the same side of the body in unison — and/or perform other novel ambling gaits. A genome-wide association analysis of Icelandic horses has identified linkage between a premature stop codon in the DMRT3 gene and the ability to perform alternative gaits. Functional studies in mice show that Dmrt3 is expressed in a subset of spinal cord neurons that are crucial for the normal development of a coordinated locomotor network that controlling limb movements. Dmrt3 may therefore have a key role in configuring the spinal circuits that control stride in vertebrates. In the domestic horses, the DMRT3 mutation has had a major impact on the creatures' diversification, because the altered gait characteristics of a number of breeds apparently require this mutation. Locomotion in mammals relies on a central pattern-generating circuitry of spinal interneurons established during development that coordinates limb movement 1 . These networks produce left–right alternation of limbs as well as coordinated activation of flexor and extensor muscles 2 . Here we show that a premature stop codon in the DMRT3 gene has a major effect on the pattern of locomotion in horses. The mutation is permissive for the ability to perform alternate gaits and has a favourable effect on harness racing performance. Examination of wild-type and Dmrt3 -null mice demonstrates that Dmrt3 is expressed in the dI6 subdivision of spinal cord neurons, takes part in neuronal specification within this subdivision, and is critical for the normal development of a coordinated locomotor network controlling limb movements. Our discovery positions Dmrt3 in a pivotal role for configuring the spinal circuits controlling stride in vertebrates. The DMRT3 mutation has had a major effect on the diversification of the domestic horse, as the altered gait characteristics of a number of breeds apparently require this mutation.

The present research aimed to characterize the Persian Kurdish horse population relative to the Persian Arabian and American Thoroughbred populations using genome-wide SNP data. Fifty-eight Kurdish, 38 Persian Arabian and 83 Thoroughbred horses were genotyped across 670,796 markers. After quality control and pruning to eliminate linkage disequilibrium between loci which resulted in 13,554 SNPs in 52 Kurdish, 24 Persian Arabian and 58 Thoroughbred horses, the Kurdish horses were generally distinguished from the Persian Arabian samples by Principal Component Analyses, cluster analyses and calculation of pairwise F ST . Both Persian breeds were discriminated from the Thoroughbred. Pairwise F ST between the two Persian samples (0.013) was significantly greater than zero and several fold less than those found between the Thoroughbred and Kurdish (0.052) or Thoroughbred and Persian Arabian (0.057). Cluster analysis assuming three genetic clusters assigned the Kurdish horse and Thoroughbred to distinct clusters (0.942 in cluster 2 and 0.953 in cluster 3 respectively); the Persian Arabian was not in a distinct cluster (0.519 in cluster 1), demonstrating shared ancestry or recent admixture with the Kurdish breed. Diversity as quantified by expected heterozygosity was the highest in the Kurdish horse (0.342), followed by the Persian Arabian (0.328) and the Thoroughbred (0.326). Analysis of Molecular Variance showed that 4.47% of the genetic variation was present among populations ( P <0.001). Population-specific inbreeding indices ( F IS ) were not significantly different from zero in any of the populations. Analysis of individual inbreeding based on runs of homozygosity using a larger SNP set suggested greater diversity in both the Kurdish and Persian Arabian than in the Thoroughbred. These results have implications for developing conservation strategies to achieve sound breeding goals while maintaining genetic diversity.

Background Allele-specific expression (ASE) analysis provides a nuanced view of cis-regulatory mechanisms affecting gene expression. Results An equine ASE analysis was performed, using integrated Iso-seq and short-read RNA sequencing data from four healthy Thoroughbreds (2 mares and 2 stallions) across 9 tissues from the Functional Annotation of Animal Genomes (FAANG) project. Allele expression was quantified by haplotypes from long-read data, with 42,900 allele expression events compared. Within these events, 635 (1.48%) demonstrated ASE, with liver tissue containing the highest proportion. Genetic variants within ASE events were located in histone modified regions 64.2% of the time. Validation of allele-specific variants, using a set of 66 equine liver samples from multiple breeds, confirmed that 97% of variants demonstrated ASE. Conclusions This valuable publicly accessible resource is poised to facilitate investigations into regulatory variation in equine tissues. Our results highlight the tissue-specific nature of allelic imbalance in the equine genome.

Background Between 2020 and 2022, eight calves in a Nebraska herd (composite Simmental, Red Angus, Gelbvieh) displayed exercise intolerance during forced activity. In some cases, the calves collapsed and did not recover. Available sire pedigrees contained a paternal ancestor within 2–4 generations in all affected calves. Pedigrees of the calves’ dams were unavailable, however, the cows were ranch-raised and retained from prior breeding seasons, where bulls used for breeding occasionally had a common ancestor. Therefore, it was hypothesized that a de novo autosomal recessive variant was causative of exercise intolerance in these calves. Results A genome-wide association analysis utilizing SNP data from 6 affected calves and 715 herd mates, followed by whole-genome sequencing of 2 affected calves led to the identification of a variant in the gene PYGM (BTA29:g.42989581G > A). The variant, confirmed to be present in the skeletal muscle transcriptome, was predicted to produce a premature stop codon (p.Arg650*). The protein product of PYGM , myophosphorylase, breaks down glycogen in skeletal muscle. Glycogen concentrations were fluorometrically assayed as glucose residues demonstrating significantly elevated glycogen concentrations in affected calves compared to cattle carrying the variant and to wild-type controls. The absence of the PYGM protein product in skeletal muscle was confirmed by immunohistochemistry and label-free quantitative proteomics analysis; muscle degeneration was confirmed in biopsy and necropsy samples. Elevated skeletal muscle glycogen persisted after harvest, resulting in a high pH and dark-cutting beef, which is negatively perceived by consumers and results in an economic loss to the industry. Carriers of the variant did not exhibit differences in meat quality or any measures of animal well-being. Conclusions Myophosphorylase deficiency poses welfare concerns for affected animals and negatively impacts the final product. The association of the recessive genotype with dark-cutting beef further demonstrates the importance of genetics to not only animal health but to the quality of their product. Although cattle heterozygous for the variant may not immediately affect the beef industry, identifying carriers will enable selection and breeding strategies to prevent the production of affected calves.

Recent advances in genomic sequencing technology and computational assembly methods have allowed scientists to improve reference genome assemblies in terms of contiguity and composition. EquCab2, a reference genome for the domestic horse, was released in 2007. Although of equal or better quality compared to other first-generation Sanger assemblies, it had many of the shortcomings common to them. In 2014, the equine genomics research community began a project to improve the reference sequence for the horse, building upon the solid foundation of EquCab2 and incorporating new short-read data, long-read data, and proximity ligation data. Here, we present EquCab3. The count of non-N bases in the incorporated chromosomes is improved from 2.33 Gb in EquCab2 to 2.41 Gb in EquCab3. Contiguity has also been improved nearly 40-fold with a contig N50 of 4.5 Mb and scaffold contiguity enhanced to where all but one of the 32 chromosomes is comprised of a single scaffold. Theodore Kalbfleisch et al. present an improved genome assembly for the domestic horse by combining short- and long-read data, as well as proximity ligation data. They improve contiguity of the assembly by 40-fold, with a 10-fold reduction in gaps.

The domestic yak (Bos grunniens) has experienced introgression with domestic cattle in its native Qinghai‐Tibetan Plateau and after introduction to North America (NA), although the extent to which the latter has occurred is not well documented. We used complete mitochondrial (mtDNA) sequences of 12 NA yak and aligned them to the B. taurus reference genome for annotation. Identified variation among the NA haplotypes included a total of 982 variants, of which 99 were nonsynonymous single nucleotide polymorphisms. Among the NA yak, we identified nine unique mitotypes, which a haplotype network separated into two distinct clusters. A maximum likelihood tree including 86 Bovidae taxa revealed six NA yak haplotypes formed a clade with B. indicus; the other three haplotypes grouped with B. grunniens and fell as a sister clade to bison, gaur, and gayal. These data demonstrate two mitochondrial origins of NA yak, likely dating prior to their importation to NA. We isolated satellite cells from seven yak that represented both major mitotypes (B. indicus [N = 4] or yak [N = 3]) to investigate possible differences in ATP production. Oxidative consumption rates and extracellular acidification rates were quantified as measures of mitochondrial respiration and glycolysis using the Seahorse ATP Rate Assay. Cells with the B. grunniens mitotype had less total energy metabolism (p = 0.016). This difference may reflect adaptations to ancestral environments and selective pressures associated with husbandry practices and breeding. Little is known about the origin of yak that were imported to North America. Using complete mtDNA sequence, we identified two distinct lineages in North American yak; one of these appears to be the consequence of past introgression from indicine cattle. Variation in the mtDNA included many putatively functional variants. In a pilot study of mitochondrial function, we observed a difference in ATP production of satellite cells associated with the mtDNA haplotype.