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Intensive selection for improved productivity has been accompanied by an increase in inbreeding rates and a reduction in genetic diversity. The increase in inbreeding tends to impact performance, especially fitness-related traits such as male fertility. Inbreeding can be monitored using runs of homozygosity (ROH), defined as contiguous lengths of homozygous genotypes observed in an individual's chromosome. The goal of this study was to evaluate the presence of ROH in Italian Brown Swiss cattle and assess its association with bull fertility. First, we evaluated the association between ROH and male fertility using 1,102 Italian Brown Swiss bulls with sire conception rate records and 572 K SNPs spanning the entire genome. Second, we split the entire population into 100 high-fertility and 100 low-fertility bulls to investigate the potential enrichment of ROH segments in the low-fertility group. Finally, we mapped the significant ROH regions to the bovine genome to identify candidate genes associated with sperm biology and male fertility. Notably, there was a negative association between bull fertility and the amount of homozygosity. Four different ROH regions located in chromosomes 6, 10, 11, and 24 were significantly overrepresented in low-fertility bulls (Fisher's exact test, p -value <0.01). Remarkably, these four genomic regions harbor many genes such as WDR19 , RPL9 , LIAS , UBE2K , DPF3 , 5S-rRNA , 7SK , U6 , and WDR7 that are related to sperm biology and male fertility. Overall, our findings suggest that inbreeding and increased homozygosity have a negative impact on male fertility in Italian Brown Swiss cattle. The quantification of ROH can contribute to minimizing the inbreeding rate and avoid its negative effect on fitness-related traits, such as male fertility., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pacheco, Rossoni, Cecchinato and Peñagaricano.)

The impact of genomic epistasis effects on the accuracy of predicting the phenotypic values of residual feed intake (RFI) in U.S. Holstein cows was evaluated using 6215 Holstein cows and 78,964 SNPs. Two SNP models and seven epistasis models were initially evaluated. Heritability estimates and the accuracy of predicting the RFI phenotypic values from 10-fold cross-validation studies identified the model with SNP additive effects and additive × additive (A×A) epistasis effects (A + A×A model) to be the best prediction model. Under the A + A×A model, additive heritability was 0.141, and A×A heritability was 0.263 that consisted of 0.260 inter-chromosome A×A heritability and 0.003 intra-chromosome A×A heritability, showing that inter-chromosome A×A effects were responsible for the accuracy increases due to A×A. Under the SNP additive model (A-only model), the additive heritability was 0.171. In the 10 validation populations, the average accuracy for predicting the RFI phenotypic values was 0.246 (with range 0.197-0.333) under A + A×A model and was 0.231 (with range of 0.188-0.319) under the A-only model. The average increase in the accuracy of predicting the RFI phenotypic values by the A + A×A model over the A-only model was 6.49% (with range of 3.02-14.29%). Results in this study showed A×A epistasis effects had a positive impact on the accuracy of predicting the RFI phenotypic values when combined with additive effects in the prediction model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liang, Prakapenka, Parker Gaddis, VandeHaar, Weigel, Tempelman, Koltes, Santos, White, Peñagaricano, Baldwin VI and Da.)

Several ocular pathologies in cattle, such as ocular squamous cell carcinoma and infectious keratoconjunctivitis, have been associated with low pigmentation of the eyelids. The main objective of this study was to analyze the transcriptome of eyelid skin in Hereford cattle using strand-specific RNA sequencing technology to characterize and identify long noncoding RNAs (lncRNAs). We compared the expression of lncRNAs between pigmented and unpigmented eyelids and analyzed the interaction of lncRNAs and putative target genes to reveal the genetic basis underlying eyelid pigmentation in cattle. We predicted 4,937 putative lncRNAs mapped to the bovine reference genome, enriching the catalog of lncRNAs in Bos taurus . We found 27 differentially expressed lncRNAs between pigmented and unpigmented eyelids, suggesting their involvement in eyelid pigmentation. In addition, we revealed potential links between some significant differentially expressed lncRNAs and target mRNAs involved in the immune response and pigmentation. Overall, this study expands the catalog of lncRNAs in cattle and contributes to a better understanding of the biology of eyelid pigmentation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jara, Peñagaricano, Armstrong, Menezes, Tardiz, Rodons and Iriarte.)

Genetic selection has been an effective strategy to improve calving traits including stillbirth in dairy cattle. The primary objectives of the present study were to characterize stillbirth data and determine the feasibility of implementing routine genetic evaluations of stillbirth in five non-Holstein dairy breeds, namely Ayrshire, Guernsey, Milking Shorthorn, Brown Swiss, and Jersey. An updated sire-maternal grandsire threshold model was used to estimate genetic parameters and genetic values for stillbirth. Stillbirth data with the birth years of dams from 1995 to 2018 were extracted from the United States national calving ease database maintained by the Council on Dairy Cattle Breeding. The extracted stillbirth records varied drastically among the five dairy breeds. There were approximately 486K stillbirth records for Jersey and more than 80K stillbirth records for Brown Swiss. The direct and maternal heritability estimates of stillbirth were 6.0% (4.5-7.6%) and 4.7% (3.3-6.1%) in Jersey and 6.8% (3.2-10.5%) and 1.1% (0.6-2.9%) in Brown Swiss. The estimated genetic correlations between direct and maternal genetic effects for stillbirth were -0.15 (-0.38 to -0.08) in Jersey and -0.35 (-0.47 to -0.12) in Brown Swiss. The estimated genetic parameters for stillbirth in these two breeds were within close ranges of previous studies. The reliabilities of predicted transmitting abilities in Jersey and Brown Swiss increased substantially, thanks to the substantial increase in available stillbirth data in the past 10 years. The stillbirth records for Ayrshire, Guernsey, and Milking Shorthorn, which ranged approximately between 3K and 12K, are insufficient to implement reliable routine genetic evaluations of stillbirth in these three dairy breeds. Estimated genetic (co)variances and genetic values deviated considerably from the reported ranges of previous studies, and the reliabilities of predicted transmitting abilities were low in these three breeds. In conclusion, routine genetic evaluations of stillbirth are feasible in Brown Swiss and Jersey. However, reliable genetic evaluations of stillbirth in Ayrshire, Guernsey, and Milking Shorthorn require further data collection on stillbirth., Competing Interests: Authors X-LW, KPG, HN, JC, JB, and JD are employees of the Council on Dairy Cattle Breeding (CDCB), a nonprofit organization. The authors have not stated any other conflicts of interest. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that can be construed as a potential conflict of interest., (Copyright © 2022 Sigdel, Wu, Parker Gaddis, Norman, Carrillo, Burchard, Peñagaricano and Dürr.)

Visceral fat is related to important metabolic processes, including insulin sensitivity and lipid mobilization. The goal of this study was to identify individual genes, pathways, and molecular processes implicated in visceral fat deposition in dairy cows. Data from 172 genotyped Holstein cows classified at slaughterhouse as having low ( n = 77; omental fold < 5 mm in thickness and minimum fat deposition in omentum) or high ( n = 95; omental fold ≥ 20 mm in thickness and marked fat deposition in omentum) omental fat were analyzed. The identification of regions with significant additive and non-additive genetic effects was performed using a two-step mixed model-based approach. Genomic scans were followed by gene-set analyses in order to reveal the genetic mechanisms controlling abdominal obesity. The association mapping revealed four regions located on BTA19, BTA20 and BTA24 with significant additive effects. These regions harbor genes, such as SMAD7 , ANKRD55 , and the HOXB family, that are implicated in lipolysis and insulin tolerance. Three regions located on BTA1, BTA13, and BTA24 showed marked non-additive effects. These regions harbor genes MRAP, MIS18A , PRNP and TSHZ1, that are directly implicated in adipocyte differentiation, lipid metabolism, and insulin sensitivity. The gene-set analysis revealed functional terms related to cell arrangement, cell metabolism, cell proliferation, cell signaling, immune response, lipid metabolism, and membrane permeability, among other functions. We further evaluated the genetic link between visceral fat and two metabolic disorders, ketosis, and displaced abomasum. For this, we analyzed 28k records of incidence of metabolic disorders from 14k cows across lactations using a single-step genomic BLUP approach. Notably, the region on BTA20 significantly associated with visceral fat deposition was also associated with the incidence of displaced abomasum. Overall, our findings suggest that visceral fat deposition in dairy cows is controlled by both additive and non-additive effects. We detected at least one region with marked pleiotropic effects affecting both visceral fat accumulation and displaced abomasum., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Novo, Cavani, Pinedo, Melendez and Peñagaricano.)

Tenderness is a major quality attribute for fresh beef steaks in the United States, and meat quality traits in general are suitable candidates for genomic research. The objectives of the present analysis were to (1) perform genome-wide association (GWA) analysis for marbling, Warner-Bratzler shear force (WBSF), tenderness, and connective tissue using whole-genome data in an Angus population, (2) identify enriched pathways in each GWA analysis; (3) construct a protein-protein interaction network using the associated genes and (4) perform a μ-calpain proteolysis assessment for associated structural proteins. An Angus-sired population of 2,285 individuals was assessed. Animals were transported to a commercial packing plant and harvested at an average age of 457 ± 46 days. After 48 h postmortem, marbling was recorded by graders' visual appraisal. Two 2.54-cm steaks were sampled from each muscle for recording of WBSF, and tenderness, and connective tissue by a sensory panel. The relevance of additive effects on marbling, WBSF, tenderness, and connective tissue was evaluated on a genome-wide scale using a two-step mixed model-based approach in single-trait analysis. A tissue-restricted gene enrichment was performed for each GWA where all polymorphisms with an association p -value lower than 1 × 10 -3 were included. The genes identified as associated were included in a protein-protein interaction network and a candidate structural protein assessment of proteolysis analyses. A total of 1,867, 3,181, 3,926, and 3,678 polymorphisms were significantly associated with marbling, WBSF, tenderness, and connective tissue, respectively. The associate region on BTA29 (36,432,655-44,313,046 bp) harbors 13 highly significant markers for meat quality traits. Enrichment for the GO term GO:0005634 (Nucleus), which includes transcription factors, was evident. The final protein-protein network included 431 interations between 349 genes. The 42 most important genes based on significance that encode structural proteins were included in a proteolysis analysis, and 81% of these proteins were potential μ-Calpain substrates. Overall, this comprehensive study unraveled genetic variants, genes and mechanisms of action responsible for the variation in meat quality traits. Our findings can provide opportunities for improving meat quality in beef cattle via marker-assisted selection., (Copyright © 2020 Leal-Gutiérrez, Rezende, Reecy, Kramer, Peñagaricano and Mateescu.)

Heat stress represents a major environmental factor that negatively affects the health and performance of dairy cows, causing huge economic losses to the dairy industry. Identifying and selecting animals that are thermotolerant is an attractive alternative for reducing the negative effects of heat stress on dairy cattle performance. As such, the objectives of the present study were to estimate genetic components of milk yield, fat yield, and protein yield considering heat stress and to perform whole-genome scans and a subsequent gene-set analysis for identifying candidate genes and functional gene-sets implicated in milk production under heat stress conditions. Data consisted of about 254k test-day records from 17,522 Holstein cows. Multi-trait repeatability test day models with random regressions on a function of temperature-humidity index (THI) values were used for genetic analyses. The models included herd-test-day and DIM classes as fixed effects, and general and thermotolerance additive genetic and permanent environmental as random effects. Notably, thermotolerance additive genetic variances for all milk traits increased across parities suggesting that cows become more sensitive to heat stress as they age. In addition, our study revealed negative genetic correlations between general and thermotolerance additive effects, ranging between -0.18 to -0.68 indicating that high producing cows are more susceptible to heat stress. The association analysis identified at least three different genomic regions on BTA5, BTA14, and BTA15 strongly associated with milk production under heat stress conditions. These regions harbor candidate genes, such as HSF1 , MAPK8IP1, and CDKN1B that are directly involved in the cellular response to heat stress. Moreover, the gene-set analysis revealed several functional terms related to heat shock proteins, apoptosis, immune response, and oxidative stress, among others. Overall, the genes and pathways identified in this study provide a better understanding of the genetic architecture underlying dairy cow performance under heat stress conditions. Our findings point out novel opportunities for improving thermotolerance in dairy cattle through marker-assisted breeding., (Copyright © 2019 Sigdel, Abdollahi-Arpanahi, Aguilar and Peñagaricano.)

Structural equation models involving latent variables are useful tools for formulating hypothesized models defined by theoretical variables and causal links between these variables. The objectives of this study were: (1) to identify latent variables underlying carcass and meat quality traits and (2) to perform whole-genome scans for these latent variables in order to identify genomic regions and individual genes with both direct and indirect effects. A total of 726 steers from an Angus-Brahman multibreed population with records for 22 phenotypes were used. A total of 480 animals were genotyped with the GGP Bovine F-250. The single-step genomic best linear unbiased prediction method was used to estimate the amount of genetic variance explained for each latent variable by chromosome regions of 20 adjacent SNP-windows across the genome. Three types of genetic effects were considered: (1) direct effects on a single latent phenotype; (2) direct effects on two latent phenotypes simultaneously; and (3) indirect effects. The final structural model included carcass quality as an independent latent variable and meat quality as a dependent latent variable. Carcass quality was defined by quality grade, fat over the ribeye and marbling, while the meat quality was described by juiciness, tenderness and connective tissue, all of them measured through a taste panel. From 571 associated genomic regions (643 genes), each one explaining at least 0.05% of the additive variance, 159 regions (179 genes) were associated with carcass quality, 106 regions (114 genes) were associated with both carcass and meat quality, 242 regions (266 genes) were associated with meat quality, and 64 regions (84 genes) were associated with carcass quality, having an indirect effect on meat quality. Three biological mechanisms emerged from these findings: postmortem proteolysis of structural proteins and cellular compartmentalization, cellular proliferation and differentiation of adipocytes, and fat deposition.

Milk fever is an important metabolic disorder that affects dairy cows around parturition. It is associated with a breakdown in the mechanisms of calcium homeostasis, resulting in very low blood calcium levels (hypocalcemia). The main objective of this study was to dissect the genetic basis underlying milk fever incidence in Holstein cattle. Data consisted of 31.6 k producer-recorded lactation incidence records from 15.3 k cows. The analysis included a whole-genome scan and a subsequent gene-set analysis in order to reveal individual genes, genetic mechanisms and biological pathways implicated in the incidence of periparturient hypocalcemia. The association analysis identified at least eight different genomic regions that explain considerable amounts of additive genetic variance for milk fever incidence. Notably, some of these regions harbor genes, such as CYP27A1, CYP2J2, GC, SNAI2 , and PIM1 , that are directly involved in vitamin D metabolic pathway. Moreover, the gene-set analysis revealed several functional terms, such as calcium ion binding, calcium ion transportation, T cell differentiation, B cell activation, protein phosphorylation, apoptosis, and protein kinase activity, among others, that could be implicated in the development of periparturient hypocalcemia. Overall, this comprehensive study contributes to a better understanding of the genetic control of this complex disease. In addition, these findings may contribute to the development of novel breeding strategies for reducing the incidence of milk fever in dairy cattle.

Studies in rats and mice have established that maternal nutrition induces epigenetic modifications, sometimes permanently, that alter gene expression in the fetus, which in turn leads to phenotypic changes. However, limited data is available on the influence of maternal diet on epigenetic modifications and gene expression in sheep. Therefore, the objectives of this study were to investigate the impact of different maternal dietary energy sources on the expression of imprinted genes in fetuses in sheep. Ewes were naturally bred to a single sire and from days 67 ± 3 of gestation until necropsy (days 130 ± 1), they were fed one of three diets of alfalfa haylage (HY; fiber), corn (CN; starch), or dried corn distiller's grains (DG; fiber plus protein plus fat). A total of 26 fetuses were removed from the dams and longissimus dorsi, semitendinosus, perirenal adipose depot, and subcutaneous adipose depot tissues were collected for expression and DNA methylation analyses. Expression analysis of nine imprinted genes and three DNA methyltransferase (DNMTs) genes showed significant effects of the different maternal diets on the expression of these genes. The methylation levels of CpG islands of both IGF2R and H19 were higher in HY and DG than CN fetuses in both males and females. This result is consistent with the low amino acid content of the CN diet, a source of methyl group donors, compared to HY and DG diets. Thus, results of this study provide evidence of association between maternal nutrition during pregnancy and transcriptomic and epigenomic alterations of imprinted genes and DNMTs in the fetal tissues.

Whole-genome association studies typically focus on genetic markers with the strongest evidence of association. However, single markers often explain only a small component of the genetic variance and hence offer a limited understanding of the trait under study. As such, the objective of this study was to perform a pathway-based association analysis in Holstein dairy cattle in order to identify relevant pathways involved in bull fertility. The results of a single-marker association analysis, using 1,755 bulls with sire conception rate data and genotypes for 38,650 single nucleotide polymorphisms (SNPs), were used in this study. A total of 16,819 annotated genes, including 2,767 significantly associated with bull fertility, were used to interrogate a total of 662 Gene Ontology (GO) terms and 248 InterPro (IP) entries using a test of proportions based on the cumulative hypergeometric distribution. After multiple-testing correction, 20 GO categories and one IP entry showed significant overrepresentation of genes statistically associated with bull fertility. Several of these functional categories such as small GTPases mediated signal transduction, neurogenesis, calcium ion binding, and cytoskeleton are known to be involved in biological processes closely related to male fertility. These results could provide insight into the genetic architecture of this complex trait in dairy cattle. In addition, this study shows that quantitative trait pathways inferred from single-marker analyses could enhance our interpretations of the results of genome-wide association studies.