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Background: Hereditary hemorrhagic telangiectasia (HHT) is characterized by extensive telangiectasias and arteriovenous malformations. The primary clinical manifestation is epistaxis that results in iron-deficiency anemia and reduced health-related quality of life., Methods: We conducted a randomized, placebo-controlled trial to evaluate the safety and efficacy of pomalidomide for the treatment of HHT. We randomly assigned patients, in a 2:1 ratio, to receive pomalidomide at a dose of 4 mg daily or matching placebo for 24 weeks. The primary outcome was the change from baseline through week 24 in the Epistaxis Severity Score (a validated bleeding score in HHT; range, 0 to 10, with higher scores indicating worse bleeding). A reduction of 0.71 points or more is considered clinically significant. A key secondary outcome was the HHT-specific quality-of-life score (range, 0 to 16, with higher scores indicating more limitations)., Results: The trial was closed to enrollment in June 2023 after a planned interim analysis met a prespecified threshold for efficacy. A total of 144 patients underwent randomization; 95 patients were assigned to receive pomalidomide and 49 to receive placebo. The baseline mean (±SD) Epistaxis Severity Score was 5.0±1.5, a finding consistent with moderate-to-severe epistaxis. At 24 weeks, the mean difference between the pomalidomide group and the placebo group in the change from baseline in the Epistaxis Severity Score was -0.94 points (95% confidence interval [CI], -1.57 to -0.31; P = 0.004). The mean difference in the changes in the HHT-specific quality-of-life score between the groups was -1.4 points (95% CI, -2.6 to -0.3). Adverse events that were more common in the pomalidomide group than in the placebo group included neutropenia, constipation, and rash., Conclusions: Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity. No unexpected safety signals were identified. (Funded by the National Heart, Lung, and Blood Institute; PATH-HHT Clinicaltrials.gov number, NCT03910244)., (Copyright © 2024 Massachusetts Medical Society.)

The Multiphase Optimization Strategy (MOST) is a three-phase iterative framework that could accelerate the development of behavioral interventions. This systematic review and meta-analysis was conducted within the MOST preparation phase and aimed to classify components included in pediatric sleep duration interventions, using the Behavior Change Technique (BCT) Taxonomy. Across 37 interventions, 46 out of 93 BCTs have been used, with an average of 8 techniques used per study. The most common BCTs used were instruction on how to perform the behavior (N = 29; code 4.1), practical social support (N = 22; code: 3.2), and behavioral practice/rehearsal (N = 22; code: 8.1). A latent class analysis identified two classes of interventions, distinguished by the presence of BCTs falling within the following behavior change groups: shaping knowledge, natural consequences, comparison of behavior, and repetition and substitution. Our meta-analysis revealed that interventions belonging to the latent class with these behavior change groups (N = 15) had a pooled positive intervention effect of 14 min (95 % CI: 8-21) versus 8 min (95 % CI: 1-15) for interventions without these behavior change groups (N = 19). This systematic review and meta-analysis will enhance the development of sleep promotion interventions and guide the selection of candidate intervention components for future optimization and randomized control trials., (Copyright © 2024. Published by Elsevier Ltd.)

Structure-based methods in drug discovery have become an integral part of the modern drug discovery process. The power of virtual screening lies in its ability to rapidly and cost-effectively explore enormous chemical spaces to select promising ligands for further experimental investigation. Relative free energy perturbation (RFEP) and similar methods are the gold standard for binding affinity prediction in drug discovery hit-to-lead and lead optimization phases, but have high computational cost and the requirement of a structural analog with a known activity. Without a reference molecule requirement, absolute FEP (AFEP) has, in theory, better accuracy for hit ID, but in practice, the slow throughput is not compatible with VS, where fast docking and unreliable scoring functions are still the standard. Here, we present an integrated workflow to virtually screen large and diverse chemical libraries efficiently, combining active learning with a physics-based scoring function based on a fast absolute free energy perturbation method. We validated the performance of the approach in the ranking of structurally related ligands, virtual screening hit rate enrichment, and active learning chemical space exploration; disclosing the largest reported collection of free energy simulations to date.

Directional selection alters the genome via hard sweeps, soft sweeps, and polygenic selection. However, mapping polygenic selection is difficult because it does not leave clear signatures on the genome like a selective sweep. In populations with temporally stratified genotypes, the Generation Proxy Selection Mapping (GPSM) method identifies variants associated with generation number (or appropriate proxy) and thus variants undergoing directional allele frequency changes. Here, we use GPSM on two large datasets of beef cattle to detect associations between an animal's generation and 11 million imputed SNPs. Using these datasets with high power and dense mapping resolution, GPSM detected a total of 294 unique loci actively under selection in two cattle breeds. We observed that GPSM has a high power to detect selection in the very recent past (<10 years), even when allele frequency changes are small. Variants identified by GPSM reside in genomic regions associated with known breed-specific selection objectives, such as fertility and maternal ability in Red Angus, and carcass merit and coat color in Simmental. Over 60% of the selected loci reside in or near (<50 kb) annotated genes. Using haplotype-based and composite selective sweep statistics, we identify hundreds of putative selective sweeps that likely occurred earlier in the evolution of these breeds; however, these sweeps have little overlap with recent polygenic selection. This makes GPSM a complementary approach to sweep detection methods when temporal genotype data are available. The selected loci that we identify across methods demonstrate the complex architecture of selection in domesticated cattle., Competing Interests: The authors declare no conflicts of interest related to this work., (© 2024 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.)

Seasonal shedding of winter hair at the start of summer is well studied in wild and domesticated populations. However, the genetic influences on this trait and their interactions are poorly understood. We use data from 13,364 cattle with 36,899 repeated phenotypes to investigate the relationship between hair shedding and environmental variables, single nucleotide polymorphisms, and their interactions to understand quantitative differences in seasonal shedding. Using deregressed estimated breeding values from a repeated records model in a genome-wide association analysis (GWAA) and meta-analysis of year-specific GWAA gave remarkably similar results. These GWAA identified hundreds of variants associated with seasonal hair shedding. There were especially strong associations between chromosomes 5 and 23. Genotype-by-environment interaction GWAA identified 1,040 day length-by-genotype interaction associations and 17 apparent temperature-by-genotype interaction associations with hair shedding, highlighting the importance of day length on hair shedding. Accurate genomic predictions of hair shedding were created for the entire dataset, Angus, Hereford, Brangus, and multibreed datasets. Loci related to metabolism and light-sensing have a large influence on seasonal hair shedding. This is one of the largest genetic analyses of a phenological trait and provides insight into both agriculture production and basic science., Competing Interests: Conflicts of interest Jared Decker and James Koltes were previously on the scientific advisory board of Vytelle, LLC., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.)

Background: Artificial selection on quantitative traits using breeding values and selection indices in commercial livestock breeding populations causes changes in allele frequency over time at hundreds or thousands of causal loci and the surrounding genomic regions. In population genetics, this type of selection is called polygenic selection. Researchers and managers of pig breeding programs are motivated to understand the genetic basis of phenotypic diversity across genetic lines, breeds, and populations using selection mapping analyses. Here, we applied generation proxy selection mapping (GPSM), a genome-wide association analysis of single nucleotide polymorphism (SNP) genotypes (38,294-46,458 markers) of birth date, in four pig populations (15,457, 15,772, 16,595 and 8447 pigs per population) to identify loci responding to artificial selection over a period of five to ten years. Gene-drop simulation analyses were conducted to provide context for the GPSM results. Selected loci within and across each population of pigs were compared in the context of swine breeding objectives., Results: The GPSM identified 49 to 854 loci as under selection (Q-values less than 0.10) across 15 subsets of pigs based on combinations of populations. The number of significant associations increased when data were pooled across populations. In addition, several significant associations were identified in more than one population. These results indicate concurrent selection objectives, similar genetic architectures, and shared causal variants responding to selection across these pig populations. Negligible error rates (less than or equal to 0.02%) of false-positive associations were found when testing GPSM on gene-drop simulated genotypes, suggesting that GPSM distinguishes selection from random genetic drift in actual pig populations., Conclusions: This work confirms the efficacy and the negligible error rates of the GPSM method in detecting selected loci in commercial pig populations. Our results suggest shared selection objectives and genetic architectures across swine populations. The identified polygenic selection highlights loci that are important to swine production., (© 2023. ’Institut National de Recherche en Agriculture, Alimentation et Environnement (INRAE).)

Background: For the first time, the 2020-2025 Dietary Guidelines for Americans provide specific guidance regarding the types of foods and beverages that should be offered in the first 2 years of life. Milk, in various forms (eg, human milk, infant formula, and cow's milk) contributes a large proportion of key nutrients to the diets of infants and toddlers in the United States., Objective: The aim of this study was to determine the types of milk (human milk, infant formula, and other milk) fed to US infants and toddlers in the past 12 years and to describe trends over time., Design: This was a cross-sectional analysis of 2-day, 24-hour dietary recalls., Participants/setting: Data from the 2007-2018 National Health and Nutrition Examination Survey were used for these analyses. Infants and toddlers aged 0 through 23.9 months with 2 days of dietary recall data (n = 3,079) were included., Main Outcome Measures: The main outcome was proportion of infants and toddlers fed different milk types., Statistical Analyses Performed: Survey-adjusted weighted percentages were used to report sociodemographic characteristics and the proportion of subjects fed each milk type category by age group and survey cycles. Binary and multinomial logistic regressions were used to assess differences in subject characteristics by age groups., Results: Sociodemographic characteristics did not differ by age group. The proportion of infants aged 0 to <6 months fed infant formula only was 60.2% in 2007-2012 and 44.8% in 2013-2018. The proportion of infants aged 6 to <12 months fed partially hydrolyzed infant formula only was 7.3% in 2007-2012 and 13.1% in 2013-2018. In toddlers (>12 months old), cow's milk was the predominant milk type in both 2007-2012 and 2013-2018., Conclusions: The percentage of infants fed any human milk increased over the past decade. Unsweetened cow's milk was the most predominate milk type consumed among toddlers., (Copyright © 2023 Academy of Nutrition and Dietetics. Published by Elsevier Inc. All rights reserved.)

Whether initiation of statins could increase survival free of dementia and disability in adults aged ≥75 years is unknown. PREVENTABLE, a double-blind, placebo-controlled randomized pragmatic clinical trial, will compare high-intensity statin therapy (atorvastatin 40 mg) with placebo in 20,000 community-dwelling adults aged ≥75 years without cardiovascular disease, disability, or dementia at baseline. Exclusion criteria include statin use in the prior year or for >5 years and inability to take a statin. Potential participants are identified using computable phenotypes derived from the electronic health record and local referrals from the community. Participants will undergo baseline cognitive testing, with physical testing and a blinded lipid panel if feasible. Cognitive testing and disability screening will be conducted annually. Multiple data sources will be queried for cardiovascular events, dementia, and disability; survival is site-reported and supplemented by a National Death Index search. The primary outcome is survival free of new dementia or persisting disability. Co-secondary outcomes are a composite of cardiovascular death, hospitalization for unstable angina or myocardial infarction, heart failure, stroke, or coronary revascularization; and a composite of mild cognitive impairment or dementia. Ancillary studies will offer mechanistic insights into the effects of statins on key outcomes. Biorepository samples are obtained and stored for future study. These results will inform the benefit of statins for increasing survival free of dementia and disability among older adults. This is a pioneering pragmatic study testing important questions with low participant burden to align with the needs of the growing population of older adults., (© 2023 The American Geriatrics Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

The primary aim of this review was to systematically evaluate the literature regarding the effect of pre-, pro-, or synbiotic supplementation in infant formula on the gastrointestinal microbiota. The Cochrane methodology for systematic reviews of randomized controlled trials (RCTs) was employed. Five databases were searched and 32 RCTs (2010-2021) were identified for inclusion: 20 prebiotic, 6 probiotic, and 6 synbiotic. The methods utilized to evaluate gastrointestinal microbiota varied across studies and included colony plating, fluorescence in situ hybridization, quantitative real-time polymerase chain reaction, or tagged sequencing of the 16S rRNA gene. Fecal Bifidobacterium levels increased with supplementation of prebiotics and synbiotics but not with probiotics alone. Probiotic and synbiotic supplementation generally increased fecal levels of the bacterial strain supplemented in the formula. Across all pre-, pro-, and synbiotic-supplemented formulas, results were inconsistent regarding fecal Clostridium levels. Fecal pH was lower with some prebiotic and synbiotic supplementation; however, no difference was seen with probiotics. Softer stools were often reported in infants supplemented with pre- and synbiotics, yet results were inconsistent for probiotic-supplemented formula. Limited evidence demonstrates that pre- and synbiotic supplementation increases fecal Bifidobacterium levels. Future studies utilizing comprehensive methodologies and additional studies in probiotics and synbiotics are warranted.

Cat domestication likely initiated as a symbiotic relationship between wildcats (Felis silvestris subspecies) and the peoples of developing agrarian societies in the Fertile Crescent. As humans transitioned from hunter-gatherers to farmers ~12,000 years ago, bold wildcats likely capitalized on increased prey density (i.e., rodents). Humans benefited from the cats' predation on these vermin. To refine the site(s) of cat domestication, over 1000 random-bred cats of primarily Eurasian descent were genotyped for single-nucleotide variants and short tandem repeats. The overall cat population structure suggested a single worldwide population with significant isolation by the distance of peripheral subpopulations. The cat population heterozygosity decreased as genetic distance from the proposed cat progenitor's (F.s. lybica) natural habitat increased. Domestic cat origins are focused in the eastern Mediterranean Basin, spreading to nearby islands, and southernly via the Levantine coast into the Nile Valley. Cat population diversity supports the migration patterns of humans and other symbiotic species., (© 2022. The Author(s).)

Background: Genotypic information produced from single nucleotide polymorphism (SNP) arrays has routinely been used to identify genomic regions associated with complex traits in beef and dairy cattle. Herein, we assembled a dataset consisting of 15,815 Red Angus beef cattle distributed across the continental U.S. and a union set of 836,118 imputed SNPs to conduct genome-wide association analyses (GWAA) for growth traits using univariate linear mixed models (LMM); including birth weight, weaning weight, and yearling weight. Genomic relationship matrix heritability estimates were produced for all growth traits, and genotype-by-environment (GxE) interactions were investigated., Results: Moderate to high heritabilities with small standard errors were estimated for birth weight (0.51 ± 0.01), weaning weight (0.25 ± 0.01), and yearling weight (0.42 ± 0.01). GWAA revealed 12 pleiotropic QTL (BTA6, BTA14, BTA20) influencing Red Angus birth weight, weaning weight, and yearling weight which met a nominal significance threshold (P ≤ 1e-05) for polygenic traits using 836K imputed SNPs. Moreover, positional candidate genes associated with Red Angus growth traits in this study (i.e., LCORL, LOC782905, NCAPG, HERC6, FAM184B, SLIT2, MMRN1, KCNIP4, CCSER1, GRID2, ARRDC3, PLAG1, IMPAD1, NSMAF, PENK, LOC112449660, MOS, SH3PXD2B, STC2, CPEB4) were also previously associated with feed efficiency, growth, and carcass traits in beef cattle. Collectively, 14 significant GxE interactions were also detected, but were less consistent among the investigated traits at a nominal significance threshold (P ≤ 1e-05); with one pleiotropic GxE interaction detected on BTA28 (24 Mb) for Red Angus weaning weight and yearling weight., Conclusions: Sixteen well-supported QTL regions detected from the GWAA and GxE GWAA for growth traits (birth weight, weaning weight, yearling weight) in U.S. Red Angus cattle were found to be pleiotropic. Twelve of these pleiotropic QTL were also identified in previous studies focusing on feed efficiency and growth traits in multiple beef breeds and/or their composites. In agreement with other beef cattle GxE studies our results implicate the role of vasodilation, metabolism, and the nervous system in the genetic sensitivity to environmental stress., (© 2022. The Author(s).)

The Neosho madtom (Noturus placidus) is a small catfish, generally less than 3 inches in length, unique to the Neosho-Spring River system within the Arkansas River Basin. It was federally listed as threatened in 1990, largely due to habitat loss. For conservation efforts, we generated whole-genome sequence data from 10 Neosho madtom individuals originating from 3 geographically separated populations to evaluate genetic diversity and population structure. A Neosho madtom genome was de novo assembled, and genome size and content were assessed. Single nucleotide polymorphisms were assessed from de Bruijn graphs, and via reference alignment with both the channel catfish (Ictalurus punctatus) reference genome and Neosho madtom reference genome. Principal component analysis and structure analysis indicated weak population structure, suggesting fish from the 3 locations represent a single population. Using a novel method, genome-wide conservation and divergence between the Neosho madtom, channel catfish, and zebrafish (Danio rerio) was assessed by pairwise contig alignment, which demonstrated that genes important to embryonic development frequently had conserved sequences. This research in a threatened species with no previously published genomic resources provides novel genetic information to guide current and future conservation efforts and demonstrates that using whole-genome sequencing provides detailed information of population structure and demography using only a limited number of rare and valuable samples., (Published by Oxford University Press on behalf of Genetics Society of America 2022. This work is written by US Government employees and is in the public domain in the US.)

Many studies suggest that information about past experience, or episodic memory, is divided into discrete units called "events." Yet we can often remember experiences that span multiple events. Events that occur in close succession might simply be linked because of their proximity to one another, but we can also build links between events that occur farther apart in time. Intuitively, some kind of organizing principle should enable temporally distant events to become bridged in memory. We tested the hypothesis that episodic memory exhibits a narrative-level organization, enabling temporally distant events to be better remembered if they form a coherent narrative. Furthermore, we tested whether post-encoding memory consolidation is necessary to integrate temporally distant events. In three experiments, participants learned and subsequently recalled events from fictional stories, in which pairs of temporally distant events involving side characters ("sideplots") either formed one coherent narrative or two unrelated narratives. Across participants, we varied whether recall was assessed immediately after learning, or after a delay: 24 hours, 12 hours between morning and evening ("wake"), or 12 hours between evening and morning ("sleep"). Participants recalled more information about coherent than unrelated narrative events, in most delay conditions, including immediate recall and wake conditions, suggesting that post-encoding consolidation was not necessary to integrate temporally distant events into a larger narrative. Furthermore, post hoc modeling across experiments suggested that narrative coherence facilitated recall over and above any effects of sentence-level semantic similarity. This reliable memory benefit for coherent narrative events supports theoretical accounts which propose that narratives provide a high-level architecture for episodic memory., (© 2021. The Author(s).)

Life's events are scattered throughout time, yet we often recall different events in the context of an integrated narrative. Prior research suggests that the hippocampus, which supports memory for past events, can support the integration of overlapping associations or separate events in memory. However, the conditions that lead to hippocampus-dependent memory integration are unclear. We used functional brain imaging to test whether the opportunity to form a larger narrative (narrative coherence) drives hippocampal memory integration. During encoding of fictional stories, patterns of hippocampal activity, including activity at boundaries between events, were more similar between distant events that formed one coherent narrative, compared with overlapping events taken from unrelated narratives. One day later, the hippocampus preferentially supported detailed recall of coherent narrative events, through reinstatement of hippocampal activity patterns from encoding. These findings demonstrate a key function of the hippocampus: the integration of events into a narrative structure for memory., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This study followed children who participated in a feeding trial in which the type of randomized infant formula fed from 2 weeks significantly affected weight gain velocity during the first 4 months and weight-for-length Z (WLZ) scores up to 11.5 months. We focused on measures of anthropometry, dietary intakes, and parenting related to the provision of snack foods that were collected at the end of the trial (1 year) and the 1.5 years follow-up visit. We not only describe what toddlers are eating, but we also determined the independent and/or interactive effects of randomized formula group, early weight gain velocity, the nutrient content of the post-formula diet, and maternal snack food practices, on toddlers' weight status. Diet quality underwent drastic changes during this 6-month period. As infant formula disappeared from the diet, fruit and 100% fruit juice intake increased slightly, while intake of "What We Eat in America" food categories sweetened beverages and snacks and sweets more than doubled. Added sugars accounted for 5% of energy needs at 1 year and 9% at 1.5 years. Generalized linear mixed models revealed that, independent of the randomized formula group, greater velocities of weight gain during early infancy and lower access to snacks as toddlers predicted higher WLZ and a greater proportion of toddlers with overweight at 1.5 years. Energy and added sugar intake had no significant effects. These findings add to the growing body of evidence that unhealthy dietary habits are formed even before formula weaning and that, along with improving early diet, transient rapid weight gain and parental feeding practices are modifiable determinants that may reduce risks for obesity.

The Caribbean is a genetically diverse region with heterogeneous admixture compositions influenced by local island ecologies, migrations, colonial conflicts, and demographic histories. The Commonwealth of Dominica is a mountainous island in the Lesser Antilles historically known to harbor communities with unique patterns of migration, mixture, and isolation. This community-based population genetic study adds biological evidence to inform post-colonial narrative histories in a Dominican horticultural village. High density single nucleotide polymorphism data paired with a previously compiled genealogy provide the first genome-wide insights on genetic ancestry and population structure in Dominica. We assessed family-based clustering, inferred global ancestry, and dated recent admixture by implementing the fastSTRUCTURE clustering algorithm, modeling graph-based migration with TreeMix, assessing patterns of linkage disequilibrium decay with ALDER, and visualizing data from Dominica with Human Genome Diversity Panel references. These analyses distinguish family-based genetic structure from variation in African, European, and indigenous Amerindian admixture proportions, and analyses of linkage disequilibrium decay estimate admixture dates 5-6 generations (~160 years) ago. African ancestry accounts for the largest mixture components, followed by European and then indigenous components; however, our global ancestry inferences are consistent with previous mitochondrial, Y chromosome, and ancestry marker data from Dominica that show uniquely higher proportions of indigenous ancestry and lower proportions of African ancestry relative to known admixture in other French- and English-speaking Caribbean islands. Our genetic results support local narratives about the community's history and founding, which indicate that newly emancipated people settled in the steep, dense vegetation along Dominica's eastern coast in the mid-19th century. Strong genetic signals of post-colonial admixture and family-based structure highlight the localized impacts of colonial forces and island ecologies in this region, and more data from other groups are needed to more broadly inform on Dominica's complex history and present diversity., Competing Interests: The authors have declared that no competing interests exist.

Development of the American Breeds of beef cattle began in the 1920s as breeders and U. S. Experiment Station researchers began to create Bos taurus taurus × Bos taurus indicus hybrids using Brahman as the B. t. indicus source. By 1954, U.S. Breed Associations had been formed for Brangus (5/8 Angus × 3/8 Brahman), Beefmaster (½ Brahman × ¼ Shorthorn × ¼ Hereford), and Santa Gertrudis (5/8 Shorthorn × 3/8 Brahman). While these breeds were developed using mating designs expected to create base generation animals with the required genome contributions from progenitor breeds, each association has now registered advanced generation animals in which selection or drift may have caused the realized genome compositions to differ from initial expected proportions. The availability of high-density SNP genotypes for 9,161 Brangus, 3,762 Beefmaster, and 1,942 Santa Gertrudis animals allowed us to compare the realized genomic architectures of breed members to the base generation expectations. We used RFMix to estimate local ancestry and identify genomic regions in which the proportion of Brahman ancestry differed significantly from a priori expectations. For all three breeds, lower than expected levels of Brahman composition were found genome-wide, particularly in early-generation animals where we demonstrate that selection on beef production traits was likely responsible for the taurine enrichment. Using a proxy for generation number, we also contrasted the genomes of early- and advanced-generation animals and found that the indicine composition of the genome has increased with generation number likely due to selection on adaptive traits. Many of the most-highly differentiated genomic regions were breed specific, suggesting that differences in breeding objectives and selection intensities exist between the breeds. Global ancestry estimation is commonly performed in admixed animals to control for stratification in association studies. However, local ancestry estimation provides the opportunity to investigate the evolution of specific chromosomal segments and estimate haplotype effects on trait variation in admixed individuals. Investigating the genomic architecture of the American Breeds not only allows the estimation of indicine and taurine genome proportions genome-wide, but also the locations within the genome where either taurine or indicine alleles confer a selective advantage., 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 © 2021 Crum, Schnabel, Decker and Taylor.)

Understanding the evolutionary history of crops, including identifying wild relatives, helps to provide insight for conservation and crop breeding efforts. Cultivated Brassica oleracea has intrigued researchers for centuries due to its wide diversity in forms, which include cabbage, broccoli, cauliflower, kale, kohlrabi, and Brussels sprouts. Yet, the evolutionary history of this species remains understudied. With such different vegetables produced from a single species, B. oleracea is a model organism for understanding the power of artificial selection. Persistent challenges in the study of B. oleracea include conflicting hypotheses regarding domestication and the identity of the closest living wild relative. Using newly generated RNA-seq data for a diversity panel of 224 accessions, which represents 14 different B. oleracea crop types and nine potential wild progenitor species, we integrate phylogenetic and population genetic techniques with ecological niche modeling, archaeological, and literary evidence to examine relationships among cultivars and wild relatives to clarify the origin of this horticulturally important species. Our analyses point to the Aegean endemic B. cretica as the closest living relative of cultivated B. oleracea, supporting an origin of cultivation in the Eastern Mediterranean region. Additionally, we identify several feral lineages, suggesting that cultivated plants of this species can revert to a wild-like state with relative ease. By expanding our understanding of the evolutionary history in B. oleracea, these results contribute to a growing body of knowledge on crop domestication that will facilitate continued breeding efforts including adaptation to changing environmental conditions., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Selection on complex traits can rapidly drive evolution, especially in stressful environments. This polygenic selection does not leave intense sweep signatures on the genome, rather many loci experience small allele frequency shifts, resulting in large cumulative phenotypic changes. Directional selection and local adaptation are changing populations; but, identifying loci underlying polygenic or environmental selection has been difficult. We use genomic data on tens of thousands of cattle from three populations, distributed over time and landscapes, in linear mixed models with novel dependent variables to map signatures of selection on complex traits and local adaptation. We identify 207 genomic loci associated with an animal's birth date, representing ongoing selection for monogenic and polygenic traits. Additionally, hundreds of additional loci are associated with continuous and discrete environments, providing evidence for historical local adaptation. These candidate loci highlight the nervous system's possible role in local adaptation. While advanced technologies have increased the rate of directional selection in cattle, it has likely been at the expense of historically generated local adaptation, which is especially problematic in changing climates. When applied to large, diverse cattle datasets, these selection mapping methods provide an insight into how selection on complex traits continually shapes the genome. Further, understanding the genomic loci implicated in adaptation may help us breed more adapted and efficient cattle, and begin to understand the basis for mammalian adaptation, especially in changing climates. These selection mapping approaches help clarify selective forces and loci in evolutionary, model, and agricultural contexts., Competing Interests: The authors have declared that no competing interests exist.

Understanding genotype-by-environment interactions (G × E) is crucial to understand environmental adaptation in mammals and improve the sustainability of agricultural production. Here, we present an extensive study investigating the interaction of genome-wide SNP markers with a vast assortment of environmental variables and searching for SNPs controlling phenotypic variance (vQTL) using a large beef cattle dataset. We showed that G × E contribute 10.1%, 3.8%, and 2.8% of the phenotypic variance of birth weight, weaning weight, and yearling weight, respectively. G × E genome-wide association analysis (GWAA) detected a large number of G × E loci affecting growth traits, which the traditional GWAA did not detect, showing that functional loci may have non-additive genetic effects regardless of differences in genotypic means. Further, variance-heterogeneity GWAA detected loci enriched with G × E effects without requiring prior knowledge of the interacting environmental factors. Functional annotation and pathway analysis of G × E genes revealed biological mechanisms by which cattle respond to changes in their environment, such as neurotransmitter activity, hypoxia-induced processes, keratinization, hormone, thermogenic and immune pathways. We unraveled the relevance and complexity of the genetic basis of G × E underlying growth traits, providing new insights into how different environmental conditions interact with specific genes influencing adaptation and productivity in beef cattle and potentially across mammals.

Domestication and subsequent selection of cattle to form breeds and biological types that can adapt to different environments partitioned ancestral genetic diversity into distinct modern lineages. Genome-wide selection particularly for adaptation to extreme environments left detectable signatures genome-wide. We used high-density genotype data for 42 cattle breeds and identified the influence of Bos grunniens and Bos javanicus on the formation of Chinese indicine breeds that led to their divergence from India-origin zebu. We also found evidence for introgression, admixture, and migration in most of the Chinese breeds. Selection signature analyses between high-altitude (≥1800 m) and low-altitude adapted breeds (<1500 m) revealed candidate genes (ACSS2, ALDOC, EPAS1, EGLN1, NUCB2) and pathways that are putatively involved in hypoxia adaptation. Immunohistochemical, real-time PCR and CRISPR/cas9 ACSS2-knockout analyses suggest that the up-regulation of ACSS2 expression in the liver promotes the metabolic adaptation of cells to hypoxia via the hypoxia-inducible factor pathway. High altitude adaptation involved the introgression of alleles from high-altitude adapted yaks into Chinese Bos taurus taurus prior to their formation into recognized breeds and followed by selection. In addition to selection, adaptation to high altitude environments has been facilitated by admixture and introgression with locally adapted cattle populations., (Copyright © 2021. Published by Elsevier Inc.)

Feral populations, those which successfully persist outside of cultivation or husbandry, provide unique opportunities to study the genomic impacts of domestication and local adaptation. We argue that by leveraging genomic resources designed for domestic counterparts, powerful phylogenetic and population genomic data collection and analyses can be designed to disentangle complex demographic processes., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Heat stress and fescue toxicosis caused by ingesting tall fescue infected with the endophytic fungus Epichloë coenophiala represent two of the most prevalent stressors to beef cattle in the United States and cost the beef industry millions of dollars each year. The rate at which a beef cow sheds her winter coat early in the summer is an indicator of adaptation to heat and an economically relevant trait in temperate or subtropical parts of the world. Furthermore, research suggests that early-summer hair shedding may reflect tolerance to fescue toxicosis, since vasoconstriction induced by fescue toxicosis limits the ability of an animal to shed its winter coat. Both heat stress and fescue toxicosis reduce profitability partly via indirect maternal effects on calf weaning weight. Here, we developed parameters for routine genetic evaluation of hair shedding score in American Angus cattle, and identified genomic loci associated with variation in hair shedding score via genome-wide association analysis (GWAA)., Results: Hair shedding score was moderately heritable (h 2  = 0.34 to 0.40), with different repeatability estimates between cattle grazing versus not grazing endophyte-infected tall fescue. Our results suggest modestly negative genetic and phenotypic correlations between a dam's hair shedding score (lower score is earlier shedding) and the weaning weight of her calf, which is one metric of performance. Together, these results indicate that economic gains can be made by using hair shedding score breeding values to select for heat-tolerant cattle. GWAA identified 176 variants significant at FDR < 0.05. Functional enrichment analyses using genes that were located within 50 kb of these variants identified pathways involved in keratin formation, prolactin signalling, host-virus interaction, and other biological processes., Conclusions: This work contributes to a continuing trend in the development of genetic evaluations for environmental adaptation. Our results will aid beef cattle producers in selecting more sustainable and climate-adapted cattle, as well as enable the development of similar routine genetic evaluations in other breeds.

With the availability of a new highly contiguous Bos taurus reference genome assembly (ARS-UCD1.2), it is the opportune time to upgrade the bovine gene set by seeking input from researchers. Furthermore, advances in graphical genome annotation tools now make it possible for researchers to leverage sequence data generated with the latest technologies to collaboratively curate genes. For many years the Bovine Genome Database (BGD) has provided tools such as the Apollo genome annotation editor to support manual bovine gene curation. The goal of this paper is to explain the reasoning behind the decisions made in the manual gene curation process while providing examples using the existing BGD tools. We will describe the sources of gene annotation evidence provided at the BGD, including RNA-seq and Iso-Seq data. We will also explain how to interpret various data visualizations when curating gene models, and will demonstrate the value of manual gene annotation. The process described here can be applied to manual gene curation for other species with similar tools. With a better understanding of manual gene annotation, researchers will be encouraged to edit gene models and contribute to the enhancement of livestock gene sets., (© 2020 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

The objectives of this study were to explore the usefulness of blood-based traits as indicators of health and performance in beef cattle at weaning and identify the genetic basis underlying the different blood parameters obtained from complete blood counts (CBCs). Disease costs represent one of the main factors determining profitability in animal production. Previous research has observed associations between blood cell counts and an animal's health status in some species. CBC were recorded from approximately 570 Angus based, crossbred beef calves at weaning born between 2015 and 2016 and raised on toxic or novel tall fescue. The calves ( N = ∼600) were genotyped at a density of 50k SNPs and the genotypes ( N = 1160) were imputed to a density of 270k SNPs. Genetic parameters were estimated for 15 blood and 4 production. Finally, with the objective of identifying the genetic basis underlying the different blood-based traits, genome-wide association studies (GWAS) were performed for all traits. Heritability estimates ranged from 0.11 to 0.60, and generally weak phenotypic correlations and strong genetic correlations were observed among blood-based traits only. Genome-wide association study identified ninety-one 1-Mb windows that accounted for 0.5% or more of the estimated genetic variance for at least 1 trait with 21 windows overlapping across two or more traits (explaining more than 0.5% of estimated genetic variance for two or more traits). Five candidate genes have been identified in the most interesting overlapping regions related to blood-based traits. Overall, this study represents one of the first efforts represented in scientific literature to identify the genetic basis of blood cell traits in beef cattle. The results presented in this study allow us to conclude that: (1) blood-based traits have weak phenotypic correlations but strong genetic correlations among themselves. (2) Blood-based traits have moderate to high heritability. (3) There is evidence of an important overlap of genetic control among similar blood-based traits which will allow for their use in improvement programs in beef cattle., (Copyright © 2020 Chinchilla-Vargas, Kramer, Tucker, Hubbell, Powell, Lester, Backes, Anschutz, Decker, Stalder, Rothschild and Koltes.)

Background: During the last decade, the use of common-variant array-based single nucleotide polymorphism (SNP) genotyping in the beef and dairy industries has produced an astounding amount of medium-to-low density genomic data. Although low-density assays work well in the context of genomic prediction, they are less useful for detecting and mapping causal variants and the effects of rare variants are not captured. The objective of this project was to maximize the accuracies of genotype imputation from medium- and low-density assays to the marker set obtained by combining two high-density research assays (~ 850,000 SNPs), the Illumina BovineHD and the GGP-F250 assays, which contains a large proportion of rare and potentially functional variants and for which the assay design is described here. This 850 K SNP set is useful for both imputation to sequence-level genotypes and direct downstream analysis., Results: We found that a large multi-breed composite imputation reference panel that includes 36,131 samples with either BovineHD and/or GGP-F250 genotypes significantly increased imputation accuracy compared with a within-breed reference panel, particularly at variants with low minor allele frequencies. Individual animal imputation accuracies were maximized when more genetically similar animals were represented in the composite reference panel, particularly with complete 850 K genotypes. The addition of rare variants from the GGP-F250 assay to our composite reference panel significantly increased the imputation accuracy of rare variants that are exclusively present on the BovineHD assay. In addition, we show that an assay marker density of 50 K SNPs balances cost and accuracy for imputation to 850 K., Conclusions: Using high-density genotypes on all available individuals in a multi-breed reference panel maximized imputation accuracy for tested cattle populations. Admixed animals or those from breeds with a limited representation in the composite reference panel were still imputed at high accuracy, which is expected to further increase as the reference panel expands. We anticipate that the addition of rare variants from the GGP-F250 assay will increase the accuracy of imputation to sequence level.

Background: Single nucleotide polymorphism (SNP) arrays have facilitated discovery of genetic markers associated with complex traits in domestic cattle; thereby enabling modern breeding and selection programs. Genome-wide association analyses (GWAA) for growth traits were conducted on 10,837 geographically diverse U.S. Gelbvieh cattle using a union set of 856,527 imputed SNPs. Birth weight (BW), weaning weight (WW), and yearling weight (YW) were analyzed using GEMMA and EMMAX (via imputed genotypes). Genotype-by-environment (GxE) interactions were also investigated., Results: GEMMA and EMMAX produced moderate marker-based heritability estimates that were similar for BW (0.36-0.37, SE = 0.02-0.06), WW (0.27-0.29, SE = 0.01), and YW (0.39-0.41, SE = 0.01-0.02). GWAA using 856K imputed SNPs (GEMMA; EMMAX) revealed common positional candidate genes underlying pleiotropic QTL for Gelbvieh growth traits on BTA6, BTA7, BTA14, and BTA20. The estimated proportion of phenotypic variance explained (PVE) by the lead SNP defining these QTL (EMMAX) was larger and most similar for BW and YW, and smaller for WW. Collectively, GWAAs (GEMMA; EMMAX) produced a highly concordant set of BW, WW, and YW QTL that met a nominal significance level (P ≤ 1e-05), with prioritization of common positional candidate genes; including genes previously associated with stature, feed efficiency, and growth traits (i.e., PLAG1, NCAPG, LCORL, ARRDC3, STC2). Genotype-by-environment QTL were not consistent among traits at the nominal significance threshold (P ≤ 1e-05); although some shared QTL were apparent at less stringent significance thresholds (i.e., P ≤ 2e-05)., Conclusions: Pleiotropic QTL for growth traits were detected on BTA6, BTA7, BTA14, and BTA20 for U.S. Gelbvieh beef cattle. Seven QTL detected for Gelbvieh growth traits were also recently detected for feed efficiency and growth traits in U.S. Angus, SimAngus, and Hereford cattle. Marker-based heritability estimates and the detection of pleiotropic QTL segregating in multiple breeds support the implementation of multiple-breed genomic selection.

In many beef and some dairy production systems, crossbreeding is used to take advantage of breed complementarity and heterosis. Admixed animals are frequently identified by their coat color and body conformation phenotypes, however, without pedigree information it is not possible to identify the expected breed composition of an admixed animal and in the presence of selection, the actual composition may differ from expectation. As the roles of DNA and genotype data become more pervasive in animal agriculture, a systematic method for estimating the breed composition (the proportions of an animal's genome originating from ancestral pure breeds) has utility for a variety of downstream analyses including the estimation of genomic breeding values for crossbred animals, the estimation of quantitative trait locus effects, and heterosis and heterosis retention in advanced generation composite animals. Currently, there is no automated or semi-automated ancestry estimation platform for cattle and the objective of this study was to evaluate the utility of extant public software for ancestry estimation and determine the effects of reference population size and composition and number of utilized single nucleotide polymorphism loci on ancestry estimation. We also sought to develop an analysis pipeline that would simplify this process for members of the livestock genomics research community. We developed and tested a tool, "CRUMBLER", to estimate the global ancestry of cattle using ADMIXTURE and SNPweights based on a defined reference panel. CRUMBLER, was developed and evaluated in cattle, but is a species agnostic pipeline that facilitates the streamlined estimation of breed composition for individuals with potentially complex ancestries using publicly available global ancestry software and a specified reference population SNP dataset. We developed the reference panel from a large cattle genotype data set and breed association pedigree information using iterative analyses to identify purebred individuals that were representative of each breed. We also evaluated the numbers of markers necessary for breed composition estimation and simulated genotypes for advanced generation composite animals to evaluate the precision of the developed tool. The developed CRUMBLER pipeline extracts a specified subset of genotypes that is common to all current commercially available genotyping platforms, processes these into the file formats required for the analysis software, and predicts admixture proportions using the specified reference population allele frequencies., Competing Interests: The authors have declared that no competing interests exist.

Background: National genetic evaluations for disease resistance do not exist, precluding the genetic improvement of cattle for these traits. We imputed BovineHD genotypes to whole genome sequence for 2703 Holsteins that were cases or controls for Bovine Respiratory Disease and sampled from either California or New Mexico to construct and compare genomic prediction models. The sequence variation reference dataset comprised variants called for 1578 animals from Run 5 of the 1000 Bull Genomes Project, including 450 Holsteins and 29 animals sequenced from this study population. Genotypes for 9,282,726 variants with minor allele frequencies ≥5% were imputed and used to obtain genomic predictions in GEMMA using a Bayesian Sparse Linear Mixed Model., Results: Variation explained by markers increased from 13.6% using BovineHD data to 14.4% using imputed whole genome sequence data and the resolution of genomic regions detected as harbouring QTL substantially increased. Explained variation in the analysis of the combined California and New Mexico data was less than when data for each state were separately analysed and the estimated genetic correlation between risk of Bovine Respiratory Disease in California and New Mexico Holsteins was - 0.36. Consequently, genomic predictions trained using the data from one state did not accurately predict disease risk in the other state. To determine if a prediction model could be developed with utility in both states, we selected variants within genomic regions harbouring: 1) genes involved in the normal immune response to infection by pathogens responsible for Bovine Respiratory Disease detected by RNA-Seq analysis, and/or 2) QTL identified in the association analysis of the imputed sequence variants. The model based on QTL selected variants is biased but when trained in one state generated BRD risk predictions with positive accuracies in the other state., Conclusions: We demonstrate the utility of sequence-based and biology-driven model development for genomic selection. Disease phenotypes cannot be routinely recorded in most livestock species and the observed phenotypes may vary in their genomic architecture due to variation in the pathogen composition across environments. Elucidation of trait biology and genetic architecture may guide the development of prediction models with utility across breeds and environments.

The development of high throughput SNP genotyping technologies has improved the genetic dissection of simple and complex traits in many species including cats. The properties of feline 62,897 SNPs Illumina Infinium iSelect DNA array are described using a dataset of over 2,000 feline samples, the most extensive to date, representing 41 cat breeds, a random bred population, and four wild felid species. Accuracy and efficiency of the array's genotypes and its utility in performing population-based analyses were evaluated. Average marker distance across the array was 37,741 Kb, and across the dataset, only 1% (625) of the markers exhibited poor genotyping and only 0.35% (221) showed Mendelian errors. Marker polymorphism varied across cat breeds and the average minor allele frequency (MAF) of all markers across domestic cats was 0.21. Population structure analysis confirmed a Western to Eastern structural continuum of cat breeds. Genome-wide linkage disequilibrium ranged from 50-1,500 Kb for domestic cats and 750 Kb for European wildcats (Felis silvestris silvestris). Array use in trait association mapping was investigated under different modes of inheritance, selection and population sizes. The efficient array design and cat genotype dataset continues to advance the understanding of cat breeds and will support monogenic health studies across feline breeds and populations.

A population structure study was performed in South African ovine populations using the OvineSNP50 beadchip. Blood samples were obtained from 295 sheep of which 172 had been identified as smallholder Dorpers, 4 smallholder White Dorpers, 46 purebred Dorpers, 26 purebred South African Mutton Merinos and 47 purebred Namaqua Afrikaners. Blood from the latter three breeds were obtained from a resource flock maintained on the Nortier research farm. Genetic diversity was estimated using allelic richness (A r ), observed heterozygosity (H o ), expected heterozygosity (H e ) and inbreeding coefficient (F). Population structure analysis was performed using fastSTRUCTURE to determine the breed composition of each genotyped individual. The Namaqua Afrikaner had the lowest H e of 0.280 ± 0.18 while the H e of smallholder Dorper, Dorper and South African Mutton Merino did not differ and were 0.364 ± 0.13, 0.332 ± 0.16 and 0.329 ± 0.17, respectively. The average inbreeding coefficient was highest for the pure breeds, Namaqua Afrikaner, Dorper and South African Mutton Merino compared to the average inbreeding coefficient for the smallholder Dorper population. The smallholder Dorper were introgressed with Namaqua Afrikaner, South African Mutton Merino and White Dorpers. Similarly, the smallholder Dorper population was more genetically diverse than the purebred Dorper, South African Mutton Merino and Namaqua Afrikaner from the research farm. The higher genetic diversity among the smallholder sheep may be advantageous for their fitness and can be used to facilitate selective breeding.

Background: If unmanaged, high rates of inbreeding in livestock populations adversely impact their reproductive fitness. In beef cattle, historical selection strategies have increased the frequency of several segregating fatal autosomal recessive polymorphisms. Selective breeding has also decreased the extent of haplotypic diversity genome-wide. By identifying haplotypes for which homozygotes are not observed but would be expected based on their frequency, candidates for developmentally lethal recessive loci can be localized. This analysis comes without the need for observation of the loss-associated phenotype (e.g., failure to implant, first trimester abortion, deformity at birth). In this study, haplotypes were estimated for 3961 registered Angus individuals using 52,545 SNP loci using findhap v2, which exploited the complex pedigree among the individuals in this population., Results: Seven loci were detected to possess haplotypes that were not observed in homozygous form despite a sufficiently high frequency and pedigree-based expectation of homozygote occurrence. These haplotypes were identified as candidates for harboring autosomal recessive lethal alleles. Of the genotyped individuals, 109 were resequenced to an average 27X depth of coverage to identify putative loss-of-function alleles genome-wide and had variants called using a custom in-house developed pipeline. For the candidate lethal-harboring haplotypes present in these bulls, sequence-called genotypes were used to identify concordant variants. In addition, whole-genome sequence imputation of variants was performed into the set of 3961 genotyped animals using the 109 resequenced animals to identify candidate lethal recessive variants at the seven loci. Following the imputation, no variants were identified that were fully concordant with the marker-based diplotypes., Conclusions: Selective breeding programs could utilize the predicted lethal haplotypes associated with SNP genotypes. Sequencing and other methods for identifying the causal variants underlying these haplotypes can allow for more efficient methods of management such as gene editing. These two methods in total will reduce the negative impacts of inbreeding on fertility and maximize overall genetic gains.

Northern bobwhite ( Colinus virginianus ; hereafter bobwhite) and scaled quail ( Callipepla squamata ) populations have suffered precipitous declines across most of their US ranges. Illumina-based first- (v1.0) and second- (v2.0) generation draft genome assemblies for the scaled quail and the bobwhite produced N50 scaffold sizes of 1.035 and 2.042 Mb, thereby producing a 45-fold improvement in contiguity over the existing bobwhite assembly, and ≥90% of the assembled genomes were captured within 1313 and 8990 scaffolds, respectively. The scaled quail assembly (v1.0 = 1.045 Gb) was ∼20% smaller than the bobwhite (v2.0 = 1.254 Gb), which was supported by kmer-based estimates of genome size. Nevertheless, estimates of GC content (41.72%; 42.66%), genome-wide repetitive content (10.40%; 10.43%), and MAKER-predicted protein coding genes (17,131; 17,165) were similar for the scaled quail (v1.0) and bobwhite (v2.0) assemblies, respectively. BUSCO analyses utilizing 3023 single-copy orthologs revealed a high level of assembly completeness for the scaled quail (v1.0; 84.8%) and the bobwhite (v2.0; 82.5%), as verified by comparison with well-established avian genomes. We also detected 273 putative segmental duplications in the scaled quail genome (v1.0), and 711 in the bobwhite genome (v2.0), including some that were shared among both species. Autosomal variant prediction revealed ∼2.48 and 4.17 heterozygous variants per kilobase within the scaled quail (v1.0) and bobwhite (v2.0) genomes, respectively, and estimates of historic effective population size were uniformly higher for the bobwhite across all time points in a coalescent model. However, large-scale declines were predicted for both species beginning ∼15-20 KYA., (Copyright © 2017 Oldeschulte et al.)

Background: Single nucleotide polymorphism (SNP) arrays for domestic cattle have catalyzed the identification of genetic markers associated with complex traits for inclusion in modern breeding and selection programs. Using actual and imputed Illumina 778K genotypes for 3887 U.S. beef cattle from 3 populations (Angus, Hereford, SimAngus), we performed genome-wide association analyses for feed efficiency and growth traits including average daily gain (ADG), dry matter intake (DMI), mid-test metabolic weight (MMWT), and residual feed intake (RFI), with marker-based heritability estimates produced for all traits and populations., Results: Moderate and/or large-effect QTL were detected for all traits in all populations, as jointly defined by the estimated proportion of variance explained (PVE) by marker effects (PVE ≥ 1.0%) and a nominal P-value threshold (P ≤ 5e-05). Lead SNPs with PVE ≥ 2.0% were considered putative evidence of large-effect QTL (n = 52), whereas those with PVE ≥ 1.0% but < 2.0% were considered putative evidence for moderate-effect QTL (n = 35). Identical or proximal lead SNPs associated with ADG, DMI, MMWT, and RFI collectively supported the potential for either pleiotropic QTL, or independent but proximal causal mutations for multiple traits within and between the analyzed populations. Marker-based heritability estimates for all investigated traits ranged from 0.18 to 0.60 using 778K genotypes, or from 0.17 to 0.57 using 50K genotypes (reduced from Illumina 778K HD to Illumina Bovine SNP50). An investigation to determine if QTL detected by 778K analysis could also be detected using 50K genotypes produced variable results, suggesting that 50K analyses were generally insufficient for QTL detection in these populations, and that relevant breeding or selection programs should be based on higher density analyses (imputed or directly ascertained)., Conclusions: Fourteen moderate to large-effect QTL regions which ranged from being physically proximal (lead SNPs ≤ 3Mb) to fully overlapping for RFI, DMI, ADG, and MMWT were detected within and between populations, and included evidence for pleiotropy, proximal but independent causal mutations, and multi-breed QTL. Bovine positional candidate genes for these traits were functionally conserved across vertebrate species.

Recent strong selection for dairy traits in water buffalo has been associated with higher levels of inbreeding, leading to an increase in the prevalence of genetic diseases such as transverse hemimelia (TH), a congenital developmental abnormality characterized by absence of a variable distal portion of the hindlimbs. Limited genomic resources available for water buffalo required an original approach to identify genetic variants associated with the disease. The genomes of 4 bilateral and 7 unilateral affected cases and 14 controls were sequenced. A concordance analysis of SNPs and INDELs requiring homozygosity unique to all unilateral and bilateral cases revealed two genes, WNT7A and SMARCA4, known to play a role in embryonic hindlimb development. Additionally, SNP alleles in NOTCH1 and RARB were homozygous exclusively in the bilateral cases, suggesting an oligogenic mode of inheritance. Homozygosity mapping by whole genome de novo assembly also supported oligogenic inheritance; implicating 13 genes involved in hindlimb development in bilateral cases and 11 in unilateral cases. A genome-wide association study (GWAS) predicted additional modifier genes. Although our data show a complex inheritance of TH, we predict that homozygous variants in WNT7A and SMARCA4 are necessary for expression of TH and selection against these variants should eradicate TH.

Residual feed intake (RFI), a measure of feed efficiency (FE), is defined as the difference between the observed and the predictable feed intake considering size and growth of the animal. It is extremely important to beef production systems due to its impact on the allocation of land areas to alternative agricultural production, animal methane emissions, food demand and cost of production. Global differential gene expression analysis between high and low RFI groups (HRFI and LRFI: less and more efficient, respectively) revealed 73 differentially expressed (DE) annotated genes in Longissimus thoracis (LT) muscle of Nelore steers. These genes are involved in the overrepresented pathways Metabolism of Xenobiotics by Cytochrome P450 and Butanoate and Tryptophan Metabolism. Among the DE transcripts were several proteins related to mitochondrial function and the metabolism of lipids. Our findings indicate that observed gene expression differences are primarily related to metabolic processes underlying oxidative stress. Genes involved in the metabolism of xenobiotics and antioxidant mechanisms were primarily down-regulated, while genes responsible for lipid oxidation and ketogenesis were up-regulated in HRFI group. By using LT muscle, this study reinforces our previous findings using liver tissue and reveals new genes and likely tissue-specific regulators playing key-roles in these processes.

Background: Understanding the history of cattle breeds is important because it provides the basis for developing appropriate selection and breed improvement programs. In this study, patterns of ancestry and admixture in Afrikaner, Nguni, Drakensberger and Bonsmara cattle of South Africa were investigated. We used 50 K single nucleotide polymorphism genotypes that were previously generated for the Afrikaner (n = 36), Nguni (n = 50), Drakensberger (n = 47) and Bonsmara (n = 44) breeds, and for 394 reference animals representing European taurine, African taurine, African zebu and Bos indicus., Results and Discussion: Our findings support previous conclusions that Sanga cattle breeds are composites between African taurine and Bos indicus. Among these breeds, the Afrikaner breed has significantly diverged from its ancestral forebears, probably due to genetic drift and selection to meet breeding objectives of the breed society that enable registration. The Nguni, Drakensberger and Bonsmara breeds are admixed, perhaps unintentionally in the case of Nguni and Drakensberger, but certainly by design in the case of Bonsmara, which was developed through crossbreeding between the Afrikaner, Hereford and Shorthorn breeds., Conclusions: We established patterns of admixture and ancestry for South African Sanga cattle breeds, which provide a basis for developing appropriate strategies for their genetic improvement.

The two living species of bison (European and American) are among the few terrestrial megafauna to have survived the late Pleistocene extinctions. Despite the extensive bovid fossil record in Eurasia, the evolutionary history of the European bison (or wisent, Bison bonasus) before the Holocene (<11.7 thousand years ago (kya)) remains a mystery. We use complete ancient mitochondrial genomes and genome-wide nuclear DNA surveys to reveal that the wisent is the product of hybridization between the extinct steppe bison (Bison priscus) and ancestors of modern cattle (aurochs, Bos primigenius) before 120 kya, and contains up to 10% aurochs genomic ancestry. Although undetected within the fossil record, ancestors of the wisent have alternated ecological dominance with steppe bison in association with major environmental shifts since at least 55 kya. Early cave artists recorded distinct morphological forms consistent with these replacement events, around the Last Glacial Maximum (LGM, ∼21-18 kya).

Background: Decreasing sequencing costs and development of new protocols for characterizing global methylation, gene expression patterns and regulatory regions have stimulated the generation of large livestock datasets. Here, we discuss experiences in the analysis of whole-genome and transcriptome sequence data., Methods: We analyzed whole-genome sequence (WGS) data from 132 individuals from five canid species (Canis familiaris, C. latrans, C. dingo, C. aureus and C. lupus) and 61 breeds, three bison (Bison bison), 64 water buffalo (Bubalus bubalis) and 297 bovines from 17 breeds. By individual, data vary in extent of reference genome depth of coverage from 4.9X to 64.0X. We have also analyzed RNA-seq data for 580 samples representing 159 Bos taurus and Rattus norvegicus animals and 98 tissues. By aligning reads to a reference assembly and calling variants, we assessed effects of average depth of coverage on the actual coverage and on the number of called variants. We examined the identity of unmapped reads by assembling them and querying produced contigs against the non-redundant nucleic acids database. By imputing high-density single nucleotide polymorphism data on 4010 US registered Angus animals to WGS using Run4 of the 1000 Bull Genomes Project and assessing the accuracy of imputation, we identified misassembled reference sequence regions., Results: We estimate that a 24X depth of coverage is required to achieve 99.5 % coverage of the reference assembly and identify 95 % of the variants within an individual's genome. Genomes sequenced to low average coverage (e.g., <10X) may fail to cover 10 % of the reference genome and identify <75 % of variants. About 10 % of genomic DNA or transcriptome sequence reads fail to align to the reference assembly. These reads include loci missing from the reference assembly and misassembled genes and interesting symbionts, commensal and pathogenic organisms., Conclusions: Assembly errors and a lack of annotation of functional elements significantly limit the utility of the current draft livestock reference assemblies. The Functional Annotation of Animal Genomes initiative seeks to annotate functional elements, while a 70X Pac-Bio assembly for cow is underway and may result in a significantly improved reference assembly.

Feral livestock may harbor genetic variation of commercial, scientific, historical or esthetic value. The origins and uniqueness of feral cattle on Chirikof Island, Alaska, are uncertain. The island is now part of the Alaska Maritime Wildlife Refuge and Federal wildlife managers want grazing to cease, presumably leading to demise of the cattle. Here we characterize the cattle of Chirikof Island relative to extant breeds and discern their origins. Our analyses support the inference that Yakut cattle from Russia arrived first on Chirikof Island, then ~120 years ago the first European taurine cattle were introduced to the island, and finally a large wave of Hereford cattle were introduced on average 40 years ago. In addition, this mixture of European and East-Asian cattle is unique compared with other North American breeds and we find evidence that natural selection in the relatively harsh environment of Chirikof Island has further impacted their genetic architecture. These results provide an objective basis for decisions regarding conservation of the Chirikof Island cattle.

Background: Next-generation sequencing projects commonly commence by aligning reads to a reference genome assembly. While improvements in alignment algorithms and computational hardware have greatly enhanced the efficiency and accuracy of alignments, a significant percentage of reads often remain unmapped., Results: We generated de novo assemblies of unmapped reads from the DNA and RNA sequencing of the Bos taurus reference individual and identified the closest matching sequence to each contig by alignment to the NCBI non-redundant nucleotide database using BLAST. As expected, many of these contigs represent vertebrate sequence that is absent, incomplete, or misassembled in the UMD3.1 reference assembly. However, numerous additional contigs represent invertebrate species. Most prominent were several species of Spirurid nematodes and a blood-borne parasite, Babesia bigemina. These species are either not present in the US or are not known to infect taurine cattle and the reference animal appears to have been host to unsequenced sister species., Conclusions: We demonstrate the importance of exploring unmapped reads to ascertain sequences that are either absent or misassembled in the reference assembly and for detecting sequences indicative of parasitic or commensal organisms.