NEXT: description, rationale, and evaluation of a novel internet-based mail-delivered syringe service program.

Background: Despite proven health benefits, harm reduction services provided through in-person syringe services programs (SSPs) and pharmacies are largely unavailable to most people who inject drugs (PWID). Internet-based mail-delivered harm reduction services could overcome barriers to in-person SSPs. This manuscript describes Needle Exchange Technology (NEXT) Harm Reduction, the first formal internet-based mail delivery SSP in the US. Methods: We examined the trajectory of NEXT's growth between February 2018 and August 2021. Descriptive statistics were used to characterize program participants. All analysis were run using STATA statistical software. Results: Over the course of 42 months, 1,669 unique participants enrolled in NEXT. The program distributed 1,648,162 total syringes with a median of 79,449 syringes per month. Most participants ordered multiple times (61%); 31% had more 5 or more orders (upper range = 48 orders). The total number of syringes per month and total number of first-time syringe orders per month increased steadily over time, particularly after the onset of the COVID-19 pandemic. Conclusions: The online platform and mail-delivery model appears successful in reaching PWID at high risk for harms from IDU. Changes to state laws and additional funding support are needed to make mail-delivery harm reduction more widely available throughout the US.

Low-dose buprenorphine initiation and treatment continuation among hospitalized patients with opioid dependence: A retrospective cohort study.

BACKGROUND: Buprenorphine is an effective treatment for both opioid use disorder (OUD) and chronic pain, but buprenorphine's pharmacology complicates treatment initiation for some patients. Low-dose buprenorphine initiation is a novel strategy that may reduce precipitated withdrawal. Few studies describe what patient populations benefit most from low-dose initiations and the clinical parameters that impact treatment continuation. This study aimed to 1) describe experiences with low-dose buprenorphine initiation, including both successes and failures among hospitalized patients in an urban underserved community; 2) identify patient- and treatment-related characteristics associated with unsuccessful initiation and treatment discontinuation; and 3) assess buprenorphine treatment continuation after discharge. METHODS: This is a retrospective cohort study with opioid-dependent (meaning OUD or receiving long-term opioid therapy for chronic pain) patients who underwent low-dose buprenorphine initiation during hospital admission from October 2021 through April 2022. The primary outcome was successful completion of low-dose initiation. Bivariate analysis identified patient- and treatment-related factors associated with unsuccessful initiation. Secondary outcomes were buprenorphine treatment discontinuation at post-discharge follow-up, 30- and 90-days. RESULTS: Of 28 patients who underwent low-dose buprenorphine initiation, 68 % successfully completed initiation. Unsuccessful initiation was associated with receipt of methadone during admission and higher morphine milligram equivalents (MME) of supplemental opioids. Of 22 patients with OUD, the percent receiving a buprenorphine prescription at a follow-up visit, 30 days, and 90 days, respectively, was 46 %, 36 %, and 36 %. Of 6 patients with chronic pain, the percent receiving a buprenorphine prescription at a follow-up visit, 30 days, and 90 days, respectively, was 100 %, 100 %, and 83 %. CONCLUSION: Low-dose buprenorphine initiation can be successful in opioid-dependent hospitalized patients. Patients taking methadone or requiring higher MME of supplemental opioids may have more difficulty with the low-dose buprenorphine initiation approach, but these findings should be replicated in larger studies. This study suggests patient- and treatment-related factors that clinicians could consider when determining the optimal treatment strategy for patients wishing to transition to buprenorphine.

Association of a Gamified Journal Club on Internal Medicine Residents' Engagement and Critical Appraisal Skills.

Background: Prior literature demonstrates internal medicine residents have suboptimal competence in critical appraisal. Journal clubs are a common intervention to address this skill, but engagement and critical appraisal skill improvement are variable. Objective: We evaluated journal club engagement and critical appraisal skills after implementation of a gamified format. Methods: This was a single-arm study, conducted from July 1, 2020 to June 30, 2021, involving internal medicine residents at 2 US programs. Residents participated in a 12-month gamified journal club that sorted residents into 2 teams. Residents attended an orientation followed by 6 to 10 monthly, hour-long competitions. In each competition, a subset of the resident teams competed to answer a clinical prompt by critically appraising an original article of their choice. A chief medical resident or faculty member moderated each session and chose the winning team, which received a nominal prize of candy. The primary outcome was engagement, measured by a 7-question survey developed de novo by the authors with Likert scale responses at baseline and 12 months. The secondary outcome was critical appraisal skills assessed by the Berlin Questionnaire. Results: Sixty-one of 72 eligible residents (84.7%) completed both engagement surveys. Residents reported statistically significant improvements in most dimensions of engagement, including a higher likelihood of reading articles before sessions (posttest minus pretest score -1.08; 95% CI -1.34 to -0.82; P<.001) and valuing time spent (posttest minus pretest score -0.33; 95% CI -0.55 to -0.11; P=.004). Critical appraisal skills marginally improved at 12 months (posttest minus pretest score -0.84; 95% CI -1.54 to -0.14; P=.02). Conclusions: Our study demonstrates a gamified journal club was associated with improvements in engagement and minimal change in critical appraisal skills.

Environmental variation effects fertility in tropical beef cattle.

The northern Australia beef cattle industry operates in harsh environmental conditions which consistently suppress female fertility. To better understand the environmental effect on cattle raised extensively in northern Australia, new environmental descriptors were defined for 54 commercial herds located across the region. Three fertility traits, based on the presence of a corpus luteum at 600 d of age, indicating puberty, (CL Presence, n = 25,176), heifer pregnancy (n = 20,989) and first lactation pregnancy (n = 10,072) were recorded. Temperature, humidity, and rainfall were obtained from publicly available data based on herd location. Being pubertal at 600 d (i.e. CL Presence) increased the likelihood of success at heifer pregnancy and first lactation pregnancy (P < 0.05), underscoring the importance of early puberty in reproductive success. A temperature humidity index (THI) of 65-70 had a significant (P < 0.05) negative effect on first lactation pregnancy rate, heifer pregnancy and puberty at 600 d of age. Area under the curve of daily THI was significant (P < 0.05) and reduced the likelihood of pregnancy at first lactation and puberty at 600 days. Deviation from long-term average rainfall was not significant (P < 0.05) for any trait. Average daily weight gain had a significant and positive relationship (P < 0.05) for heifer and first lactation pregnancy. The results indicate that chronic or cumulative heat load is more determinantal to reproductive performance than acute heat stress. The reason for the lack of a clear relationship between acute heat stress and reproductive performance is unclear but may be partially explained by peak THI and peak nutrition coinciding at the same time. Sufficient evidence was found to justify the use of average daily weight gain and chronic heat load as descriptors to define an environmental gradient.

Onsite buprenorphine inductions at harm reduction agencies to increase treatment engagement and reduce HIV risk: Design and rationale.

BACKGROUND: Despite dramatic increases in opioid use disorder (OUD) and overdose deaths, the U.S. has been unable to consistently deliver OUD treatment to those who need it. Syringe services programs (SSPs) can engage an out-of-treatment population of people with OUD that has elevated overdose risk. Buprenorphine treatment is safe and effective, and US regulations allow for prescribing from diverse locations, including SSPs. This study's objective is to test buprenorphine treatment initiation at SSPs. We hypothesize that offering onsite buprenorphine treatment initiation will improve OUD treatment engagement without reducing buprenorphine treatment effectiveness or safety. METHODS: We will recruit 250 out-of-treatment SSP participants with OUD in a large urban area. Participants will be randomized to onsite buprenorphine treatment initiation or enhanced referral. Over 2 weeks, participants in the onsite treatment arm will see a buprenorphine provider twice at the SSP, receive weekly medication packs, and then their care will be transferred to a community health center for treatment continuation. In the control arm, within one week, participants will receive an appointment at the same community health center as in the intervention arm for buprenorphine initiation and continuation. Participants will be assessed with urine drug tests, questionnaires, and medical record review. The primary outcome will be engagement in buprenorphine treatment at 30 days. Secondary outcomes include buprenorphine diversion, opioid-free urine drug tests, and intervention cost-effectiveness. DISCUSSION: Our study will contribute to the growing literature on SSPs as a conduit to OUD treatment. SSPs hold promise to deliver needed care to people with OUD.

Participants of a mail delivery syringe services program are underserved by other safe sources for sterile injection supplies.

BACKGROUND: In the United States, accessing sterile injection supplies remains challenging for many people who inject drugs (PWID). Although women are less likely to inject drugs than men, women who do inject are disproportionately affected by IDU-related complications. Needle Exchange Technology (NEXT), the first formal online accessed mail delivery syringe services program (SSP) in the US, may overcome access barriers. We evaluated whether NEXT was reaching women participants and people without access to other safe sources of sterile injection supplies. METHODS: This cross-sectional study examined NEXT participants who enrolled in the mail-delivery SSP from February 2018 through March 2021. All NEXT participants completed an online questionnaire during enrollment, which included sociodemographic and clinical characteristics and injection-related risk factors (including prior sources of sterile injection supplies). Multivariable logistic regression (MVR) was used to examine associations between gender and prior use of safe sources of injection supplies (i.e., SSPs or pharmacies). RESULTS: 1,032 participants received injection supplies. Median age was 34 and participants were mostly cis-gendered women (55%) and white (93%). 34% reported infection with HCV; women were more likely to report HCV infection than men (38% vs 28%; p < 0.01). 68% of participants acquired injection supplies from less safe sources. Few participants exclusively used safe sources for injection supplies (26%). In adjusted MVR analysis, women participants had significantly lower odds than men of having exclusively used safe sources for injection supplies (adjusted OR 0.71, 95% CI 0.52, 0.98). CONCLUSION: Our findings suggest that NEXT services are utilized by women and people without prior access to sterile injection supplies. Women participants were less likely than men to have exclusively used safe sources for sterile injection supplies. Future research should explore women's preference for mail-delivery over in-person SSPs and determine whether online accessed mail delivery services can reach other underserved populations of PWID.

Low-threshold Buprenorphine Treatment in a Syringe Services Program: Program Description and Outcomes.

OBJECTIVES: Low-threshold buprenorphine treatment aims to reduce barriers to evidence-based opioid use disorder treatment. We aimed to describe the treatment philosophy, practices, and outcomes of a low-threshold syringe services program (SSP)-based buprenorphine program developed through an SSP-academic medical center partnership. METHODS: We included all SSP participants who received 1 or more buprenorphine prescription from Feb 5, 2019 to October 9, 2020. We collected data on patient characteristics, substance use, buprenorphine prescriptions, and urine drug tests (UDTs). We evaluated buprenorphine treatment retention using prescription data and buprenorphine adherence using UDTs. We used 2 retention definitions: (1) percentage of patients with buprenorphine prescriptions at 30, 90, and 180 days; and (2) total percentage of days "covered" with buprenorphine prescriptions through 180 days. RESULTS: One-hundred and eighteen patients received 1 or more buprenorphine prescriptions. Patients were largely middle-aged (mean age 44, standard deviation 11), male (68%), Hispanic (31%) or Non-Hispanic Black (32%), with heroin (90%) and crack/cocaine (62%) use, and injection drug use (59%). Retention was 62%, 43%, and 31% at 30, 90, and 180 days, respectively. The median percentage of days covered with buprenorphine prescriptions through 180 days was 43% (interquartile range 8%-92%). Of the 82 patients who completed 2 or more UDTs, the median percentage of buprenorphine-positive UDTs was 71% (interquartile range 40%-100%). CONCLUSIONS: In an SSP-based low-threshold buprenorphine treatment program, approximately one-third of patients continued buprenorphine treatment for 180 days or more, and buprenorphine adherence was high. SSPs can be a pathway to buprenorphine treatment for patients at high risk for opioid-related harms.

"The Doctor Says You Cannot Have [Buprenorphine]" Autonomy and Use of Prescribed or Non-Prescribed Buprenorphine.

BACKGROUND: People may overcome barriers to professional buprenorphine treatment by using non-prescribed buprenorphine (NPB) to manage opioid use disorder (OUD). Little is known about how people perceive NPB differently than formal treatment. This qualitative study investigated how and why people use NPB as an alternative to formal treatment. METHODS: In-depth, semi-structured interviews were conducted with participants of harm reduction agencies (N = 22) who had used buprenorphine. Investigators independently coded transcribed interviews, generating themes through iterative reading and analysis of transcripts. RESULTS: Three main factors drove decisions about prescribed and non-prescribed buprenorphine use: 1) autonomy; 2) treatment goals; and 3) negative early experiences with NPB. An overarching theme from our analysis was that participants valued autonomy in seeking to control their substance use. NPB was a valuable tool toward this goal and professional OUD treatment could impede autonomy. Participants mostly used NPB to "self-manage" OUD symptoms. Many participants had concerns about long-term buprenorphine treatment and instead used NPB over short periods of time. Several participants also reported negative experiences with NPB, including symptoms of withdrawal, which then deterred them from seeking out professional treatment. CONCLUSIONS: These results support prior studies showing that people use NPB to self-manage withdrawal symptoms and to reduce use of illicit opioids. Despite these benefits, participants focused on short-term goals and negative consequences were common. Increasing buprenorphine treatment engagement may require attention to patients' sense of autonomy, and also assurance that long-term treatment is safe, effective, and reliably accessible.

Analysis of Polycerate Mutants Reveals the Evolutionary Co-option of HOXD1 for Horn Patterning in Bovidae.

In the course of evolution, pecorans (i.e., higher ruminants) developed a remarkable diversity of osseous cranial appendages, collectively referred to as "headgear," which likely share the same origin and genetic basis. However, the nature and function of the genetic determinants underlying their number and position remain elusive. Jacob and other rare populations of sheep and goats are characterized by polyceraty, the presence of more than two horns. Here, we characterize distinct POLYCERATE alleles in each species, both associated with defective HOXD1 function. We show that haploinsufficiency at this locus results in the splitting of horn bud primordia, likely following the abnormal extension of an initial morphogenetic field. These results highlight the key role played by this gene in headgear patterning and illustrate the evolutionary co-option of a gene involved in the early development of bilateria to properly fix the position and number of these distinctive organs of Bovidae.

Early Cortisol and Inflammatory Responses to Parental Cancer and Their Impact on Functional Impairment in Youth.

PURPOSE: Chronic stress is associated with increased risk for maladaptive psychological responses during childhood, adolescence, and young adulthood. Adults exposed to chronic stress during childhood exhibit dysregulation of hypothalamic-pituitary-adrenal (HPA) axis activity and inflammation. There are no studies examining the impact of stress on biological stress responses and functional impairment in adolescents and young adults early after the onset of a stressor. METHODS: The sample consisted of 59 offspring, aged 11-25 years, 33 of parents diagnosed with cancer and 26 controls from families with no cancer or severe chronic illness in parents or siblings. Cancer patients and their families were recruited within an average of 62 days (SD = 35.9) and followed at 6 and 9 months later. Functional impairment was assessed and hair cortisol concentrations (HCC), salivary cortisol, and inflammatory markers were measured. Mixed regression analyses were conducted. RESULTS: The stress group showed higher functional impairment (ß = -5.5, 95% CI (-10.4, -0.06), p = 0.03, d= -0.40) and HCC (ß = 10.5, 95% CI (-5.5, -0.50), p < 0.001, d = 1.43). However, HCC were reduced over time in the stress group (ß= -0.3, 95% CI (-0.04, -0.01), p < 0.001, d = -1.08). Higher total cortisol output was associated with increased functional impairment over time (ß = -3.0, 95% CI (-5.5, -0.5), p = 0.02, d = -0.60). CONCLUSIONS: Parental cancer is associated with early increase in cortisol, which was associated with increased functional impairment in offspring. Clinicians need to assess and monitor psychiatric symptoms and functioning in these offspring early on following parental cancer diagnosis.

The psychiatric sequelae of the COVID-19 pandemic in adolescents, adults, and health care workers.

BACKGROUND: The COVID-19 pandemic is the most serious global public health crisis since the 1918 influenza pandemic. This study is the first to assess its mental health impact across the lifespan in the United States in adolescents, adults, and health care workers. METHODS: We recruited 4909 participants through an online survey advertising on Facebook and Instagram to assess exposure to COVID-19 and psychiatric symptoms from April 27 to July 13. We also recruited through the University of Pittsburgh, University of Pittsburgh Medical Center, and other health care systems around Pittsburgh. The primary outcomes were clinically significant depression, anxiety, and posttraumatic stress disorder (PTSD) symptoms, suicidal ideation or behavior, and grief reactions since COVID-19. RESULTS: Adolescents were significantly more likely to report moderate to severe symptoms of depression (55% vs. 29%; χ2 = 122, df = 1; p < .001), anxiety (48% vs. 29%; χ2 = 73; df = 1; p < .001), PTSD (45% vs. 33%; χ2 = 12; df = 1; p < .001), suicidal ideation or behavior (38% vs. 16%; χ2 = 117; df = 1; p < .001), and sleep problems (69% vs. 57%; χ2 = 26; df = 1; p < .001) compared to adults. The rates of intense grief reactions among those who lost someone to COVID-19 was 55%. Loneliness was the most common predictor across outcomes and higher number of hours spent on social media and exposure to media about COVID-19 predicted depression symptoms and suicidal ideation or behavior in adolescents. CONCLUSIONS: The COVID-19 pandemic is associated with increased rates of clinically significant psychiatric symptoms. Loneliness could put individuals at increased risk for the onset of psychiatric disorders.

Metastatic breast cancer presenting as acute liver injury: diagnostic dilemma in the setting of suspected hemochromatosis.

A 70-year-old female with a history of lobular carcinoma of the breast, status post-mastectomy followed by adjuvant radio-chemotherapy in remission for 4 years was admitted with the features of acute liver failure (ALF). Iron studies revealed a hemochromatosis picture and the CT and MRI scans of the abdomen suggested cirrhosis. An extensive workup failed to identify an etiology. A trans-jugular liver biopsy was obtained and revealed poorly differentiated carcinoma consistent with the metastasis of breast primary. The patient's condition deteriorated and died within a week following the onset of acute hepatic failure. DNA testing revealed that the patient was heterozygous for H63D mutation. In cases of ALF with the suspicion of malignancy, liver biopsy should be obtained to evaluate an infiltrative hepatic disease.

Quantifying the contribution of sequence variants with regulatory and evolutionary significance to 34 bovine complex traits.

Many genome variants shaping mammalian phenotype are hypothesized to regulate gene transcription and/or to be under selection. However, most of the evidence to support this hypothesis comes from human studies. Systematic evidence for regulatory and evolutionary signals contributing to complex traits in a different mammalian model is needed. Sequence variants associated with gene expression (expression quantitative trait loci [eQTLs]) and concentration of metabolites (metabolic quantitative trait loci [mQTLs]) and under histone-modification marks in several tissues were discovered from multiomics data of over 400 cattle. Variants under selection and evolutionary constraint were identified using genome databases of multiple species. These analyses defined 30 sets of variants, and for each set, we estimated the genetic variance the set explained across 34 complex traits in 11,923 bulls and 32,347 cows with 17,669,372 imputed variants. The per-variant trait heritability of these sets across traits was highly consistent (r > 0.94) between bulls and cows. Based on the per-variant heritability, conserved sites across 100 vertebrate species and mQTLs ranked the highest, followed by eQTLs, young variants, those under histone-modification marks, and selection signatures. From these results, we defined a Functional-And-Evolutionary Trait Heritability (FAETH) score indicating the functionality and predicted heritability of each variant. In additional 7,551 cattle, the high FAETH-ranking variants had significantly increased genetic variances and genomic prediction accuracies in 3 production traits compared to the low FAETH-ranking variants. The FAETH framework combines the information of gene regulation, evolution, and trait heritability to rank variants, and the publicly available FAETH data provide a set of biological priors for cattle genomic selection worldwide.

Complex Trait Prediction from Genome Data: Contrasting EBV in Livestock to PRS in Humans: Genomic Prediction.

In this Review, we focus on the similarity of the concepts underlying prediction of estimated breeding values (EBVs) in livestock and polygenic risk scores (PRS) in humans. Our research spans both fields and so we recognize factors that are very obvious for those in one field, but less so for those in the other. Differences in family size between species is the wedge that drives the different viewpoints and approaches. Large family size achievable in nonhuman species accompanied by selection generates a smaller effective population size, increased linkage disequilibrium and a higher average genetic relationship between individuals within a population. In human genetic analyses, we select individuals unrelated in the classical sense (coefficient of relationship <0.05) to estimate heritability captured by common SNPs. In livestock data, all animals within a breed are to some extent "related," and so it is not possible to select unrelated individuals and retain a data set of sufficient size to analyze. These differences directly or indirectly impact the way data analyses are undertaken. In livestock, genetic segregation variance exposed through samplings of parental genomes within families is directly observable and taken for granted. In humans, this genomic variation is under-recognized for its contribution to variation in polygenic risk of common disease, in both those with and without family history of disease. We explore the equation that predicts the expected proportion of variance explained using PRS, and quantify how GWAS sample size is the key factor for maximizing accuracy of prediction in both humans and livestock. Last, we bring together the concepts discussed to address some frequently asked questions.

Putative bovine topological association domains and CTCF binding motifs can reduce the search space for causative regulatory variants of complex traits.

BACKGROUND: Topological association domains (TADs) are chromosomal domains characterised by frequent internal DNA-DNA interactions. The transcription factor CTCF binds to conserved DNA sequence patterns called CTCF binding motifs to either prohibit or facilitate chromosomal interactions. TADs and CTCF binding motifs control gene expression, but they are not yet well defined in the bovine genome. In this paper, we sought to improve the annotation of bovine TADs and CTCF binding motifs, and assess whether the new annotation can reduce the search space for cis-regulatory variants. RESULTS: We used genomic synteny to map TADs and CTCF binding motifs from humans, mice, dogs and macaques to the bovine genome. We found that our mapped TADs exhibited the same hallmark properties of those sourced from experimental data, such as housekeeping genes, transfer RNA genes, CTCF binding motifs, short interspersed elements, H3K4me3 and H3K27ac. We showed that runs of genes with the same pattern of allele-specific expression (ASE) (either favouring paternal or maternal allele) were often located in the same TAD or between the same conserved CTCF binding motifs. Analyses of variance showed that when averaged across all bovine tissues tested, TADs explained 14% of ASE variation (standard deviation, SD: 0.056), while CTCF explained 27% (SD: 0.078). Furthermore, we showed that the quantitative trait loci (QTLs) associated with gene expression variation (eQTLs) or ASE variation (aseQTLs), which were identified from mRNA transcripts from 141 lactating cows' white blood and milk cells, were highly enriched at putative bovine CTCF binding motifs. The linearly-furthermost, and most-significant aseQTL and eQTL for each genic target were located within the same TAD as the gene more often than expected (Chi-Squared test P-value < 0.001). CONCLUSIONS: Our results suggest that genomic synteny can be used to functionally annotate conserved transcriptional components, and provides a tool to reduce the search space for causative regulatory variants in the bovine genome.

Mammalian genomic regulatory regions predicted by utilizing human genomics, transcriptomics, and epigenetics data.

Genome sequences for hundreds of mammalian species are available, but an understanding of their genomic regulatory regions, which control gene expression, is only beginning. A comprehensive prediction of potential active regulatory regions is necessary to functionally study the roles of the majority of genomic variants in evolution, domestication, and animal production. We developed a computational method to predict regulatory DNA sequences (promoters, enhancers, and transcription factor binding sites) in production animals (cows and pigs) and extended its broad applicability to other mammals. The method utilizes human regulatory features identified from thousands of tissues, cell lines, and experimental assays to find homologous regions that are conserved in sequences and genome organization and are enriched for regulatory elements in the genome sequences of other mammalian species. Importantly, we developed a filtering strategy, including a machine learning classification method, to utilize a very small number of species-specific experimental datasets available to select for the likely active regulatory regions. The method finds the optimal combination of sensitivity and accuracy to unbiasedly predict regulatory regions in mammalian species. Furthermore, we demonstrated the utility of the predicted regulatory datasets in cattle for prioritizing variants associated with multiple production and climate change adaptation traits and identifying potential genome editing targets.

An initiator codon mutation in SDE2 causes recessive embryonic lethality in Holstein cattle.

Researching depletions in homozygous genotypes for specific haplotypes among the large cohorts of animals genotyped for genomic selection is a very efficient strategy to map recessive lethal mutations. In this study, by analyzing real or imputed Illumina BovineSNP50 (Illumina Inc., San Diego, CA) genotypes from more than 250,000 Holstein animals, we identified a new locus called HH6 showing significant negative effects on conception rate and nonreturn rate at 56 d in at-risk versus control mating. We fine-mapped this locus in a 1.1-Mb interval and analyzed genome sequence data from 12 carrier and 284 noncarrier Holstein bulls. We report the identification of a strong candidate mutation in the gene encoding SDE2 telomere maintenance homolog (SDE2), a protein essential for genomic stability in eukaryotes. This A-to-G transition changes the initiator ATG (methionine) codon to ACG because the gene is transcribed on the reverse strand. Using RNA sequencing and quantitative reverse-transcription PCR, we demonstrated that this mutation does not significantly affect SDE2 splicing and expression level in heterozygous carriers compared with control animals. Initiation of translation at the closest in-frame methionine codon would truncate the SDE2 precursor by 83 amino acids, including the cleavage site necessary for its activation. Finally, no homozygote for the G allele was observed in a large population of nearly 29,000 individuals genotyped for the mutation. The low frequency (1.3%) of the derived allele in the French population and the availability of a diagnostic test on the Illumina EuroG10K SNP chip routinely used for genomic evaluation will enable rapid and efficient selection against this deleterious mutation.

A multi-trait Bayesian method for mapping QTL and genomic prediction.

BACKGROUND: Genomic prediction and quantitative trait loci (QTL) mapping typically analyze one trait at a time but this may ignore the possibility that one polymorphism affects multiple traits. The aim of this study was to develop a multivariate Bayesian approach that could be used for simultaneously elucidating genetic architecture, QTL mapping, and genomic prediction. Our approach uses information from multiple traits to divide markers into 'unassociated' (no association with any trait) and 'associated' (associated with one or more traits). The effect of associated markers is estimated independently for each trait to avoid the assumption that QTL effects follow a multi-variate normal distribution. RESULTS: Using simulated data, our multivariate method (BayesMV) detected a larger number of true QTL (with a posterior probability > 0.9) and increased the accuracy of genomic prediction compared to an equivalent univariate method (BayesR). With real data, accuracies of genomic prediction in validation sets for milk yield traits with high-density genotypes were approximately equal to those from equivalent single-trait methods. BayesMV tended to select a similar number of single nucleotide polymorphisms (SNPs) per trait for genomic prediction compared to BayesR (i.e. those with non-zero effects), but BayesR selected different sets of SNPs for each trait, whereas BayesMV selected a common set of SNPs across traits. Despite these two dramatically different estimates of genetic architecture (i.e. different SNPs affecting each trait vs. pleiotropic SNPs), both models indicated that 3000 to 4000 SNPs are associated with a trait. The BayesMV approach may be advantageous when the aim is to develop a low-density SNP chip that works well for a number of traits. SNPs for milk yield traits identified by BayesMV and BayesR were also found to be associated with detailed milk composition. CONCLUSIONS: The BayesMV method simultaneously estimates the proportion of SNPs that are associated with a combination of traits. When applied to milk production traits, most of the identified SNPs were associated with all three traits (milk, fat and protein yield). BayesMV aims at exploiting pleiotropic QTL and selects a small number of SNPs that could be used to predict multiple traits.