Meta-analysis of genome-wide association studies for cattle stature identifies common genes that regulate body size in mammals

peer-reviewedH.D.D., A.J.C., P.J.B. and B.J.H. would like to acknowledge the Dairy Futures Cooperative Research Centre for funding. H.P. and R.F. acknowledge funding from the German Federal Ministry of Education and Research (BMBF) within the AgroClustEr ‘Synbreed—Synergistic Plant and Animal Breeding’ (grant 0315527B). H.P., R.F., R.E. and K.-U.G. acknowledge the Arbeitsgemeinschaft Süddeutscher Rinderzüchter, the Arbeitsgemeinschaft Österreichischer Fleckviehzüchter and ZuchtData EDV Dienstleistungen for providing genotype data. A. Bagnato acknowledges the European Union (EU) Collaborative Project LowInputBreeds (grant agreement 222623) for providing Brown Swiss genotypes. Braunvieh Schweiz is acknowledged for providing Brown Swiss phenotypes. H.P. and R.F. acknowledge the German Holstein Association (DHV) and the Confederación de Asociaciones de Frisona Española (CONCAFE) for sharing genotype data. H.P. was financially supported by a postdoctoral fellowship from the Deutsche Forschungsgemeinschaft (DFG) (grant PA 2789/1-1). D.B. and D.C.P. acknowledge funding from the Research Stimulus Fund (11/S/112) and Science Foundation Ireland (14/IA/2576). M.S. and F.S.S. acknowledge the Canadian Dairy Network (CDN) for providing the Holstein genotypes. P.S. acknowledges funding from the Genome Canada project entitled ‘Whole Genome Selection through Genome Wide Imputation in Beef Cattle’ and acknowledges WestGrid and Compute/Calcul Canada for providing computing resources. J.F.T. was supported by the National Institute of Food and Agriculture, US Department of Agriculture, under awards 2013-68004-20364 and 2015-67015-23183. A. Bagnato, F.P., M.D. and J.W. acknowledge EU Collaborative Project Quantomics (grant 516 agreement 222664) for providing Brown Swiss and Finnish Ayrshire sequences and genotypes. A.C.B. and R.F.V. acknowledge funding from the public–private partnership ‘Breed4Food’ (code BO-22.04-011- 001-ASG-LR) and EU FP7 IRSES SEQSEL (grant 317697). A.C.B. and R.F.V. acknowledge CRV (Arnhem, the Netherlands) for providing data on Dutch and New Zealand Holstein and Jersey bulls.Stature is affected by many polymorphisms of small effect in humans1. In contrast, variation in dogs, even within breeds, has been suggested to be largely due to variants in a small number of genes2,3. Here we use data from cattle to compare the genetic architecture of stature to those in humans and dogs. We conducted a meta-analysis for stature using 58,265 cattle from 17 populations with 25.4 million imputed whole-genome sequence variants. Results showed that the genetic architecture of stature in cattle is similar to that in humans, as the lead variants in 163 significantly associated genomic regions (P < 5 × 10−8) explained at most 13.8% of the phenotypic variance. Most of these variants were noncoding, including variants that were also expression quantitative trait loci (eQTLs) and in ChIP–seq peaks. There was significant overlap in loci for stature with humans and dogs, suggesting that a set of common genes regulates body size in mammals

Sequence-based GWAS meta-analyses for beef production traits

International audienceFive partners of the H2020 BovReg project have performed sequence-based GWAS for 28 beef production traits (4 growth, 9 morphology, and/or 15 carcass traits) using 54,782 animals from 15 different purebred or crossbred cattle populations. These results were herein combined to conduct 16 different meta-analyses (MA) with both the z-score and the fixed effects MA methods. We identified QTL in 15 MA on BTA2, 5, 6, 7, 10, 11, 13, 14, 15, 17, and 20, most of them being common to several MA. Overall, the fixed effects method outperformed the zscore method in terms of significance level and number of QTL detected. Compared to withinpopulation GWAS, MA found a higher number of QTL in which variants were more frequently located in genes (e.g. MSTN, LCORL, ARRDC3, PLAG1, COL3A1)

Sequence-based GWAS meta-analyses for beef production traits

When performed at the whole genome sequence level, the meta-analysis (MA) of within-population GWAS results can be powerful and accurate to identify causal variants for complex traits. An objective of the H2020 BovReg project is to perform MA at the sequence level for various dairy and beef cattle traits. For beef production, five partners from France, Switzerland, Germany, and Canada contributed with 54,782 animals from 15 purebred populations Charolais, Montbéliarde, Normande, Limousine, Blonde d’Aquitaine, Brown Swiss, Original Braunvieh or crossbred Charolais x Holstein, and Angus, Charolais and beef composite. Each partner conducted sequence-based within-population GWAS for 4 growth, 9 morphology, and/or 15 carcass traits. We combined these GWAS results to conduct 16 MA with both fixed effects and z-score methods.This study demonstrates the value of MA, in complement to within-population GWAS, in identifying a larger number of QTL, a lower number of variants in QTL and candidate variants located more frequently in genes. By applying here the most commonly MA methods used for GWAS, we confirm that the fixed effects method appears more powerful in detecting QTL, although MA combine substantially different traits in the present study. In several regions, MA directly pointed out variants in genes, including MSTN, LCORL, ARRDC3, and PLAG1, previously associated with morphology and carcass traits in various studies. For example, the Q204X mutation, ranked 1st in the QTL peaks at the proximal end of BTA2 and causing a premature stop codon in the gene encoding myostatin (MSTN), was reported as one of the polymorphisms responsible for the double-muscled phenotype in several cattle breeds. We also identified dozens of other variants located in genes having a function that may be related to meat production traits (e.g. COL3A1 collagen type III alpha 1 chain). By better identifying genes and candidate causative variants associated with beef production traits in cattle, MA appear to be of great interest to decipher the biological mechanisms underlying these traits.The BovReg project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 815668

Effector function does not contribute to protection from virus challenge by a highly potent HIV broadly neutralizing antibody in nonhuman primates

Protection from immunodeficiency virus challenge in nonhuman primates (NHPs) by a first-generation HIV broadly neutralizing antibody (bnAb) b12 has previously been shown to benefit from interaction between the bnAb and Fcγ receptors (FcγRs) on immune cells. To investigate the mechanism of protection for a more potent second-generation bnAb currently in clinical trials, PGT121, we carried out a series of NHP studies. These studies included treating with PGT121 at a concentration at which only half of the animals were protected to avoid potential masking of FcγR effector function benefits by dominant neutralization and using a new variant that more completely eliminated all rhesus FcγR binding than earlier variants. In contrast to b12, which required FcγR binding for optimal protection, we concluded that PGT121-mediated protection is not augmented by FcγR interaction. Thus, for HIV-passive antibody prophylaxis, these results, together with existing literature, emphasize the importance of neutralization potency for clinical antibodies, with effector function requiring evaluation for individual antibodies. </p