Involvement of DNA polymerase μ in the repair of a specific subset of DNA double-strand breaks in mammalian cells

The repair of DNA double-strand breaks (DSB) requires processing of the broken ends to complete the ligation process. Recently, it has been shown that DNA polymerase μ (polμ) and DNA polymerase λ (polλ) are both involved in such processing during non-homologous end joining in vitro. However, no phenotype was observed in animal models defective for either polμ and/or polλ. Such observations could result from a functional redundancy shared by the X family of DNA polymerases. To avoid such redundancy and to clarify the role of polμ in the end joining process, we generated cells over-expressing the wild type as well as an inactive form of polμ (polμD). We observed that cell sensitivity to ionizing radiation (IR) was increased when either polμ or polμD was over-expressed. However, the genetic instability in response to IR increased only in cells expressing polμD. Moreover, analysis of intrachromosomal repair of the I-SceI-induced DNA DSB, did not reveal any effect of either polμ or polμD expression on the efficiency of ligation of both cohesive and partially complementary ends. Finally, the sequences of the repaired ends were specifically affected when polμ or polμD was over-expressed, supporting the hypothesis that polμ could be involved in the repair of a DSB subset when resolution of junctions requires some gap filling

Rigoletto

De cada obra s'ha digitalitzat un programa sencer. De la resta s'han digitalitzat les parts que són diferents.Director: José Sabate

53BP1 regulates DNA resection and the choice between classical and alternative end joining during class switch recombination

Class switch recombination (CSR) diversifies antibodies by joining highly repetitive DNA elements, which are separated by 60–200 kbp. CSR is initiated by activation-induced cytidine deaminase, an enzyme that produces multiple DNA double-strand breaks (DSBs) in switch regions. Switch regions are joined by a mechanism that requires an intact DNA damage response and classical or alternative nonhomologous end joining (A-NHEJ). Among the DNA damage response factors, 53BP1 has the most profound effect on CSR. We explore the role of 53BP1 in intrachromosomal DNA repair using I-SceI to introduce paired DSBs in the IgH locus. We find that the absence of 53BP1 results in an ataxia telangiectasia mutated–dependent increase in DNA end resection and that resected DNA is preferentially repaired by microhomology-mediated A-NHEJ. We propose that 53BP1 favors long-range CSR in part by protecting DNA ends against resection, which prevents A-NHEJ–dependent short-range rejoining of intra–switch region DSBs

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

Effet du croisement Holstein sur les caractères laitiers en population Pie Noir

International audienc

Le modèle sous-jacent à l'évaluation des valeurs génétiques

International audienc

L'évaluation des reproducteurs. Le modèle sous-jacent à l'estimation des valeurs génétiques

National audienceLa valeur génétique additive peut être prédite en modélisant d’une part les performances, d’autre part le déterminisme génétique des caractères. Les performances sont décomposées en effets génétiques, en effets de milieu identifiés et en une résiduelle du modèle, constituée de multiples effets génétiques ou de milieu non identifiés et non maîtrisés. Si le déterminisme du caractère est polygénique additif, la corrélation entre les valeurs génétiques de deux individus est proportionnelle à leur coefficient de parenté. Toute l’information (performances, facteurs de variation, relations de parenté) est combinée en un système d’équations unique qui permet d’estimer simultanément les effets génétiques et les effets de milieu. L’adoption d’un modèle "animal" permet de combiner toute cette information de façon optimale et de prendre en compte l’effet de la sélection et des accouplements non au hasard dans la population. Grâce à la structure de l’inverse de la matrice de parentés, le modèle animal fournit des équations très simples, facilitant l’explication et la diffusion de son principe : un effet de milieu est estimé par une moyenne de performances ajustées ; l’index d’un individu combine trois informations, sur ascendance, sur descendance et sur performances propres. Le modèle est souple et peut facilement être modifié pour prendre en compte des situations complexes. L’évaluation génétique est bien sûr un outil de sélection mais, compte tenu de ses propriétés, représente aussi un outil puissant de diagnostic et de prévision

Consequences of the inscription of local breeds in protected designation of origin cow cheese specifications for the genetic management of the herds

In the mountainous areas of Europe with a humid climate, dairy cattle production is a major agricultural activity, and the milk is often processed into cheese according to protected designation of origin (PDO) specifications. We analyzed the extent to which PDO specifications and/or a mountain environment influence the spatial distribution of estimated breeding values (EBVs) of cows and the herd–year effects (HYEs) for milk yield (kg/lactation) and protein and fat contents (g/kg), as well as lactation ranks and calving months. The study focused on the northern French Alps. A total of 37 023 lactations, recorded in 2006, in 1153 herds were analyzed. The cows belonged to the Montbéliarde (21 516 lactations), Abondance (10 346 lactations) and Tarentaise (5161 lactations) breeds. The two factors of variation considered were the status of the commune where the farm was located in relation to PDO (three categories: area with no PDO, area with a PDO with no milk yield limit, area with a PDO with a milk yield limit) and ‘mountain’ environment (four categories based on the European regulation: plain, piedmont, mountain and high mountain). In the Abondance breed, the average lactation rank increased with an increase in production constraints due to the PDO or to a mountain environment. In the Abondance and Tarentaise breeds, grouping of calving in winter was most marked in the ‘PDO with a milk yield limit’ and ‘high-mountain’ categories. In the Tarentaise breed, no significant effect on any trait and any variable was found in the ‘PDO’ or ‘mountain’ categories. In the other two breeds, the average EBV for milk yield decreased with an increase in the constraints due to PDO, with differences of 226 and 93 kg between extreme values in the Abondance and Montbéliarde breeds, respectively. The average HYE for milk yield was higher in the Abondance breed in the ‘PDO with no milk yield limit’ category than in the other categories (+740 and +1110 kg, respectively); HYE was not affected by the ‘PDO’ factor in the Montbéliarde breed or by the ‘mountain’ factor in either breed. Concerning the protein and fat contents, the effect of the ‘PDO’ and ‘mountain’ factors depended on the trait, the variable and the breed. The proportion of individual decisions (the farmer makes the decision) v. collective decisions (breed management) concerning herd dynamics in the face of existing constraints is discussed

La méthode française d'évaluation génétique des reproducteurs laitiers

National audienceLes principales caractéristiques de la méthode d’évaluation génétique des reproducteurs laitiers, appliquée en France à partir de 1990, sont décrites. Les différences avec la méthode précédente sont soulignées. La méthode BLUP, appliquée à un modèle animal, permet d’utiliser toute l’information disponible de façon optimale. Pour chaque individu évalué, cette information est résumée en trois sources synthétiques : la moyenne des index de ses parents ; deux fois la moyenne pondérée des index de ses descendants, corrigés pour la valeur de ses conjoints ; la moyenne pondérée de ses propres performances, corrigées pour les effets de milieu. Les coefficients de pondération à appliquer à chacune de ces sources sont explicités et justifiés. Quelques exemples illustrent la contribution relative de chacune des trois sources d’information dans des situations courantes