Microsatellite mapping of QTLs affecting resistance to coccidiosis (Eimeria tenella) in a Fayoumi × White Leghorn cross

<p>Abstract</p> <p>Background</p> <p>Avian coccidiosis is a major parasitic disease of poultry, causing severe economical loss to poultry production by affecting growth and feed efficiency of infected birds. Current control strategies using mainly drugs and more recently vaccination are showing drawbacks and alternative strategies are needed. Using genetic resistance that would limit the negative and very costly effects of the disease would be highly relevant. The purpose of this work was to detect for the first time QTL for disease resistance traits to <it>Eimeria tenella </it>in chicken by performing a genome scan in an F2 cross issued from a resistant Fayoumi line and a susceptible Leghorn line.</p> <p>Results</p> <p>The QTL analysis detected 21 chromosome-wide significant QTL for the different traits related to disease resistance (body weight growth, plasma coloration, hematocrit, rectal temperature and lesion) on 6 chromosomes. Out of these, a genome-wide very significant QTL for body weight growth was found on GGA1, five genome-wide significant QTL for body weight growth, plasma coloration and hematocrit and one for plasma coloration were found on GGA1 and GGA6, respectively. Two genome-wide suggestive QTL for plasma coloration and rectal temperature were found on GGA1 and GGA2, respectively. Other chromosme-wide significant QTL were identified on GGA2, GGA3, GGA6, GGA15 and GGA23. Parent-of-origin effects were found for QTL for body weight growth and plasma coloration on GGA1 and GGA3. Several QTL for different resistance phenotypes were identified as co-localized on the same location.</p> <p>Conclusion</p> <p>Using an F2 cross from resistant and susceptible chicken lines proved to be a successful strategy to identify QTL for different resistance traits to <it>Eimeria tenella</it>, opening the way for further gene identification and underlying mechanisms and hopefully possibilities for new breeding strategies for resistance to coccidiosis in the chicken. From the QTL regions identified, several candidate genes and relevant pathways linked to innate immune and inflammatory responses were suggested. These results will be combined with functional genomics approaches on the same lines to provide positional candidate genes for resistance loci for coccidiosis. Results suggested also for further analysis, models tackling the complexity of the genetic architecture of these correlated disease resistance traits including potential epistatic effects.</p

Pyroséquençage pour le développement d'EST et de SNP aviaires

Le but du programme est de combler les déficits en marqueurs observés pour trois espèces aviaires : la caille, le canard et la poule. La stratégie choisie est l'obtention, à partir de plusieurs individus de lignées d'intérêt, de SNP (Single Nucleotide Polymorphism, polymorphisme d'un nucléotide) par une nouvelle technologie de séquençage à haut débit (séquenceur 454 GS-FLX, Roche). Nous séquençons des représentations réduites du génome, en sélectionnant d'une part des fragments de restriction d'ADN génomique - les mêmes chez tous les individus - et d'autre part les transcrits qui représentent globalement la partie du génome correspondant aux gènes exprimés. Ces expérimentations sont réalisées à partir d'échantillons d'ADN ou d'ARN issus d'individus de lignées à l'origine de croisements existants, pour chacune des trois espèces. Les données générées par plusieurs "runs" de séquence seront traitées in silico : contigage à haut débit, recherche de SNP, comparaison avec les banques de séquences connues...En plus de l'intérêt que représente la production d'un très grand nombre de SNP nouveaux, cette technologie devrait permettre de mieux séquencer les régions riches en (G+C) correspondant aux plus petits des microchromosomes pour lesquels il n'y a pas de séquence chez la poule. La comparaison des séquences des transcrits obtenues chez la caille et le canard avec la séquence du génome de la poule permettra d'établir une "cartographie virtuelle" des SNP obtenus, grâce à la grande conservation de synténie existant entre ces trois espèces

Storms and Precipitation Across the continental Divide Experiment (SPADE)

Canada First Research Excellence Fund’s Global Water Futures programme (GWF), NSERC Discovery Grants (Julie M. Thériault, Stephen J. Déry, John W. Pomeroy, and Ronald E. Stewart), the Canada Research Chairs Program (Julie M. Thériault, John W. Pomeroy), UNBC (Selina Mitchell), NSERC CGS-M, and a FRQNT fellowship (Aurélie Desroches-Lapointe)Peer ReviewedThe Canadian Rockies are a triple-continental divide, whose high mountains are drained by major snow-fed and rain-fed rivers flowing to the Pacific, Atlantic, and Arctic Oceans. The objective of the April–June 2019 Storms and Precipitation Across the continental Divide Experiment (SPADE) was to determine the atmospheric processes producing precipitation on the eastern and western sides of the Canadian Rockies during springtime, a period when upslope events of variable phase dominate precipitation on the eastern slopes. To do so, three observing sites across the divide were instrumented with advanced meteorological sensors. During the 13 observed events, the western side recorded only 25% of the eastern side’s precipitation accumulation, rainfall occurred rather than snowfall, and skies were mainly clear. Moisture sources and amounts varied markedly between events. An atmospheric river landfall in California led to moisture flowing persistently northward and producing the longest duration of precipitation on both sides of the divide. Moisture from the continental interior always produced precipitation on the eastern side but only in specific conditions on the western side. Mainly slow-falling ice crystals, sometimes rimed, formed at higher elevations on the eastern side (>3 km MSL), were lifted, and subsequently drifted westward over the divide during nonconvective storms to produce rain at the surface on the western side. Overall, precipitation generally crossed the divide in the Canadian Rockies during specific spring-storm atmospheric conditions although amounts at the surface varied with elevation, condensate type, and local and large-scale flow fields

Genome Evolution of Two Genetically Homogeneous Infectious Bursal Disease Virus Strains During Passages in vitro and ex vivo in the Presence of a Mutagenic Nucleoside Analog

The avibirnavirus infectious bursal disease virus (IBDV) is responsible for a highly contagious and sometimes lethal disease of chickens (Gallus gallus). IBDV genetic variation is well-described for both field and live-attenuated vaccine strains, however, the dynamics and selection pressures behind this genetic evolution remain poorly documented. Here, genetically homogeneous virus stocks were generated using reverse genetics for a very virulent strain, rvv, and a vaccine-related strain, rCu-1. These viruses were serially passaged at controlled multiplicities of infection in several biological systems, including primary chickens B cells, the main cell type targeted by IBDV in vivo. Passages were also performed in the absence or presence of a strong selective pressure using the antiviral nucleoside analog 7-deaza-2′-C-methyladenosine (7DMA). Next Generation Sequencing (NGS) of viral genomes after the last passage in each biological system revealed that (i) a higher viral diversity was generated in segment A than in segment B, regardless 7DMA treatment and viral strain, (ii) diversity in segment B was increased by 7DMA treatment in both viruses, (iii) passaging of IBDV in primary chicken B cells, regardless of 7DMA treatment, did not select cell-culture adapted variants of rvv, preserving its capsid protein (VP2) properties, (iv) mutations in coding and non-coding regions of rCu-1 segment A could potentially associate to higher viral fitness, and (v) a specific selection, upon 7DMA addition, of a Thr329Ala substitution occurred in the viral polymerase VP1. The latter change, together with Ala270Thr change in VP2, proved to be associated with viral attenuation in vivo. These results identify genome sequences that are important for IBDV evolution in response to selection pressures. Such information will help tailor better strategies for controlling IBDV infection in chickens

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Abstract: Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Caractérisation et évolution des flux détritiques et authigènes en contexte lacustre carbonaté au cours du Tardiglaciaire et de l'Holocène (Lac Saint-Point, Haute-Chaîne du Jura) : implications paléoclimatiques et paléoenvironnementales

Located in the high chain of the Jura Mountains, Lake Saint-Point appears to be one of the most significant natural lake systems in France. A coring campaign was carried out in 2005 and resulted in the extraction of a 12.5 m long continuous sequence in its deep zone. Based on various dating methods (ie radiocarbon dating, tephrochronology...), this sequence's chronology spans over the Late Glacial and actual periods. A multi-parameter approach to this sequence consists in characterizing its inorganic (mineralogy, major element geochemistry, granulometry, ostracods assemblage) as well as organic fractions (rates of organic carbon, pollen). The comparison of different markers in different parts of the system (soils, vegetation, water column) highlights different evolution periods influenced by climate and human impacts. The sequence is thus composed of two distinct sedimentary sections, one being associated to the Late Glacial (from 18,500 to 11,300 cal BP) and the other to the Holocene (from 11,300 to the actual period). This bipartition is the consequence of a dramatic early Holocene authigenic production increase and a pedogenetic evolution combined with the development of forests (mixed oak) in the catchment basin. This evolution corresponds to the Holocene Climatic Optimum. Another transition occurs in 6,300 BP with the shift from Holocene Climatic Optimum to Neoglaciation due to the influence of the orbital impact. Vegetation then evolves to an Abies-Picea forest, resulting in soil and soil erodibility modifications. Even though some anthropization related pollen data have been detected from 7,200 cal BP, human impact on sedimentary response can only be observed from 2,600 cal BP on. It takes two different forms. From 2,600 cal BP to 1,200 cal BP, agricultural activities (cereals) prompt an increase in global detritism. From 1,200 cal BP, a decrease in silicate inputs, concurrent with increased anthropization related pollen data, can be seen as the consequence of a shift in agricultural practices from cereal growing to dominant pastoralism.Le lac Saint-Point, situé dans la Haute Chaîne du Jura (à proximité de Pontarlier) constitue l'un des systèmes lacustres naturels les plus importants de France. Une campagne de forage (2005) a permis l'extraction d'une séquence continue de 12,5 m dans sa partie profonde. La chronologie de cette séquence, basée sur diverses méthodes de datation (datations radiocarbone, téphrochronologie...), couvre une période s'étendant du Tardiglaciaire à l'actuel. L'approche multi-paramètres de cette séquence consiste en une caractérisation des fractions inorganiques (minéralogie, géochimie des éléments majeurs, granulométrie, assemblages d'ostracodes) et organiques (teneurs en carbone organique, pollen). La comparaison de l'évolution des différents marqueurs dans les différents compartiments du système (sols, végétation, colonne d'eau) souligne différentes périodes d'évolution sous l'influence des forçages climatiques et anthropiques. Ainsi, la séquence se compose de deux ensembles sédimentaires distincts, associés au Tardiglaciaire d'une part (environ 18 500 à 11 300 cal BP), et à l'Holocène d'autre part (environ 11 300 cal BP à l'actuel). Cette bipartition est la conséquence d'une explosion de la production authigène, au début de l'Holocène, et de l'évolution de la pédogénèse, associée à la mise en place d'une forêt (de type chênaie-mixte) sur le bassin versant. Cette évolution du système correspond à l'Optimum holocène. Une nouvelle transition apparaît à 6 300 cal BP. Cette transition marque le passage depuis l'Optimum holocène vers le Néoglaciaire, sous l'influence du forçage orbital. Le couvert végétal évolue alors vers une hêtraie-sapinière, entraînant une modification des sols et de leur érodabilité. Malgré l'observation d'indices polliniques d'anthropisation ténus à partir de 7 200 cal BP, l'impact anthropique sur la réponse sédimentaire ne semble discernable qu'à partir de 2 600 cal BP. Il revêt deux formes distinctes. De 2 600 cal BP à 1 200 cal BP, les activités agricoles (céréales) génèrent une accentuation du détritisme global. A partir de 1 200 cal BP, une décroissance des flux silicatés, contemporaine d'une accentuation des indices polliniques d'anthropisation, serait la conséquence d'une évolution des pratiques agricoles vers un pastoralisme dominant