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International audience; The use of CNN and segmentation to extract image features for the prediction of four postures for sows kept in crates was examined. The extracted features were used as input variables in an SVM classification method to estimate posture. The possibility of using a posture prediction model with images not necessarily obtained under the same conditions as those used for the training set was explored. As a reference case, the efficacy of the posture prediction model was explored when training and testing datasets were built using the same pool of images. In this case, all the models produced satisfactory results, with a maximum f1-score of 97.7% with CNNs and 93.3% with segmentation. To evaluate the impact of environmental variations, the models were trained and tested on different monitoring days. In this case, the best f1-score dropped to 86.7%. The impact of using the posture prediction model on animals that were not present in the training dataset was then explored. The best f1-score reduced to 63.4% when the posture prediction models were trained on one animal and tested on 11 other different animals. Conversely, when the models were tested on one animal and trained on the 11 others, the f1-score only decreased to 86% with the best model. On average, a decrease of around 17% caused by environmental and individual variations between training and testing was observed.; Nous avons comparé l’utilisation des CNN et de la segmentation pour extraire des caractéristiques d’intérêts dans les images (features), afin de prédire la posture de truies allaitantes. Une fois extraite, les features peuvent être utilisées comme variable d’entrée d’une méthode de classification, de type SVM, pour prédire la posture de la truie. Nous avons exploré l’impact de l’ensemble d’apprentissage sur la qualité de la prédiction, notamment lorsque l’ensemble d’apprentissage et de test ne sont pas obtenues dans les mêmes conditions. Nous avons d’abord considéré un cas de référence, où la méthode d’estimation de la posture était entrainée et testée sur des images prises dans les mêmes conditions. Dans ce cas, tous les modèles testés ont fournis des résultats satisfaisants, avec un f1-score de 97.7% pour le meilleur CNN et de 93.3% pour la méthode basée sur la segmentation d’images. Pour évaluer l’impact des changements environnementaux lors de la prise de vue des images, nous avons ensuite entrainé et testé les modèles sur des images provenants de deux jours différents. Dans ce cas, le meilleur f1-score est réduit à 86.7%. Enfin, nous avons considéré le cas où des animaux présent dans l’ensemble test, ne le sont pas dans l’ensemble d’apprentissage. Lorsque le modèle de prediction de posture est entrainé sur une truie, et testé sur les 11 truies, le meilleur f1-score obtenu est de 63.4%. Lorsque le modèle est entrainé sur 11 truies et testé sur 1 truie, le f1-score est de 86%. En moyenne, nous avons observé que les variations environnementales et individuelles faisaient baisser le f1-score de 17%.

International audience; Deciphering the molecular architecture of coat coloration for a better understanding of the biological mechanisms underlying pigmentation still remains a challenge. We took advantage of a rabbit French experimental population in which both a pattern and a gradient of coloration from white to brown segregated within the himalayan phenotype. The whole experimental design was genotyped using the high density Affymetrix® AxiomOrcun™ SNP Array and phenotyped into 6 different groups ordered from the lighter to the darker. Genome-wide association analyses pinpointed an oligogenic determinism, under recessive and additive inheritance, involving genes already known in melanogenesis (ASIP, KIT, MC1R, TYR), and likely processed pseudogenes linked to ribosomal function, RPS20 and RPS14. We also identified (i) gene-gene interactions through ASIP:MC1R affecting light cream/beige phenotypes while KIT:RPS responsible of dark chocolate/brown colors and (ii) a genome-wide epistatic network involving several others coloration genes such as POT1 or HPS5. Finally, we determined the recessive inheritance of the English spotting phenotype likely involving a copy number variation affecting at least the end of the coding sequence of the KIT gene. Our analyses of coloration as a continuous trait allowed us to go beyond much of the established knowledge through the detection of additional genes and gene-gene interactions that may contribute to the molecular architecture of the coloration phenotype.

Background Most genomic predictions use a unique population that is split into a training and a validation set. However, genomic prediction using genetically heterogeneous training sets could provide more flexibility when constructing the training sets in small populations. The aim of our study was to investigate the potential of genomic prediction of feed efficiency related traits using training sets that combine animals from two different, but genetically-related lines. We compared realized prediction accuracy and prediction bias for different training set compositions for five production traits. Results Genomic breeding values (GEBV) were predicted using the single-step genomic best linear unbiased prediction method in six scenarios applied iteratively to two genetically-related lines (i.e. 12 scenarios). The objective for all scenarios was to predict GEBV of pigs in the last three generations (~ 400 pigs, G7 to G9) of a given line. For each line, a control scenario was set up with a training set that included only animals from that line (target line). For all traits, adding more animals from the other line to the training set did not increase prediction accuracy compared to the control scenario. A small decrease in prediction accuracies was found for average daily gain, backfat thickness, and daily feed intake as the number of animals from the target line decreased in the training set. Including more animals from the other line did not decrease prediction accuracy for feed conversion ratio and residual feed intake, which were both highly affected by selection within lines. However, prediction biases were systematic for these cases and might be reduced with bivariate analyses. Conclusions Our results show that genomic prediction using a training set that includes animals from genetically-related lines can be as accurate as genomic prediction using a training set from the target population. With combined reference sets, accuracy increased for traits that were highly affected by selection. Our results provide insights into the design of reference populations, especially to initiate genomic selection in small-sized lines, for which the number of historical samples is small and that are developed simultaneously. This applies especially to poultry and pig breeding and to other crossbreeding schemes.

Background Feed efficiency is a major driver of the sustainability of pig production systems. Understanding the biological mechanisms that underlie these agronomic traits is an important issue for environment questions and farms' economy. This study aimed at identifying genomic regions that affect residual feed intake (RFI) and other production traits in two pig lines divergently selected for RFI during nine generations (LRFI, low RFI; HRFI, high RFI). Results We built a whole dataset of 570,447 single nucleotide polymorphisms (SNPs) in 2426 pigs with records for 24 production traits after both imputation and prediction of genotypes using pedigree information. Genome-wide association studies (GWAS) were performed including both lines (global-GWAS) or each line independently (LRFI-GWAS and HRFI-GWAS). Forty-five chromosomal regions were detected in the global-GWAS, whereas 28 and 42 regions were detected in the HRFI-GWAS and LRFI-GWAS, respectively. Among these 45 regions, only 13 were shared between at least two analyses, and only one was common between the three GWAS but it affects different traits. Among the five quantitative trait loci (QTL) detected for RFI, two were close to QTL for meat quality traits and two pinpointed novel genomic regions that harbor candidate genes involved in cell proliferation and differentiation processes of gastrointestinal tissues or in lipid metabolism-related signaling pathways. In most cases, different QTL regions were detected between the three designs, which suggests a strong impact of the dataset structure on the detection power and could be due to the changes in allelic frequencies during the establishment of lines. Conclusions In addition to efficiently detecting known and new QTL regions for feed efficiency, the combination of GWAS carried out per line or simultaneously using all individuals highlighted chromosomal regions that affect production traits and presented significant changes in allelic frequencies across generations. Further analyses are needed to estimate whether these regions correspond to traces of selection or result from genetic drift. Supplementary Information The online version contains supplementary material available at 10.1186/s12711-021-00642-1.

Deciphering the molecular architecture of coat coloration for a better understanding of the biological mechanisms underlying pigmentation still remains a challenge. We took advantage of a rabbit French experimental population in which both a pattern and a gradient of coloration from white to brown segregated within the himalayan phenotype. The whole experimental design was genotyped using the high density Affymetrix® AxiomOrcun™ SNP Array and phenotyped into 6 different groups ordered from the lighter to the darker. Genome-wide association analyses pinpointed an oligogenic determinism, under recessive and additive inheritance, involving genes already known in melanogenesis (ASIP, KIT, MC1R, TYR), and likely processed pseudogenes linked to ribosomal function, RPS20 and RPS14. We also identified (i) gene-gene interactions through ASIP:MC1R affecting light cream/beige phenotypes while KIT:RPS responsible of dark chocolate/brown colors and (ii) a genome-wide epistatic network involving several others coloration genes such as POT1 or HPS5. Finally, we determined the recessive inheritance of the English spotting phenotype likely involving a copy number variation affecting at least the end of the coding sequence of the KIT gene. Our analyses of coloration as a continuous trait allowed us to go beyond much of the established knowledge through the detection of additional genes and gene-gene interactions that may contribute to the molecular architecture of the coloration phenotype. Moreover, the characterization of a network including genes that contribute to melanogenesis and pigmentation, two processes affected in various human disorders, shows the potential interest of our rabbit model for transversal studies.

Understanding the molecular mechanism of coloration has been the goal of many genetic and evolutionary studies in a broad number of species. Nevertheless, most of our current knowledge is restricted to colour traits exhibiting relatively simple discrete variation and inheritance patterns. More than a hundred of genes are involved in coloration traits in rodents and many mutations have been identified. In the European rabbit (Oryctolagus cuniculus), different coat colours have been selected through domestication and are nowadays fixed in specific breeds. Although numerous mutations affecting coat colour have been discovered in various rabbit breeds, additional variants have still to be identified. Despite the evolution of technologies through the genomics era, understanding the molecular architecture of such complex phenotypes still remains a challenge. Here, we propose a genome-wide investigation of coat colour using rabbit high-density SNP array. We performed genome-wide association studies (GWAS) considering the variation of coat colour as quantitative and binary phenotypes. We identified several significant SNPs marking loci already known to affect coat colour as well as in a few other chromosome regions not yet described to affect this phenotype in rabbits (e.g. a genomic region on chromosome 14). Moreover, we determined the best model of inheritance for each region associated to coat colour. Our results bring new insights into the molecular architecture of the coloration phenotype pinpointing its oligogenic determinism.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Nearly three-quarters of the 143 genetic signals associated with platelet and erythrocyte phenotypes identified by meta-analyses of genome-wide association (GWA) studies are located at non-protein-coding regions. Here, we assessed the role of candidate regulatory variants associated with cell type-restricted, closely related hematological quantitative traits in biologically relevant hematopoietic cell types. We used formaldehyde-assisted isolation of regulatory elements followed by next-generation sequencing (FAIRE-seq) to map regions of open chromatin in three primary human blood cells of the myeloid lineage. In the precursors of platelets and erythrocytes, as well as in monocytes, we found that open chromatin signatures reflect the corresponding hematopoietic lineages of the studied cell types and associate with the cell type-specific gene expression patterns. Dependent on their signal strength, open chromatin regions showed correlation with promoter and enhancer histone marks, distance to the transcription start site, and ontology classes of nearby genes. Cell type-restricted regions of open chromatin were enriched in sequence variants associated with hematological indices. The majority (63.6%) of such candidate functional variants at platelet quantitative trait loci (QTLs) coincided with binding sites of five transcription factors key in regulating megakaryopoiesis. We experimentally tested 13 candidate regulatory variants at 10 platelet QTLs and found that 10 (76.9%) affected protein binding, suggesting that this is a frequent mechanism by which regulatory variants influence quantitative trait levels. Our findings demonstrate that combining large-scale GWA data with open chromatin profiles of relevant cell types can be a powerful means of dissecting the genetic architecture of closely related quantitative traits. Marie-Curie Initial Training Network NETSIM British Heart Foundation RG/09/12/28096 National Institutes for Health RP-PG-0310-1002 Wellcome Trust 098051 info:eu-repo/grantAgreement/EC/FP7/282510

Background Environmental exposures, for instance to chemicals, are known to impact plant and animal phenotypes on the long term, sometimes across several generations. Such transgenerational phenotypes were shown to be promoted by epigenetic alterations such as DNA methylation, an epigenetic mark involved in the regulation of gene expression. However, it is yet unknown whether transgenerational epigenetic inheritance of altered phenotypes exists in birds. The purpose of this study was to develop an avian model to investigate whether changes to the embryonic environment had a transgenerational effect that could alter the phenotypes of third-generation offspring. Given its impact on the mammalian epigenome and the reproductive system in birds, genistein was used as an environment stressor. Results We compared several third-generation phenotypes of two quail “epilines”, which were obtained from genistein-injected eggs (Epi+) or from untreated eggs (Epi−) from the same founders. A “mirrored” crossing strategy was used to minimize between-line genetic variability by maintaining similar ancestor contributions across generations in each line. Three generations after genistein treatment, a significant difference in the sexual maturity of the females, which, after three generations, could not be attributed to direct maternal effects, was observed between the lines, with Epi+ females starting to lay eggs later. Adult body weight was significantly affected by genistein treatment applied in a previous generation, and a significant interaction between line and sex was observed for body weight at 3 weeks. Behavioral traits, such as evaluating the birds’ reaction to social isolation, were also significantly affected by genistein treatment. Yet, global methylation analyses revealed no significant difference between the epilines. Conclusions These findings demonstrate that embryonic environment affects the phenotype of offspring three generations later in quail. While one cannot rule out the existence of some initial genetic variability between the lines, the mirrored animal design should have minimized its effects, and thus, the observed differences in animals of the third generation may be attributed, at least partly, to transgenerational epigenetic phenomena. Electronic supplementary material The online version of this article (doi:10.1186/s12711-017-0292-7) contains supplementary material, which is available to authorized users.

Aims Recent genome-wide association studies (GWAS) and previous approaches have identified many genetic variants associated with type 2 diabetes (T2D) in populations of European descent, but their contribution in Arab populations from North Africa is unknown. Our study aimed to validate these markers and to assess their combined effects, using large case-control studies of Moroccan and Tunisian individuals. Methods Overall, 44 polymorphisms, located at 37 validated European loci, were first analyzed in 1055 normoglycaemic controls and 1193 T2D cases from Morocco. Associations and trends were then assessed in 942 normoglycaemic controls and 1446 T2D cases from Tunisia. Finally, their ability to discriminate cases from controls was evaluated. Results Carrying a genetic variant in BCL11A , ADAMTS9 , IGF2BP2 , WFS1 , CDKAL1 , TP53INP1 , CDKN2A/B , TCF7L2 , KCNQ1 , HNF1A , FTO , MC4R and GCK increased the risk of T2D when assessing the Moroccan and Tunisian samples together. Each additional risk allele increased the susceptibility for developing the disease by 12% ( P =9.0×10 −9 ). Genotype information for 13 polymorphisms slightly improved the classification of North Africans with and without T2D, as assessed by clinical parameters, with an increase in the area under the receiver operating characteristic curve from 0.64 to 0.67 ( P =0.004). Conclusion In addition to TCF7L2 , 12 additional loci were found to be shared between Europeans and North African Arabs. As for Europeans, the reliability of genetic testing based on these markers to determine the risk for T2D is low. More genome-wide studies, including next-generation sequencing, in North African populations are needed to identify the genetic variants responsible for ethnic disparities in T2D susceptibility.

Twenty-four single-nucleotide polymorphisms (SNPs) have been reproducibly associated with obesity. We performed a follow-up study for obesity in the Greek adult population. A total of 510 obese and 469 lean adults were genotyped for 24 SNPs. We tested the association with obesity status using logistic regression and we evaluated the combined genetic risk of 24 SNPs by calculating the area under the receiver-operating characteristic (ROC) curves. We nominally replicated the association with obesity (BMI ≥30 kg/m(2)) of six SNPs in or near the FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 loci (1.28 ≤ odds ratio (OR) ≤ 1.35; 0.004 ≤ P ≤ 0.043). The discrimination ability for obesity was slightly stronger (P = 9.59 × 10(-6)) when the genetic information of the 24 SNPs was added to nongenetic risk factors (area under the curve (AUC) = 0.722) in comparison with nongenetic factors analyzed alone (AUC = 0.685). Our data suggest that SNPs in or near the FTO, MC4R, TMEM18, PRL, AIF1, and PCSK1 loci contribute to obesity risk in the Greek population.

Long-term function of kidney allografts depends on multiple variables, one of which may be the compatibility in size between the graft and the recipient. Here, we assessed the long-term consequences of the ratio of the weight of the kidney to the weight of the recipient (KwRw ratio) in a multicenter cohort of 1189 patients who received a transplant between 1995 and 2006. The graft filtration rate increased by a mean of 5.74 ml/min between the third and sixth posttransplantation months among patients with a low KwRw ratio (

OBJECTIVE A1C is widely considered the gold standard for monitoring effective blood glucose levels. Recently, a genome-wide association study reported an association between A1C and rs7072268 within HK1 (encoding hexokinase 1), which catalyzes the first step of glycolysis. HK1 deficiency in erythrocytes (red blood cells [RBCs]) causes severe nonspherocytic hemolytic anemia in both humans and mice. RESEARCH DESIGN AND METHODS The contribution of rs7072268 to A1C and the RBC-related traits was assessed in 6,953 nondiabetic European participants. We additionally analyzed the association with hematologic traits in 5,229 nondiabetic European individuals (in whom A1C was not measured) and 1,924 diabetic patients. Glucose control–related markers other than A1C were analyzed in 18,694 nondiabetic European individuals. A type 2 diabetes case-control study included 7,447 French diabetic patients. RESULTS Our study confirms a strong association between the rs7072268–T allele and increased A1C (β = 0.029%; P = 2.22 × 10−7). Surprisingly, despite adequate study power, rs7072268 showed no association with any other markers of glucose control (fasting- and 2-h post-OGTT–related parameters, n = 18,694). In contrast, rs7072268–T allele decreases hemoglobin levels (n = 13,416; β = −0.054 g/dl; P = 3.74 × 10−6) and hematocrit (n = 11,492; β = −0.13%; P = 2.26 × 10−4), suggesting a proanemic effect. The T allele also increases risk for anemia (836 cases; odds ratio 1.13; P = 0.018). CONCLUSIONS HK1 variation, although strongly associated with A1C, does not seem to be involved in blood glucose control. Since HK1 rs7072268 is associated with reduced hemoglobin levels and favors anemia, we propose that HK1 may influence A1C levels through its anemic effect or its effect on glucose metabolism in RBCs. These findings may have implications for type 2 diabetes diagnosis and clinical management because anemia is a frequent complication of the diabetes state.

Common diseases such as type 2 diabetes are phenotypically heterogeneous. Obesity is a major risk factor for type 2 diabetes, but patients vary appreciably in body mass index. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI, Author Summary Individuals with Type 2 diabetes (T2D) can present with variable clinical characteristics. It is well known that obesity is a major risk factor for type 2 diabetes, yet patients can vary considerably—there are many lean diabetes patients and many overweight people without diabetes. We hypothesized that the genetic predisposition to the disease may be different in lean (BMI

Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far.We used a genome-wide association study initially conducted in 631 French children followed by a replication in three additional European sample sets and we identified a common single nucleotide polymorphism (SNP), rs2000999 located in the Haptoglobin gene (HP) as a strong genetic predictor of circulating Haptoglobin levels (P(overall) = 8.1 × 10(-59)), explaining 45.4% of its genetic variability (11.8% of Hp global variance). The functional relevance of rs2000999 was further demonstrated by its specific association with HP mRNA levels (β = 0.23 ± 0.08, P = 0.007). Finally, SNP rs2000999 was associated with decreased total and low-density lipoprotein cholesterol in 8,789 European children (P(total cholesterol) = 0.002 and P(LDL) = 0.0008).Given the central position of haptoglobin in many inflammation-related metabolic pathways, the relevance of rs2000999 genotyping when evaluating haptoglobin concentration should be further investigated in order to improve its diagnostic/therapeutic and/or prevention impact.

A recent study suggested that four CD36 polymorphisms (namely rs3211867, rs3211883, rs3211908, and rs1527483) were associated with an increased risk of obesity, an increased BMI and percentage of body fat in European adolescents. We first attempted to confirm these results in three independent case-control genome-wide association studies (GWAS) data totaling 3,509 subjects of French and German origin, but we were unable to find any association of these variants with early onset obesity risk. We then genotyped the four CD36 single-nucleotide polymorphisms (SNPs) in a large population-based study of 4,667 Finnish subjects and we did not replicate any of the recently reported associations with BMI. By combining all available data in a meta-analysis (N = 9,973), we found no evidence for an association of the reported four variants in CD36 with increased obesity risk or increased BMI (0.07 ≤ P values ≤ 0.93). Finally, we assessed the contribution of the full CD36 locus gene variation to obesity risk in 3,509 subjects and we did not detect any significant association with obesity after correction for multiple testing. In summary, we were unable to confirm the recently reported association of variants in CD36 with early onset obesity in populations of European ancestry.

Introduction L’efficacite de la chirurgie bariatrique depend de la perte de poids obtenue a terme, mais aussi de l’amelioration ou la « disparition » apparente de comorbidites telles que le diabete de type 2 et de la survenue de complications. Les causes des echecs de la chirurgie sont peu connues, et il a ete recemment propose que des facteurs genetiques puissent en influencer les resultats. Si les mutations non-synonymes pertes de fonction du recepteur 4 aux melanocortines (MC4R) sont les plus frequentes causes d’obesite monogenique, deux variants gain-de-fonction protecteurs contre l’obesite ont aussi ete decrits. Patients et Methodes 2 199 patients obeses suisses operes par chirurgie bariatrique ont ete suivis pendant 6 ans. Les donnees cliniques et de comportement alimentaire ont ete collectees a l’inclusion. L’evolution de la corpulence et des comorbidites, l’apparition de complications et la necessite de reoperation ont ete collectees tous les ans. Les sujets ont ete repartis en 3 groupes suivant leur genotype pour MC4R : porteur d’une mutation perte de fonction (N = 24), d’un variant gain-de-fonction (N = 70), ou controle (N = 1 301). Resultats A l’inclusion, les patients porteurs d’une mutation sont significativement plus jeunes (-5 ans, p = 0,02) et plus obeses (+5,5 kg/m2, p = 3,4 × 10-5). Ils sont plus frequemment « binge eaters » (p = 0,007) et sont plus souvent operes par diversion bilio-pancreatique. Au bout de 6 ans, leur IMC est toujours plus eleve (35,0 vs.31,4 kg/m2, p = 6,5 × 10-3) meme si ils ont perdu un peu plus de poids (p = 0,04). La corpulence des porteurs d’un variant gain-de-fonction est similaire aux controles. Par contre, ils sont plus souvent « binge eaters » (p = 0,007) et moins « sweet eaters » (mangent moins de sucre) (p = 0,014) et necessitent plus de reoperations (3 × 10-4). Conclusion Cette etude montre que les sujets porteurs de mutations de MC4R se distinguent des autres sujets obeses face a la chirurgie bariatrique avec une obesite plus precoce et plus severe et des resultats insuffisants 6 ans apres l’operation. On peut s’interroger sur l’interet de recommander l’inclusion du genotypage MC4R pour une meilleure prise en charge chirurgicale et post chirurgicale des obeses morbides.

Master

Platelets are the second most abundant cell type in blood and are essential for maintaining haemostasis. Their count and volume are tightly controlled within narrow physiological ranges, but there is only limited understanding of the molecular processes controlling both traits. Here we carried out a high-powered meta-analysis of genome-wide association studies (GWAS) in up to 66,867 individuals of European ancestry, followed by extensive biological and functional assessment. We identified 68 genomic loci reliably associated with platelet count and volume mapping to established and putative novel regulators of megakaryopoiesis and platelet formation. These genes show megakaryocyte-specific gene expression patterns and extensive network connectivity. Using gene silencing in Danio rerio and Drosophila melanogaster, we identified 11 of the genes as novel regulators of blood cell formation. Taken together, our findings advance understanding of novel gene functions controlling fate-determining events during megakaryopoiesis and platelet formation, providing a new example of successful translation of GWAS to function. © 2011 Macmillan Publishers Limited. All rights reserved.