A multi-parent recombinant inbred line population of C. elegans allows identification of novel QTLs for complex life history traits

Background The nematode Caenorhabditis elegans has been extensively used to explore the relationships between complex traits, genotypes, and environments. Complex traits can vary across different genotypes of a species, and the genetic regulators of trait variation can be mapped on the genome using quantitative trait locus (QTL) analysis of recombinant inbred lines (RILs) derived from genetically and phenotypically divergent parents. Most RILs have been derived from crossing two parents from globally distant locations. However, the genetic diversity between local C. elegans populations can be as diverse as between global populations and could thus provide means of identifying genetic variation associated with complex traits relevant on a broader scale. Results To investigate the effect of local genetic variation on heritable traits, we developed a new RIL population derived from 4 parental wild isolates collected from 2 closely located sites in France: Orsay and Santeuil. We crossed these 4 genetically diverse parental isolates to generate a population of 200 multi-parental RILs and used RNA-seq to obtain sequence polymorphisms identifying almost 9000 SNPs variable between the 4 genotypes with an average spacing of 11 kb, doubling the mapping resolution relative to currently available RIL panels for many loci. The SNPs were used to construct a genetic map to facilitate QTL analysis. We measured life history traits such as lifespan, stress resistance, developmental speed, and population growth in different environments, and found substantial variation for most traits. We detected multiple QTLs for most traits, including novel QTLs not found in previous QTL analysis, including those for lifespan and pathogen responses. This shows that recombining genetic variation across C. elegans populations that are in geographical close proximity provides ample variation for QTL mapping. Conclusion Taken together, we show that using more parents than the classical two parental genotypes to construct a RIL population facilitates the detection of QTLs and that the use of wild isolates facilitates the detection of QTLs. The use of multi-parent RIL populations can further enhance our understanding of local adaptation and life history trade-offs

Preference for a prefilled syringe or an auto-injection device for delivering golimumab in patients with moderate-to-severe ulcerative colitis: a randomized crossover study

Séverine Vermeire,1 François D’heygere,2 Antoine Nakad,3 Denis Franchimont,4 Fernand Fontaine,5 Edouard Louis,6 Philippe Van Hootegem,7 Olivier Dewit,8 Guy Lambrecht,9 Beatrijs Strubbe,10 Filip Baert11 1Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium; 2Department of Gastroenterology, AZ Groeninge, Kortrijk, Belgium; 3Department of Gastroenterology, CHWAPI, Tournai, Belgium; 4Department of Gastroenterology, Erasme Hospital, Brussels, Belgium; 5Department of Gastroenterology, CHC St Joseph, Liège, Belgium; 6Department of Gastroenterology, University Hospital CHU Sart Tilman, Liège, Belgium; 7Department of Gastroenterology, AZ St Lucas, Brugge, Belgium; 8Department of Gastroenterology, UCL St Luc, Brussels, Belgium; 9Department of Gastroenterology, AZ Damiaan, Oostende, Belgium; 10Department of Gastroenterology, OLV Hospital, Aalst, Belgium; 11Department of Gastroenterology, AZ Delta, Roeselare-Menen, Belgium Purpose: Simponi® (golimumab, MSD) is a fully human monoclonal antibody against tumor necrosis factor alpha administered subcutaneously using an autoinjector or a prefilled syringe. This study examined preference for administration of golimumab by autoinjector or prefilled syringe in patients with moderate-to-severe ulcerative colitis (UC). Patients and methods: This was a multicenter, open-label, randomized crossover trial (EudraCT no 2014-000656-29). Patients with moderate-to-severe UC were randomized 1:1 to receive 2 subcutaneous injections of 50 mg golimumab with the autoinjector followed by 2 injections of 50 mg with the prefilled syringe or the same 4 injections administered in the opposite order. Patients assessed preference, ease of use, and discomfort immediately after the injections and 2 weeks later. Results: Ninety-one patients were included (median age=42.7 years [range, 19.7–93.7]; 58% male). The autoinjector was preferred by 76.9% of patients immediately after injections and by 71.4% 2 weeks later. The autoinjector was more often considered extremely easy or easy to use (94.5%) than the prefilled syringe (73.6%). Moderate discomfort or worse was reported by more patients when using the prefilled syringe (20.9%) than when using the autoinjector (5.5%), and severe discomfort or discomfort preventing injection of future doses was reported by 8.8% for the prefilled syringe but not at all when using the autoinjector. A favorable or extremely favorable overall impression was reported by 89.0% for the autoinjector and 72.5% for the prefilled syringe. Conclusion: Most patients with moderate-to-severe UC preferred to self-administer golimumab with the autoinjector over a prefilled syringe. Keywords: autoinjector, adherence, anti-TNF, subcutaneous injection, treatment, self-injectio

A multi-parent recombinant inbred line population of C. elegans allows identification of novel QTLs for complex life history traits

The nematode Caenorhabditis elegans has been extensively used to explore the relationships between complex traits, genotypes, and environments. Complex traits can vary across different genotypes of a species, and the genetic regulators of trait variation can be mapped on the genome using quantitative trait locus (QTL) analysis of recombinant inbred lines (RILs) derived from genetically and phenotypically divergent parents. Most RILs have been derived from crossing two parents from globally distant locations. However, the genetic diversity between local C. elegans populations can be as diverse as between global populations and could thus provide means of identifying genetic variation associated with complex traits relevant on a broader scale. To investigate the effect of local genetic variation on heritable traits, we developed a new RIL population derived from 4 parental wild isolates collected from 2 closely located sites in France: Orsay and Santeuil. We crossed these 4 genetically diverse parental isolates to generate a population of 200 multi-parental RILs and used RNA-seq to obtain sequence polymorphisms identifying almost 9000 SNPs variable between the 4 genotypes with an average spacing of 11 kb, doubling the mapping resolution relative to currently available RIL panels for many loci. The SNPs were used to construct a genetic map to facilitate QTL analysis. We measured life history traits such as lifespan, stress resistance, developmental speed, and population growth in different environments, and found substantial variation for most traits. We detected multiple QTLs for most traits, including novel QTLs not found in previous QTL analysis, including those for lifespan and pathogen responses. This shows that recombining genetic variation across C. elegans populations that are in geographical close proximity provides ample variation for QTL mapping. Taken together, we show that using more parents than the classical two parental genotypes to construct a RIL population facilitates the detection of QTLs and that the use of wild isolates facilitates the detection of QTLs. The use of multi-parent RIL populations can further enhance our understanding of local adaptation and life history trade-offs