The adaptative function of melanin-based colour variants

Résumé : Les mécanismes de contrôle des couleurs mélaniques chez les vertébrés sont encore discutés parmi les biologistes de l'évolution. Une hypothèse récente affirme que les effets pléiotropies du système des mélanocortines expliquent l'association fréquente entre la coloration eumélanique noire (due à la déposition d'eumélanine) et de nombreux traits physiologiques et comportementaux. De nombreuses études suggèrent, en effet, que des niveaux plus élevés des mélanocortines induisent l'assombrissement des téguments eumélaniques et affectent d'autres traits phénotypiques simultanément. Cependant, il n'est pas encore établi si ce mécanisme de pléiotropie peut s'appliquer aux colorations dues à la déposition de phaeomélanine, une autre forme commune de mélanine. Les antagonistes des mélanocortines déclenchent le phaeomélanogenèse et bloquent l'effet des mélanocortines ou ont un effet pharmacologique opposé. Nous nous proposons donc d'évaluer l'hypothèse que les effets pléiotropes des antagonistes des mélanocortines génèrent des covariations entre la coloration phaeomélanique et des aspects de la qualité individuelle. Comme prédit par cette hypothèse, nous constatons chez la chouette effraie (Tyto alba) que les traits phénotypiques (résistance au stress oxydatif et aux parasites) corrèlent positivement au degré d'expression d'une couleur eumélanique mais négativement au degré d'expression d'une coloration phaeomélanique. Puis, nous montrons chez la chouette hulotte (Strix aluco) que les associations génétiques entre la coloration phaeomélanique et la physiologie (immunité et la régulation de l'homéostasie) confèrent des avantages aux individus de différentes couleurs dans différents environnements caractérisés par l'abondance de nourriture et le niveau d'exposition aux parasites. Ainsi, nos études soutiennent l'hypothèse que les effets pléiotropes des antagonistes des mélanocortines génèrent des covariations entre les traits mélaniques et divers aspects de la qualité individuelle. Finalement, nous montrons chez le faucon crécerelle (Falco Tinnunculus) que l'expression des ornements mélaniques est sensible à la qualité de l'environnement dans lequel les individus grandissent. Ceci suggère que les gènes codant pour les mélanocortines et leurs antagonistes pourraient induire une expression des traits mélaniques dépendante de la condition de l'individu, un pattern d'expression rarement observé pour des traits généralement sous fort contrôle génétique. Summary : The information content and control mechanisms of melanin-based colour signals in vertebrates are still debated among evolutionary biologists. A recent hypothesis contends that pleiotropic effects of the melanocortin system accounts for the frequent association between black eumelanic coloration and physiological and behavioural traits. Accordingly, empirical evidence suggests that higher levels of melanocortins concurrently promote darker eumelanic integuments and affect other phenotypic traits. However, whether this mechanism may apply to signals relying on phaeomelanin, another common form of melanin pigments, remains to be established. Melanocortin antagonists trigger phaeomelanogenesis and block the effect of melanocortins or result in the opposite pharmacological effect. Therefore, we tested the hypothesis that pleiotropic effects of melanocortin antagonists and inverse agonists account for covariations between phaeomelanin-based coloration and aspects of individual quality. As predicted, we found that phenotypic traits (resistance to oxidative stress and parasites) correlated positively with a eumelanic trait and negatively with a phaeomelanic trait in the barn owl (Tyto alba). Then, we showed in the tawny owl (Strix aluco) that genetic associations between phaeomelanin-based coloration and physiology (immunity and regulation of energy homeostasis) confer benefits to differently coloured individuals under different levels of food abundance and parasite exposure. Altogether, our studies support the hypothesis that pleiotropic effects of melanocortins antagonists can indeed account for covariations between phaeomelanin-based traits and aspects of individual quality. Eventually, we show in the Eurasian kestrel (Falco Tinnunculus) that expression of melanin-based ornaments is sensitive to the environment in which individuals grow. This suggests that genes coding for melanocortins and their antagonists can mediate the condition-dependent component of melanin-based traits.

Meta-analysis of gene-level associations for rare variants based on single-variant statistics.

Meta-analysis of genome-wide association studies (GWASs) has led to the discoveries of many common variants associated with complex human diseases. There is a growing recognition that identifying "causal" rare variants also requires large-scale meta-analysis. The fact that association tests with rare variants are performed at the gene level rather than at the variant level poses unprecedented challenges in the meta-analysis. First, different studies may adopt different gene-level tests, so the results are not compatible. Second, gene-level tests require multivariate statistics (i.e., components of the test statistic and their covariance matrix), which are difficult to obtain. To overcome these challenges, we propose to perform gene-level tests for rare variants by combining the results of single-variant analysis (i.e., p values of association tests and effect estimates) from participating studies. This simple strategy is possible because of an insight that multivariate statistics can be recovered from single-variant statistics, together with the correlation matrix of the single-variant test statistics, which can be estimated from one of the participating studies or from a publicly available database. We show both theoretically and numerically that the proposed meta-analysis approach provides accurate control of the type I error and is as powerful as joint analysis of individual participant data. This approach accommodates any disease phenotype and any study design and produces all commonly used gene-level tests. An application to the GWAS summary results of the Genetic Investigation of ANthropometric Traits (GIANT) consortium reveals rare and low-frequency variants associated with human height. The relevant software is freely available.

Independent evolution of hypervariable regions of HIV-1 gp120: V4 as a swarm of N-Linked glycosylation variants

In this study we have characterized intra-patient length polymorphism in V4 by cloning and sequencing a C2-C4 fragment from HIV plasma RNA in patients at different stages of HIV disease. Clonal analysis of clade B, G, and CRF02 isolates during early infection shows extensive intra-patient V4 variability, due to the presence of indel-associated polymorphism. Indels, coupled to amino acid substitution events, affect the number and distribution of potential N-glycosylation sites, resulting in the coexistence, within the same patient, of V4 subsets, each characterized by different sizes, amino acid sequences, and potential N-glycosylation patterns. In contrast, V3 appears to be relatively homogeneous, with similar V3 associated to significantly different V4 within the same clinical specimen. Based on these data, we propose that during early chronic infection V4 is present as a highly divergent quasispecies, enabling the virus to adopt different conformational structures according to immune constrains and other selective pressures

Genome-wide association study to identify common variants associated with brachial circumference: a meta-analysis of 14 cohorts.

Brachial circumference (BC), also known as upper arm or mid arm circumference, can be used as an indicator of muscle mass and fat tissue, which are distributed differently in men and women. Analysis of anthropometric measures of peripheral fat distribution such as BC could help in understanding the complex pathophysiology behind overweight and obesity. The purpose of this study is to identify genetic variants associated with BC through a large-scale genome-wide association scan (GWAS) meta-analysis. We used fixed-effects meta-analysis to synthesise summary results across 14 GWAS discovery and 4 replication cohorts comprising overall 22,376 individuals (12,031 women and 10,345 men) of European ancestry. Individual analyses were carried out for men, women, and combined across sexes using linear regression and an additive genetic model: adjusted for age and adjusted for age and BMI. We prioritised signals for follow-up in two-stages. We did not detect any signals reaching genome-wide significance. The FTO rs9939609 SNP showed nominal evidence for association (p<0.05) in the age-adjusted strata for men and across both sexes. In this first GWAS meta-analysis for BC to date, we have not identified any genome-wide significant signals and do not observe robust association of previously established obesity loci with BC. Large-scale collaborations will be necessary to achieve higher power to detect loci underlying BC.

Infrequent transmission of HIV-1 drug-resistant variants.

Transmission of drug-resistant variants is influenced by several factors, including the prevalence of drug resistance in the population of HIV-1-infected patients, HIV-1 RNA levels and transmission by recently infected patients. In order to evaluate the impact of these factors on the transmission of drug-resistant variants, we have defined the population of potential transmitters and compared their resistance profiles to those of newly infected patients. Sequencing of pol gene was performed in 220 recently infected patients and in 373 chronically infected patients with HIV-1 RNA >1000 copies/ml. Minimal and maximal drug-resistance profiles of potential transmitters were estimated by weighting resistance profiles of chronically infected patients with estimates of the Swiss HIV-1-infected population, the prevalence of exposure to antiviral drugs and the proportion of infections attributed to primary HIV infections. The drug-resistance prevalence in recently infected patients was 10.5% (one class drug resistance: 9.1%; two classes: 1.4%; three classes: 0%). Phylogenetic analysis revealed significant clustering for 30% of recent infections. The drug-resistance prevalence in chronically infected patients was 72.4% (one class: 29%; two classes: 27.6%; three classes: 15.8%). After adjustment, the risk of transmission relative to wild-type was reduced both for one class drug resistance (minimal and maximal estimates: odds ratio: 0.39, P<0.001; and odds ratio: 0.55, P=0.011, respectively), and for two to three class drug resistance (odds ratios: 0.05 and 0.07, respectively, P<0.001). Neither sexual behaviour nor HIV-1 RNA levels explained the low transmission of drug-resistant variants. These data suggest that drug-resistant variants and in particular multidrug-resistant variants have a substantially reduced transmission capacity.

Use of transgenic mice for the characterization of human alpha 1-acid glycoprotein (orosomucoid) variants.

Sera from transgenic mice (TM) carrying human genes of alpha 1-acid glycoprotein (orosomucoid or ORM) have been analyzed by isoelectrofocusing and subsequent immunoblotting with antihuman ORM antibodies. With this technique it is possible to reveal selectively the human protein secreted in the TM sera. Orosomucoid bands present in TM sera have been compared with those of the most common human ORM phenotypes to correlate the products of specific genes to previously identified genetic variants. In this paper, we report the identification of the genes encoding for variants ORM1 F1 and ORM2 A, which are genes AGP-A and AGP-B/B' respectively. The nucleotide sequences of these genes are known; therefore a direct correlation between variants and specific amino acid sequences can be established.

Monophyly of beta-tubulin and H+-ATPase gene variants in Glomus intraradices: consequences for molecular evolutionary studies of AM fungal genes.

Arbuscular mycorrhizal fungi (AMF) are an ecologically important group of fungi. Previous studies showed the presence of divergent copies of beta-tubulin and V-type vacuolar H+-ATPase genes in AMF genomes and suggested horizontal gene transfer from host plants or mycoparasites to AMF. We sequenced these genes from DNA isolated from an in vitro cultured isolate of Glomus intraradices that was free of any obvious contaminants. We found two highly variable beta-tubulin sequences and variable H+-ATPase sequences. Despite this high variation, comparison of the sequences with those in gene banks supported a glomeromycotan origin of G. intraradices beta-tubulin and H+-ATPase sequences. Thus, our results are in sharp contrast with the previously reported polyphyletic origin of those genes. We present evidence that some highly divergent sequences of beta-tubulin and H+-ATPase deposited in the databases are likely to be contaminants. We therefore reject the prediction of horizontal transfer to AMF genomes. High differences in GC content between glomeromycotan sequences and sequences grouping in other lineages are shown and we suggest they can be used as an indicator to detect such contaminants. H+-ATPase phylogeny gave unexpected results and failed to resolve fungi as a natural group. beta-Tubulin phylogeny supported Glomeromeromycota as sister group of the Chytridiomycota. Contrasts between our results and trees previously generated using rDNA sequences are discussed.

Identification and validation of copy number variants using SNP genotyping arrays from a large clinical cohort.

BACKGROUND: Genotypes obtained with commercial SNP arrays have been extensively used in many large case-control or population-based cohorts for SNP-based genome-wide association studies for a multitude of traits. Yet, these genotypes capture only a small fraction of the variance of the studied traits. Genomic structural variants (GSV) such as Copy Number Variation (CNV) may account for part of the missing heritability, but their comprehensive detection requires either next-generation arrays or sequencing. Sophisticated algorithms that infer CNVs by combining the intensities from SNP-probes for the two alleles can already be used to extract a partial view of such GSV from existing data sets. RESULTS: Here we present several advances to facilitate the latter approach. First, we introduce a novel CNV detection method based on a Gaussian Mixture Model. Second, we propose a new algorithm, PCA merge, for combining copy-number profiles from many individuals into consensus regions. We applied both our new methods as well as existing ones to data from 5612 individuals from the CoLaus study who were genotyped on Affymetrix 500K arrays. We developed a number of procedures in order to evaluate the performance of the different methods. This includes comparison with previously published CNVs as well as using a replication sample of 239 individuals, genotyped with Illumina 550K arrays. We also established a new evaluation procedure that employs the fact that related individuals are expected to share their CNVs more frequently than randomly selected individuals. The ability to detect both rare and common CNVs provides a valuable resource that will facilitate association studies exploring potential phenotypic associations with CNVs. CONCLUSION: Our new methodologies for CNV detection and their evaluation will help in extracting additional information from the large amount of SNP-genotyping data on various cohorts and use this to explore structural variants and their impact on complex traits.

Variants : The Journal of the European Society for Textual Scholarship

This volume is the 10th issue of Variants . In keeping with the mission of the European Society for Textual Scholarship, the articles are richly interdisciplinary and transnational. They bring to bear a wide range of topics and disciplines on the field of textual scholarship: historical linguistics, digital scholarly editing, classical philology, Dutch, English, Finnish and Swedish Literature, publishing traditions in Japan, book history, cultural history and folklore. The questions that are explored - what texts are worth editing? what is the nature of the relationship between text, work, document and book? what is a critical digital edition? - all return to fundamental issues that have been at the heart of the editorial discipline for decades. With refreshing insight they assess the increasingly hybrid nature of the theoretical considerations and practical methodologies employed by textual scholars, while reasserting the relevance and need for producing scholarly editions, whether in print or digital, and continuing advanced research in bibliographical codes, textual transmissions, genetic dossiers, the fluidity of texts and other such subjects that connect textual scholarship with broader investigations into our nations' literary culture and written heritage.

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis.

Common variants near MC4R are associated with fat mass, weight and risk of obesity.

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.

Evolutionary analysis of genetic variants involved in rare diseases

Next-generation sequencing techniques such as exome sequencing can successfully detect all genetic variants in a human exome and it has been useful together with the implementation of variant filters to identify causing-disease mutations. Two filters aremainly used for the mutations identification: low allele frequency and the computational annotation of the genetic variant. Bioinformatic tools to predict the effect of a givenvariant may have errors due to the existing bias in databases and sometimes show a limited coincidence among them. Advances in functional and comparative genomics are needed in order to properly annotate these variants.The goal of this study is to: first, functionally annotate Common Variable Immunodeficiency disease (CVID) variants with the available bioinformatic methods in order to assess the reliability of these strategies. Sencondly, as the development of new methods to reduce the number of candidate genetic variants is an active and necessary field of research, we are exploring the utility of gene function information at organism level as a filter for rare disease genes identification. Recently, it has been proposed that only 10-15% of human genes are essential and therefore we would expect that severe rare diseases are mostly caused by mutations on them. Our goal is to determine whether or not these rare and severe diseases are caused by deleterious mutations in these essential genes. If this hypothesis were true, taking into account essential genes as a filter would be an interesting parameter to identify causingdisease mutations.

Association of bGH and Pit-1 gene variants with milk production traits in dairy Gyr bulls

The objective of this study was to obtain genetic marker information in the Gyr breed by analyzing bGH and Pit-1 gene polymorphisms and to verify their association with milk production traits. One sample including 40 Gyr bulls were genotyped at two bGH gene restriction sites (bGH- AluI and bGH-MspI) and at one restriction site in the Pit-1 gene (Pit-1 HinfI). The bGH-MspI(-) allele was favorable for fat milk percentage. The heterozigous Pit-1 HinfI (+/-) bulls were superior for fat milk production, in relation to homozigous Pit-1 HinfI (+/+). The Pit-1 and bGH genes are strong candidates in the dairy cattle QTL search, and zebuine populations are promising samples for this purpose.