Tryptophan metabolism activation by indoleamine 2,3-dioxygenase in adipose tissue of obese women: an attempt to maintain immune homeostasis and vascular tone

Human obesity is characterized by chronic low-grade inflammation in white adipose tissue and is often associated with hypertension. The potential induction of indoleamine 2,3-dioxygenase-1 (IDO1), the rate-limiting enzyme in tryptophan/kynurenine degradation pathway, by proinflammatory cytokines, could be associated with these disorders but has remained unexplored in obesity. Using immunohistochemistry, we detected IDO1 expression in white adipose tissue of obese patients, and we focused on its contribution in the regulation of vascular tone and on its immunoregulatory effects. Concentrations of tryptophan and kynurenine were measured in sera of 36 obese and 15 lean women. The expression of IDO1 in corresponding omental and subcutaneous adipose tissues and liver was evaluated. Proinflammatory markers and T-cell subsets were analyzed in adipose tissue via the expression of CD14, IL-18, CD68, TNFα, CD3ε, FOXP3 [a regulatory T-cell (Treg) marker] and RORC (a Th17 marker). In obese subjects, the ratio of kynurenine to tryptophan, which reflects IDO1 activation, is higher than in lean subjects. Furthermore, IDO1 expression in both adipose tissues and liver is increased and is inversely correlated with arterial blood pressure. Inflammation is associated with a T-cell infiltration in obese adipose tissue, with predominance of Th17 in the omental compartment and of Treg in the subcutaneous depot. The Th17/Treg balance is decreased in subcutaneous fat and correlates with IDO1 activation. In contrast, in the omental compartment, despite IDO1 activation, the Th17/Treg balance control is impaired. Taken together, our results suggest that IDO1 activation represents a local compensatory mechanism to limit obesity-induced inflammation and hypertension.     

Evaluation of DNA Variants Associated with Androgenetic Alopecia and Their Potential to Predict Male Pattern Baldness

Androgenetic alopecia, known in men as male pattern baldness (MPB), is a very conspicuous condition that is particularly frequent among European men and thus contributes markedly to variation in physical appearance traits amongst Europeans. Recent studies have revealed multiple genes and polymorphisms to be associated with susceptibility to MPB. In this study, 50 candidate SNPs for androgenetic alopecia were analyzed in order to verify their potential to predict MPB. Significant associations were confirmed for 29 SNPs from chromosomes X, 1, 5, 7, 18 and 20. A simple 5-SNP prediction model and an extended 20-SNP model were developed based on a discovery panel of 305 males from various European populations fitting one of two distinct phenotype categories. The first category consisted of men below 50 years of age with significant baldness and the second; men aged 50 years or older lacking baldness. The simple model comprised the five best predictors: rs5919324 near AR, rs1998076 in the 20p11 region, rs929626 in EBF1, rs12565727 in TARDBP and rs756853 in HDAC9. The extended prediction model added 15 SNPs from five genomic regions that improved overall prevalence-adjusted predictive accuracy measured by area under the receiver characteristic operating curve (AUC). Both models were evaluated for predictive accuracy using a test set of 300 males reflecting the general European population. Applying a 65% probability threshold, high prediction sensitivity of 87.1% but low specificity of 42.4% was obtained in men aged <50 years. In men aged ≥50, prediction sensitivity was slightly lower at 67.7% while specificity reached 90%. Overall, the AUC=0.761 calculated for men at or above 50 years of age indicates these SNPs offer considerable potential for the application of genetic tests to predict MPB patterns, adding a highly informative predictive system to the emerging field of forensic analysis of externally visible characteristics.     

Linkage disequilibrium over short physical distances measured in sheep using a high‐density SNP chip

The extent of linkage disequilibrium (LD) between genetic loci has implications for both association studies and the accuracy of genomic prediction. To characterise the persistence of LD in diverse sheep breeds, two SNP genotyping platforms were used. First, existing SNP genotypes from 63 breeds obtained using the ovine SNP50 BeadChip (49 034 loci) were used to estimate LD decay in populations with contrasting levels of genetic diversity. Given the paucity of marker pairs separated by short physical distances on the SNP50 BeadChip, genotyping was subsequently performed for four breeds using the recently developed ovine HD BeadChip that assays approximately 600 000 SNPs with an average genomic spacing of 5 kb. This facilitated a highly accurate estimate of LD over short genomic distances (<30 kb) and revealed LD varies considerably between sheep breeds. Further, sheep appear to contain generally lower levels of LD than do other domestic species, likely a reflection of aspects of their past population history.     

Deleterious- and Disease-Allele Prevalence in Healthy Individuals: Insights from Current Predictions,Mutation Databases,and Population-Scale Resequencing

We have assessed the numbers of potentially deleterious variants in the genomes of apparently healthy humans by using (1) low-coverage whole-genome sequence data from 179 individuals in the 1000 Genomes Pilot Project and (2) current predictions and databases of deleterious variants. Each individual carried 281–515 missense substitutions, 40–85 of which were homozygous, predicted to be highly damaging. They also carried 40–110 variants classified by the Human Gene Mutation Database (HGMD) as disease-causing mutations (DMs), 3–24 variants in the homozygous state, and many polymorphisms putatively associated with disease. Whereas many of these DMs are likely to represent disease-allele-annotation errors, between 0 and 8 DMs (0–1 homozygous) per individual are predicted to be highly damaging, and some of them provide information of medical relevance. These analyses emphasize the need for improved annotation of disease alleles both in mutation databases and in the primary literature; some HGMD mutation data have been recategorized on the basis of the present findings, an iterative process that is both necessary and ongoing. Our estimates of deleterious-allele numbers are likely to be subject to both overcounting and undercounting. However, our current best mean estimates of ∼400 damaging variants and ∼2 bona fide disease mutations per individual are likely to increase rather than decrease as sequencing studies ascertain rare variants more effectively and as additional disease alleles are discovered.     

A high‐density SNP chip for genotyping great tit (Parus major) populations and its application to studying the genetic architecture of exploration behaviour

High‐density SNP microarrays (“SNP chips”) are a rapid, accurate and efficient method for genotyping several hundred thousand polymorphisms in large numbers of individuals. While SNP chips are routinely used in human genetics and in animal and plant breeding, they are less widely used in evolutionary and ecological research. In this article, we describe the development and application of a high‐density Affymetrix Axiom chip with around 500,000 SNPs, designed to perform genomics studies of great tit (Parus major) populations. We demonstrate that the per‐SNP genotype error rate is well below 1% and that the chip can also be used to identify structural or copy number variation. The chip is used to explore the genetic architecture of exploration behaviour (EB), a personality trait that has been widely studied in great tits and other species. No SNPs reached genomewide significance, including at DRD4, a candidate gene. However, EB is heritable and appears to have a polygenic architecture. Researchers developing similar SNP chips may note: (i) SNPs previously typed on alternative platforms are more likely to be converted to working assays; (ii) detecting SNPs by more than one pipeline, and in independent data sets, ensures a high proportion of working assays; (iii) allele frequency ascertainment bias is minimized by performing SNP discovery in individuals from multiple populations; and (iv) samples with the lowest call rates tend to also have the greatest genotyping error rates.     

Training in High-Throughput Sequencing: Common Guidelines to Enable Material Sharing,Dissemination, and Reusability

The advancement of high-throughput sequencing (HTS) technologies and the rapid development of numerous analysis algorithms and pipelines in this field has resulted in an unprecedentedly high demand for training scientists in HTS data analysis. Embarking on developing new training materials is challenging for many reasons. Trainers often do not have prior experience in preparing or delivering such materials and struggle to keep them up to date. A repository of curated HTS training materials would support trainers in materials preparation, reduce the duplication of effort by increasing the usage of existing materials, and allow for the sharing of teaching experience among the HTS trainers’ community. To achieve this, we have developed a strategy for materials’ curation and dissemination. Standards for describing training materials have been proposed and applied to the curation of existing materials. A Git repository has been set up for sharing annotated materials that can now be reused, modified, or incorporated into new courses. This repository uses Git; hence, it is decentralized and self-managed by the community and can be forked/built-upon by all users. The repository is accessible at http://bioinformatics.upsc.se/htmr.     

Genetic and Environmental Contributions to Facial Morphological Variation: A 3D Population-Based Twin Study

IntroductionFacial phenotype is influenced by genes and environment; however, little is known about their relative contributions to normal facial morphology. The aim of this study was to assess the relative genetic and environmental contributions to facial morphological variation using a three-dimensional (3D) population-based approach and the classical twin study design.ResultsHeritability of 13 uPC and 17 sPC reached statistical significance, with h² ranging from 38.8% to 78.5% in the former and 30.5% to 84.8% in the latter group. Also, 1222 distances showed evidence of genetic control. Common environment contributed to one PC in both groups and 53 linear distances (4.3%). Unique environment contributed to 17 uPC and 20 sPC and 1245 distances.ConclusionsGenetic factors can explain more than 70% of the phenotypic facial variation in facial size, nose (width, prominence and height), lips prominence and inter-ocular distance. A few traits have shown potential dominant genetic influence: the prominence and height of the nose, the lower lip prominence in relation to the chin and upper lip philtrum length. Environmental contribution to facial variation seems to be the greatest for the mandibular ramus height and horizontal facial asymmetry.