Over the past several years, more focus has been placed on dissecting the genetic basis of complex diseases and traits through genome-wide association studies. In contrast, Mendelian disorders have received little attention mainly due to the lack of newer and more powerful methods to study these disorders. Linkage studies have previously been the main tool to elucidate the genetics of Mendelian disorders; however, extremely rare disorders or sporadic cases caused by de novo variants are not amendable to this study design. Exome sequencing has now become technically feasible and more cost-effective due to the recent advances in high-throughput sequence capture methods and next-generation sequencing technologies which have offered new opportunities for Mendelian disorder research. Exome sequencing has been swiftly applied to the discovery of new causal variants and candidate genes for a number of Mendelian disorders such as Kabuki syndrome, Miller syndrome and Fowler syndrome. In addition, de novo variants were also identified for sporadic cases, which would have not been possible without exome sequencing. Although exome sequencing has been proven to be a promising approach to study Mendelian disorders, several shortcomings of this method must be noted, such as the inability to capture regulatory or evolutionary conserved sequences in non-coding regions and the incomplete capturing of all exons.

Recent developments in high-throughput sequence capture methods and next-generation sequencing technologies have now made exome sequencing a viable approach to elucidate the genetic basis of Mendelian disorders with hitherto unknown etiology. In addition, exome sequencing is increasingly being employed as a diagnostic tool for specific genetic diseases, particularly in the context of those disorders characterized by significant genetic and phenotypic heterogeneity, for example, Charcot-Marie-Tooth disease and congenital disorders of glycosylation. Such disorders are challenging to interrogate with conventional polymerase chain reaction-Sanger sequencing methods, because of the inherent difficulty in prioritizing candidate genes for diagnostic testing. Here, we explore the value of exome sequencing as a diagnostic tool and discuss whether exome sequencing can come to serve a dual role in diagnosis and discovery. We summarize the current status of exome sequencing, the technical challenges facing it, and its adaptation to diagnostics, and make recommendations for the use of exome sequencing as a routine diagnostic tool. Finally, we discuss pertinent ethical concerns, such as the use of exome sequencing data, originally generated in a diagnostic context, in research investigations.

Evidence from cohort studies and randomized trials suggest beneficial effects of food sources of anthocyanidins (berries) and flavan-3-ols (green tea and cocoa) on cardiovascular health. These findings need to be confirmed in long-term randomized trials, and evaluation of pure compounds will be important to establish what specific flavonoids and doses are effective.

Regions of homozygosity (ROHs) are more abundant in the human genome than previously thought. These regions are without heterozygosity, i.e. all the genetic variations within the regions have two identical alleles. At present there are no standardized criteria for defining the ROHs resulting in the different studies using their own criteria in the analysis of homozygosity. Compared to the era of genotyping microsatellite markers, the advent of high-density single nucleotide polymorphism genotyping arrays has provided an unparalleled opportunity to comprehensively detect these regions in the whole genome in different populations. Several studies have identified ROHs which were associated with complex phenotypes such as schizophrenia, late-onset of Alzheimer's disease and height. Collectively, these studies have conclusively shown the abundance of ROHs larger than 1 Mb in outbred populations. The homozygosity association approach holds great promise in identifying genetic susceptibility loci harboring recessive variants for complex diseases and traits.

In this Asian population with high carbohydrate intake, the total amount of carbohydrates consumed was not substantially associated with IHD mortality. In contrast, the shifting of food sources of carbohydrates toward a higher consumption of fruit, vegetables, and whole grains was associated with lower risk of IHD death.

In the light of the growing involvement of community advisory boards (CABs) in health research, this study presents empirical findings of the functions and operations of CABs in HIV/AIDS vaccine trials in South Africa. The individual and focus group interviews with CAB members, principal investigators, research staff, community educators, recruiters, ethics committee members, trial participants and South African AIDS Vaccine Initiative (SAAVI) staff members demonstrated differences in the respondents' perceptions of the roles and responsibilities of CABs. These findings question the roles of the CABs. Are they primarily there to serve and be accountable to the community, or to serve the accomplishment of the research objectives? Four emergent themes are discussed here: purpose; membership and representation; power and authority; sources of support and independence. The CABs' primary purpose carries significant implications for a wide range of issues regarding their functioning. The dual functions of advancing the research and protecting the community appear to be fraught with tension, and require careful reconsideration. Résumé À la lumière de l'implication croissante des conseils consultatifs communautaires (CAB) dans la recherche dans le domaine de la santé, cette étude présente les résultats empiriques des fonctions et des opérations des CAB dans les essais vaccinaux sur le VIH/ SIDA en Afrique du Sud. Les entretiens individuels et en groupe ont été menés avec les membres des CAB, les principaux chercheurs, le reste du personnel, les éducateurs de la communauté, les recruteurs, les membres du comité d' éthique, les participants aux essais et la South African AIDS Vaccine Initiative (SAAVI). Les auteurs ont mis en évidence les différences de perception des personnes interrogées à propos des rôles et des responsabilités des CAB. Ces conclusions posent la question du rôle de ces derniers. Sont-ils d'abord là pour être au service de la communauté et être responsable devant elle, ou sont-ils là pour permettre d'atteindre les objectifs de l' étude menée ? Quatre thèmes ont été relevés et sont examinés ici : le but du CAB, sa composition et sa représentation, son pouvoir et son autorité, ses soutiens et son indépendance. S'interroger sur le principal objectif des CAB est essentiel car le choix de telle ou telle réponse entraîne des conséquences importantes sur leur mode de fonctionnement. Sa double fonction consistant à la fois à faire progresser la recherche et à protéger la communauté semble entraîner des tensions et ne plus être tenable. Keywords

The advances in next generation sequencing (NGS) technologies have had a significant impact on epigenomic research. The arrival of NGS technologies has enabled a more powerful sequencing based method--that is, ChIP-Seq--to interrogate whole genome histone modifications, improving on the conventional microarray based method (ChIP-chip). Similarly, the first human DNA methylome was mapped using NGS technologies. More importantly, studies of DNA methylation and histone modification using NGS technologies have yielded new discoveries and improved our knowledge of human biology and diseases. The concept that cytosine methylation was restricted to CpG dinucleotides has only been recently challenged by new data generated from sequencing the DNA methylome. Approximately 25% of all cytosine methylation identified in stem cells was in a non-CG context. The non-CG methylation was more enriched in gene bodies and depleted in protein binding sites and enhancers. The recent developments of third generation sequencing technologies have shown promising results of directly sequencing methylated nucleotides and having the ability to differentiate between 5-methylcytosine and 5-hydroxymethylcytosine. The importance of 5-hydroxymethylcytosine remains largely unknown, but it has been found in various tissues. 5-hydroxymethylcytosine was particularly enriched at promoters and in intragenic regions (gene bodies) but was largely absent from non-gene regions in DNA from human brain frontal lobe tissue. The presence of 5-hydroxymethylcytosine in gene bodies was more positively correlated with gene expression levels. The importance of studying 5-methylcytosine and 5-hydroxymethylcytosine separately for their biological roles will become clearer when more efficient methods to distinguish them are available.

BackgroundHigher coffee consumption has been associated with a lower risk of type 2 diabetes in cohort studies, but the physiological pathways through which coffee affects glucose metabolism are not fully understood. The aim of this study was to evaluate the associations between habitual coffee and tea consumption and glucose metabolism in a multi-ethnic Asian population and possible mediation by inflammation.MethodsWe cross-sectionally examined the association between coffee, green tea, black tea and Oolong tea consumption and glycemic (fasting plasma glucose, HOMA-IR, HOMA-beta, plasma HbA1c) and inflammatory (plasma adiponectin and C-reactive protein) markers in a multi-ethnic Asian population (N = 4139).ResultsAfter adjusting for multiple confounders, we observed inverse associations between coffee and HOMA-IR (percent difference: - 8.8% for ≥ 3 cups/day versus rarely or never; Ptrend = 0.007), but no significant associations between coffee and inflammatory markers. Tea consumption was not associated with glycemic markers, but green tea was inversely associated with plasma C-reactive protein concentrations (percent difference: - 12.2% for ≥ 1 cup/day versus < 1 cup/week; Ptrend = 0.042).ConclusionsThese data provide additional evidence for a beneficial effect of habitual caffeinated coffee consumption on insulin sensitivity, and suggest that this effect is unlikely to be mediated by anti-inflammatory mechanisms.