Current status and future prospects for epigenetic psychopharmacology

Mounting evidence suggest that epigenetic regulation of brain functions is important in the etiology of psychiatric disorders. These epigenetic regulatory mechanisms, such as DNA methylation and histone acetylation, are influenced by many pharmaceutical compounds including psychiatric drugs. It is therefore of interest to investigate how psychiatric drugs are of influence and what the potential is of new epigenetic drugs for psychiatric disorders. With this targeted review we summarize the current state of knowledge in order to provide insight in this developing field. Several traditional psychiatric drugs have been found to alter the epigenome and in a variety of animal studies, experimental compounds with epigenetic targets have been investigated as potential psychiatric drugs. After discussion of the most relevant epigenetic mechanisms we present the evidence for epigenetic effects for the most relevant classes of drugs.     

Socio Economic Position in TB Prevalence and Access to Services: Results from a Population Prevalence Survey and a Facility-Based Survey in Bangladesh

Background

In Bangladesh DOTS has been provided free of charge since 1993, yet information on access to TB services by different population group is not well documented. The objective of this study was to assess and compare the socio economic position (SEP) of actively detected cases from the community and the cases being routinely detected under National Tuberculosis Control Programme (NTP) in Bangladesh.

Methods and Findings

SEP was assessed by validated asset item for each of the 21,427 households included in the national tuberculosis prevalence survey 2007–2009. A principal component analysis generated household scores and categorized in quartiles. The distribution of 33 actively identified cases was compared with the 240 NTP cases over the identical SEP quartiles to evaluate access to TB services by different groups of the population. The population prevalence of tuberculosis was 5 times higher in the lowest quartiles of population (95.4, 95% CI: 48.0–189.7) to highest quartile population (19.5, 95% CI: 6.9–55.0). Among the 33 cases detected during survey, 25 (75.8%) were from lower two quartiles, and the rest 8 (24.3%) were from upper two quartiles. Among TB cases detected passively under NTP, more than half of them 137 (57.1%) were from uppermost two quartiles, 98 (41%) from the second quartile, and 5 (2%) in the lowest quartile of the population. This distribution is not affected when adjusted for other factors or interactions among them.

Conclusions

The findings indicate that despite availability free of charge, DOTS is not equally accessed by the poorer sections of the population. However, these figures should be interpreted with caution since there is a need for additional studies that assess in-depth poverty indicators and its determinants in relation to access of the TB services provided in Bangladesh.     

The imprinted gene DIO3 is a candidate gene for litter size in pigs

Genomic imprinting is an important epigenetic phenomenon, which on the phenotypic level can be detected by the difference between the two heterozygote classes of a gene. Imprinted genes are important in both the development of the placenta and the embryo, and we hypothesized that imprinted genes might be involved in female fertility traits. We therefore performed an association study for imprinted genes related to female fertility traits in two commercial pig populations. For this purpose, 309 SNPs in fifteen evolutionary conserved imprinted regions were genotyped on 689 and 1050 pigs from the two pig populations. A single SNP association study was used to detect additive, dominant and imprinting effects related to four reproduction traits; total number of piglets born, the number of piglets born alive, the total weight of the piglets born and the total weight of the piglets born alive. Several SNPs showed significant (q-value < 0.10) additive and dominant effects and one SNP showed a significant imprinting effect. The SNP with a significant imprinting effect is closely linked to DIO3, a gene involved in thyroid metabolism. The imprinting effect of this SNP explained approximately 1.6% of the phenotypic variance, which corresponded to approximately 15.5% of the additive genetic variance. In the other population, the imprinting effect of this QTL was not significant (q-value > 0.10), but had a similar effect as in the first population. The results of this study indicate a possible association between the imprinted gene DIO3 and female fertility traits in pigs.     

Sex-dependent novelty response in neurexin-1α mutant mice

Neurexin-1 alpha (NRXN1α) belongs to the family of cell adhesion molecules (CAMs), which are involved in the formation of neuronal networks and synapses. NRXN1α gene mutations have been identified in neuropsychiatric diseases including Schizophrenia (SCZ) and Autism Spectrum Disorder (ASD). In order to get a better understanding of the pleiotropic behavioral manifestations caused by NRXN1α gene mutations, we performed a behavioral study of Nrxn1α heterozygous knock-out (+/-) mice and observed increased responsiveness to novelty and accelerated habituation to novel environments compared to wild type (+/+) litter-mates. However, this effect was mainly observed in male mice, strongly suggesting that gender-specific mechanisms play an important role in Nrxn1α-induced phenotypes.     

Whole genome SNP discovery and analysis of genetic diversity in Turkey (Meleagris gallopavo)

ABSTRACT: BACKGROUND: The turkey (Meleagris gallopavo) is an important agricultural species and the second largest contributor to the world's poultry meat production. Genetic improvement is attributed largely to selective breeding programs that rely on highly heritable phenotypic traits, such as body size and breast muscle development. Commercial breeding with small effective population sizes and epistasis can result in loss of genetic diversity, which in turn can lead to reduced individual fitness and reduced response to selection. The presence of genomic diversity in domestic livestock species therefore, is of great importance and a prerequisite for rapid and accurate genetic improvement of selected breeds in various environments, as well as to facilitate rapid adaptation to potential changes in breeding goals. Genomic selection requires a large number of genetic markers such as e.g. single nucleotide polymorphisms (SNPs) the most abundant source of genetic variation within the genome. RESULTS: Alignment of next generation sequencing data of 32 individual turkeys from different populations was used for the discovery of 5.49 million SNPs, which subsequently were used for the analysis of genetic diversity among the different populations. All of the commercial lines branched from a single node relative to the heritage varieties and the South Mexican turkey population. Heterozygosity of all individuals from the different turkey populations ranged from 0.17-2.73 SNPs/Kb, while heterozygosity of populations ranged from 0.73-1.64 SNPs/Kb. The average frequency of heterozygous SNPs in individual turkeys was 1.07 SNPs/Kb. Five genomic regions with very low nucleotide variation were identified in domestic turkeys that showed state of fixation towards alleles different than wild alleles. CONCLUSION: The turkey genome is much less diverse with a relatively low frequency of heterozygous SNPs as compared to other livestock species like chicken and pig. The whole genome SNP discovery study in turkey resulted in the detection of 5.49 million putative SNPs compared to the reference genome. All commercial lines appear to share a common origin. Presence of different alleles/haplotypes in the SM population highlights that specific haplotypes have been selected in the modern domesticated turkey.     

The design and cross-population application of a genome-wide SNP chip for the great tit Parus major

The vast amount of phenotypic information collected in some wild animal populations makes them extremely valuable for unravelling the genetics of ecologically important traits and understanding how populations adapt to changes in their environment. Next generation sequencing has revolutionized the development of large marker panels in species previously lacking genomic resources. In this study, a unique genomics toolkit was developed for the great tit (Parus major), a model species in ecology and behavioural biology. This toolkit consists of nearly 100,000 SNPs, over 250 million nucleotides of assembled genomic DNA and more than 80 million nucleotides of assembled expressed sequences. A SNP chip with 9193 SNP markers expected to be spaced evenly along the great tit genome was used to genotype 4702 birds from two of the most intensively studied natural vertebrate populations [Wytham Woods/Bagley Woods (United Kingdom) and de Hoge Veluwe/Westerheide (The Netherlands)]. We show that (i) SNPs identified in either of the two populations have a high genotyping success in the other population, (ii) the minor allele frequencies of the SNPs are highly correlated between the two populations and (iii) despite this high correlation, a large number of SNPs display significant differentiation (F(ST) ) between the populations, with an overrepresentation of genes involved in cardiovascular development close to these SNPs. The developed resources provide the basis for unravelling the genetics of important traits in many long-term studies of great tits. More generally, the protocols and pitfalls encountered will be of use for those developing similar resources.     

An assessment of European pig diversity using molecular markers: Partitioning of diversity among breeds

Genetic diversity within and between breeds (and lines) of pigs was investigated. The sample comprised 68 European domestic breeds (and lines), including 29 local breeds, 18 varieties of major international breeds, namely Duroc, Hampshire, Landrace, Large White and Piétrain, and 21 commercial lines either purebred or synthetic, to which the Chinese Meishan and a sample of European wild pig were added. On average 46 animals per breed were sampled (range 12–68). The genetic markers were microsatellites (50 loci) and AFLP (amplified fragment length polymorphism, 148 loci). The analysis of diversity showed that the local breeds accounted for 56% of the total European between-breed microsatellite diversity, and slightly less for AFLP, followed by commercial lines and international breeds. Conversely, the group of international breeds contributed most to within-breed diversity, followed by commercial lines and local breeds. Individual breed contributions to the overall European between- and within-breed diversity were estimated. The range in between-breed diversity contributions among the 68 breeds was 0.04–3.94% for microsatellites and 0.24–2.94% for AFLP. The within-breed diversity contributions varied very little for both types of markers, but microsatellite contributions were negatively correlated with the between-breed contributions, so care is needed in balancing the two types of contribution when making conservation decisions. By taking into account the risks of extinction of the 29 local breeds, a cryopreservation potential (priority) was estimated for each of them.     

Biodiversity of pig breeds from China and Europe estimated from pooled DNA samples: differences in microsatellite variation between two areas of domestication

Microsatellite diversity in European and Chinese pigs was assessed using a pooled sampling method on 52 European and 46 Chinese pig populations. A Neighbor Joining analysis on genetic distances revealed that European breeds were grouped together and showed little evidence for geographic structure, although a southern European and English group could tentatively be assigned. Populations from international breeds formed breed specific clusters. The Chinese breeds formed a second major group, with the Sino-European synthetic Tia Meslan in-between the two large clusters. Within Chinese breeds, in contrast to the European pigs, a large degree of geographic structure was noted, in line with previous classification schemes for Chinese pigs that were based on morphology and geography. The Northern Chinese breeds were most similar to the European breeds. Although some overlap exists, Chinese breeds showed a higher average degree of heterozygosity and genetic distance compared to European ones. Between breed diversity was even more pronounced and was the highest in the Central Chinese pigs, reflecting the geographically central position in China. Comparing correlations between genetic distance and heterozygosity revealed that China and Europe represent different domestication or breed formation processes. A likely cause is a more diverse wild boar population in Asia, but various other possible contributing factors are discussed.     

Survey of moniliformin in wheat- and corn-based products using a straightforward analytical method

A straightforward analytical method was developed and validated to determine the mycotoxin moniliformin in cereal-based foods. Moniliformin is extracted with water and quantified with liquid chromatography tandem mass spectrometry, and its presence confirmed with liquid chromatography-Orbitrap-high-resolution mass spectrometry. The method was validated for flour, bread, pasta and maize samples in terms of linearity, matrix effect, recovery, repeatability and limit of quantification. Quantification was conducted by matrix-matched calibration. Positive samples were confirmed by standard addition. Recovery ranged from 77 to 114% and repeatability from 1 to 14%. The limit of quantification, defined as the lowest concentration tested at which the validation criteria of recovery and repeatability were fulfilled, was 10 μg/kg. The method was applied to 102 cereal-based food samples collected in the Netherlands and Germany. Moniliformin was not detected in bread samples. One of 22 flour samples contained moniliformin at 10.6 μg/kg. Moniliformin occurred in seven out of 25 pasta samples at levels around 10 μg/kg. Moniliformin (MON) was present in eight out of 23 maize products at levels ranging from 12 to 207 μg/kg.     

Familial social structure and socially driven genetic differentiation in Hawaiian short‐finned pilot whales

Social structure can have a significant impact on divergence and evolution within species, especially in the marine environment, which has few environmental boundaries to dispersal. On the other hand, genetic structure can affect social structure in many species, through an individual preference towards associating with relatives. One social species, the short‐finned pilot whale (Globicephala macrorhynchus), has been shown to live in stable social groups for periods of at least a decade. Using mitochondrial control sequences from 242 individuals and single nucleotide polymorphisms from 106 individuals, we examine population structure among geographic and social groups of short‐finned pilot whales in the Hawaiian Islands, and test for links between social and genetic structure. Our results show that there are at least two geographic populations in the Hawaiian Islands: a Main Hawaiian Islands (MHI) population and a Northwestern Hawaiian Islands/Pelagic population (F_ST and Φ_ST p < .001), as well as an eastern MHI community and a western MHI community (F_ST p = .009). We find genetically driven social structure, or high relatedness among social units and clusters (p < .001), and a positive relationship between relatedness and association between individuals (p < .0001). Further, socially organized clusters are genetically distinct, indicating that social structure drives genetic divergence within the population, likely through restricted mate selection (F_ST p = .05). This genetic divergence among social groups can make the species less resilient to anthropogenic or ecological disturbance. Conservation of this species therefore depends on understanding links among social structure, genetic structure and ecological variability within the species.