Analysis of genetic diversity in Brown Swiss, Jersey and Holstein populations using genome-wide single nucleotide polymorphism markers

BACKGROUND: Studies of genetic diversity are essential in understanding the extent of differentiation between breeds, and in designing successful diversity conservation strategies. The objective of this study was to evaluate the level of genetic diversity within and between North American Brown Swiss (BS, n = 900), Jersey (JE, n = 2,922) and Holstein (HO, n = 3,535) cattle, using genotyped bulls. GENEPOP and FSTAT software were used to evaluate the level of genetic diversity within each breed and between each pair of the three breeds based on genome-wide SNP markers (n = 50,972). RESULTS: Hardy-Weinberg equilibrium (HWE) exact test within breeds showed a significant deviation from equilibrium within each population (P < 0.01), which could be a result of selection, genetic drift and inbreeding within each breed. Hardy-Weinberg test also confirmed significant heterozygote deficit in each breed over several loci. Moreover, results from population differentiation tests showed that the majority of loci have alleles or genotypes drawn from different distributions in each breed. Average gene diversity, expressed in terms of observed heterozygosity, over all loci in BS, JE and HO was 0.27, 0.26 and 0.31, respectively. The proportion of genetic diversity due to allele frequency differences among breeds (F(st)) indicated that the combination of BS and HO in an ideally amalgamated population had higher genetic diversity than the other pairs of breeds. CONCLUSION: Results suggest that the three bull populations have substantially different gene pools. BS and HO show the largest gene differentiation and jointly the highest total expected gene diversity compared to when JE is considered. If the loss of genetic diversity within breeds worsens in the future, the use of crossbreeding might be an option to recover genetic diversity, especially for the breeds with small population size

Changes in DNA Sequence and Methylation Contribute to the Predisposition of Schizophrenia: Toward an Epigenetic Therapy

Schizophrenia has a heterogeneous and complex etiology that includes multiple candidate genes affected by a variety of mutational mechanisms including epigenetics, functional pathways, and environmental factors. This chapter mainly focuses on reviewing two sets of studies. The first one is whole‐genome next‐generation sequencing datasets involving monozygotic twins discordant for schizophrenia. The findings suggest that de novo sequence variations may underlie the discordance of monozygotic twins for schizophrenia. Second, whole‐genome DNA methylation study suggesting the role of DNA methylation in the mechanisms of actions of antipsychotic drugs in treating the disorder as well as the manifestation of side effects such as metabolic disorders. Furthermore, we are reporting original research results using next‐generation mitochondrial DNA sequence analysis of a pair of monozygotic twins discordant for schizophrenia as well as their mother. The chapter sheds light on the interplay between sequence variations and epigenetic signatures, including DNA methylation changes, in the etiology and pathophysiology of schizophrenia. Given the dynamic nature of methylation, it may be possible to develop a new treatment strategy for schizophrenia that is based on reversion of genomic methylation. This may involve environmental, dietary, and/or pharmaceutical approaches

Insights into the Origin of DNA Methylation Differences between Monozygotic Twins Discordant for Schizophrenia

BACKGROUND: DNA methylation differences between monozygotic twins discordant for schizophrenia have been previously reported. However, the origin of methylation differences between monozygotic twins discordant for schizophrenia is not clear. The findings here argue that all DNA methylation differences may not necessarily represent the cause of the disease; rather some may result from the effect of antipsychotics. METHODS: Methylation differences in rat brain regions and also in two pairs of unrelated monozygotic twins discordant for schizophrenia have been studied using genome-wide DNA methylation arrays at Arraystar Inc. (Rockville, Maryland, USA). The identified gene promoters showing significant alterations to DNA methylation were then further characterized using ingenuity pathway analysis (Ingenuity System Inc, CA, USA). RESULTS: Pathway analysis of the most significant gene promoter hyper/hypomethylation revealed a significant enrichment of DNA methylation changes in biological networks and pathways directly relevant to neural development and psychiatric disorders. These included HIPPO signaling (p = 3.93E-03) and MAPK signaling (p = 4.27E-03) pathways involving hypermethylated genes in schizophrenia-affected patients as compared to their unaffected co-twins. Also, a number of significant pathways and networks involving genes with hypomethylated gene promoters have been identified. These included CREB signaling in neurons (p = 1.53E-02), Dopamine-DARPP32 feedback in cAMP signaling (p = 7.43E-03) and Ephrin receptors (p = 1.13E-02). Further, there was significant enrichment for pathways involved in nervous system development and function (p = 1.71E-03-4.28E-02). CONCLUSION: The findings highlight the significance of antipsychotic drugs on DNA methylation in schizophrenia patients. The unique pathways affected by DNA methylation in the two pairs of monozygotic twins suggest that patient-specific pathways are responsible for the disease; suggesting that patient-specific treatment strategies may be necessary in treating the disorder. The study reflects the need for developing personalized medicine approaches that take into consideration epigenetic variations between patients

Olanzapine-Induced Methylation Alters Cadherin Gene Families and Associated Pathways Implicated in Psychosis

BACKGROUND: The complex aetiology of most mental disorders involves gene-environment interactions that may operate using epigenetic mechanisms particularly DNA methylation. It may explain many of the features seen in mental disorders including transmission, expression and antipsychotic treatment responses. This report deals with the assessment of DNA methylation in response to an antipsychotic drug (olanzapine) on brain (cerebellum and hippocampus), and liver as a non-neural reference in a rat model. The study focuses on the Cadherin/protocadherins encoded by a multi-gene family that serve as adhesion molecules and are involved in cell-cell communication in the mammalian brain. A number of these molecules have been implicated in the causation of schizophrenia and related disorders. RESULTS: The results show that olanzapine causes changes in DNA methylation, most specific to the promoter region of specific genes. This response is tissue specific and involves a number of cadherin genes, particularly in cerebellum. Also, the genes identified have led to the identification of several pathways significantly affected by DNA methylation in cerebellum, hippocampus and liver. These included the Gα12/13 Signalling (p = 9.2E-08) and Wnt signalling (p = 0.01) pathways as contributors to psychosis that is based on its responsiveness to antipsychotics used in its treatment. CONCLUSION: The results suggest that DNA methylation changes on the promoter regions of the Cadherin/protocadherin genes impact the response of olanzapine treatment. These impacts have been revealed through the identified pathways and particularly in the identification of pathways that have been previously implicated in psychosis

DNA Methylation Differences in Monozygotic Twin Pairs Discordant for Schizophrenia Identifies Psychosis Related Genes and Networks

Background Despite their singular origin, monozygotic twin pairs often display discordance for complex disorders including schizophrenia. It is a common (1%) and often familial disease with a discordance rate of ~50% in monozygotic twins. This high discordance is often explained by the role of yet unknown environmental, random, and epigenetic factors. The involvement of DNA methylation in this disease appears logical, but remains to be established. Methods We have used blood DNA from two pairs of monozygotic twins discordant for schizophrenia and their parents in order to assess genome-wide methylation using a NimbleGen Methylation Promoter Microarray. Results The genome-wide results show that differentially methylated regions (DMRs) exist between members representing discordant monozygotic twins. Some DMRs are shared with parent(s) and others appear to be de novo. We found twenty-seven genes affected by DMR changes that were shared in the affected member of two discordant monozygotic pairs from unrelated families. Interestingly, the genes affected by pair specific DMRs share specific networks. Specifically, this study has identified two networks; “cell death and survival” and a “cellular movement and immune cell trafficking”. These two networks and the genes affected have been previously implicated in the aetiology of schizophrenia. Conclusions The results are compatible with the suggestion that DNA methylation may contribute to the discordance of monozygotic twins for schizophrenia. Also, this may be accomplished by the direct effect of gene specific methylation changes on specific biological networks rather than individual genes. It supports the extensive genetic, epigenetic and phenotypic heterogeneity implicated in schizophrenia

The effects of olanzapine on genome-wide DNA methylation in the hippocampus and cerebellum

Background: The mechanism of action of olanzapine in treating schizophrenia is not clear. This research reports the effects of a therapeutic equivalent treatment of olanzapine on DNA methylation in a rat model in vivo. Genome-wide DNA methylation was assessed using a MeDIP-chip analysis. All methylated DNA immunoprecipitation (MeDIP), sample labelling, hybridization and processing were performed by Arraystar Inc (Rockville, MD, USA). The identified gene promoters showing significant alterations to DNA methylation were then subjected to Ingenuity Pathway Analysis (Ingenuity System Inc, CA, USA). Results: The results show that olanzapine causes an increase in methylation in 1,140, 1,294 and 1,313 genes and a decrease in methylation in 633, 565 and 532 genes in the hippocampus, cerebellum and liver, respectively. Most genes affected are tissue specific. Only 41 affected genes (approximately 3%) showed an increase and no gene showed a decrease in methylation in all three tissues. Further, the two brain regions shared 123 affected genes (approximately 10%). The affected genes are enriched in pathways affecting dopamine signalling, molecular transport, nervous system development and functions in the hippocampus; ephrin receptor signalling and synaptic long-term potentiation in the cerebellum; and tissue morphology, cellular assembly and organization in the liver. Also, the affected genes included those previously implicated in psychosis. Conclusions: The known functions of affected genes suggest that the observed epigenetic changes may underlie the amelioration of symptoms as well as accounting for certain adverse effects including the metabolic syndrome. The results give insights into the mechanism of action of olanzapine, therapeutic effects and the side effects of antipsychotics. © 2014 Melka et al.; licensee BioMed Central Ltd

Clustering of the metabolic syndrome components in adolescence : role of visceral fat

Visceral fat (VF) promotes the development of metabolic syndrome (MetS), which emerges as early as in adolescence. The clustering of MetS components suggests shared etiologies, but these are largely unknown and may vary between males and females. Here, we investigated the latent structure of pre-clinical MetS in a community-based sample of 286 male and 312 female adolescents, assessing their abdominal adiposity (VF) directly with magnetic resonance imaging. Principal component analysis of the five MetS-defining variables (VF, blood pressure [BP], fasting serum triglycerides, HDL-cholesterol and glucose) identified two independent components in both males and females. The first component was sex-similar; it explained >30% of variance and was loaded by all but BP variables. The second component explained >20% of variance; it was loaded by BP similarly in both sexes but additional loading by metabolic variables was sex-specific. This sex-specificity was not detected in analyses that used waist circumference instead of VF. In adolescence, MetS-defining variables cluster into at least two sub-syndromes: (1) sex-similar metabolic abnormalities of obesity-induced insulin resistance and (2) sex-specific metabolic abnormalities associated with BP elevation. These results suggest that the etiology of MetS may involve more than one pathway and that some of the pathways may differ between males and females. Further, the sex-specific metabolic abnormalities associated with BP elevation suggest the need for sex-specific prevention and treatment strategies of MetS

The effects of olanzapine on genome-wide DNA methylation in the hippocampus and cerebellum

Background: The mechanism of action of olanzapine in treating schizophrenia is not clear. This research reports the effects of a therapeutic equivalent treatment of olanzapine on DNA methylation in a rat model in vivo. Genome-wide DNA methylation was assessed using a MeDIP-chip analysis. All methylated DNA immunoprecipitation (MeDIP), sample labelling, hybridization and processing were performed by Arraystar Inc (Rockville, MD, USA). The identified gene promoters showing significant alterations to DNA methylation were then subjected to Ingenuity Pathway Analysis (Ingenuity System Inc, CA, USA). Results: The results show that olanzapine causes an increase in methylation in 1,140, 1,294 and 1,313 genes and a decrease in methylation in 633, 565 and 532 genes in the hippocampus, cerebellum and liver, respectively. Most genes affected are tissue specific. Only 41 affected genes (approximately 3%) showed an increase and no gene showed a decrease in methylation in all three tissues. Further, the two brain regions shared 123 affected genes (approximately 10%). The affected genes are enriched in pathways affecting dopamine signalling, molecular transport, nervous system development and functions in the hippocampus; ephrin receptor signalling and synaptic long-term potentiation in the cerebellum; and tissue morphology, cellular assembly and organization in the liver. Also, the affected genes included those previously implicated in psychosis. Conclusions: The known functions of affected genes suggest that the observed epigenetic changes may underlie the amelioration of symptoms as well as accounting for certain adverse effects including the metabolic syndrome. The results give insights into the mechanism of action of olanzapine, therapeutic effects and the side effects of antipsychotics. © 2014 Melka et al.; licensee BioMed Central Ltd