Haplotype analysis of APOE intragenic SNPs

BACKGROUND: APOE epsilon4 allele is most common genetic risk factor for Alzheimer\u27s disease (AD) and cognitive decline. However, it remains poorly understood why only some carriers of APOE epsilon4 develop AD and how ethnic variabilities in APOE locus contribute to AD risk. Here, to address the role of APOE haplotypes, we reassessed the diversity of APOE locus in major ethnic groups and in Alzheimer\u27s Disease Neuroimaging Initiative (ADNI) dataset on patients with AD, and subjects with mild cognitive impairment (MCI), and control non-demented individuals. RESULTS: We performed APOE gene haplotype analysis for a short block of five SNPs across the gene using the ADNI whole genome sequencing dataset. The compilation of ADNI data with 1000 Genomes identified the APOE epsilon4 linked haplotypes, which appeared to be distant for the Asian, African and European populations. The common European epsilon4-bearing haplotype is associated with AD but not with MCI, and the Africans lack this haplotype. Haplotypic inference revealed alleles that may confer protection against AD. By assessing the DNA methylation profile of the APOE haplotypes, we found that the AD-associated haplotype features elevated APOE CpG content, implying that this locus can also be regulated by genetic-epigenetic interactions. CONCLUSIONS: We showed that SNP frequency profiles within APOE locus are highly skewed to population-specific haplotypes, suggesting that the ancestral background within different sites at APOE gene may shape the disease phenotype. We propose that our results can be utilized for more specific risk assessment based on population descent of the individuals and on higher specificity of five site haplotypes associated with AD

Chromatin profiling of cortical neurons identifies individual epigenetic signatures in schizophrenia

Both heritability and environment contribute to risk for schizophrenia. However, the molecular mechanisms of interactions between genetic and non-genetic factors remain unclear. Epigenetic regulation of neuronal genome may be a presumable mechanism in pathogenesis of schizophrenia. Here, we performed analysis of open chromatin landscape of gene promoters in prefrontal cortical (PFC) neurons from schizophrenic patients. We cataloged cell-type-based epigenetic signals of transcriptional start sites (TSS) marked by histone H3-K4 trimethylation (H3K4me3) across the genome in PFC from multiple schizophrenia subjects and age-matched control individuals. One of the top-ranked chromatin alterations was found in the major histocompatibility (MHC) locus on chromosome 6 highlighting the overlap between genetic and epigenetic risk factors in schizophrenia. The chromosome conformation capture (3C) analysis in human brain cells revealed the architecture of multipoint chromatin interactions between the schizophrenia-associated genetic and epigenetic polymorphic sites and distantly located HLA-DRB5 and BTNL2 genes. In addition, schizophrenia-specific chromatin modifications in neurons were particularly prominent for non-coding RNA genes, including an uncharacterized LINC01115 gene and recently identified BNRNA_052780. Notably, protein-coding genes with altered epigenetic state in schizophrenia are enriched for oxidative stress and cell motility pathways. Our results imply the rare individual epigenetic alterations in brain neurons are involved in the pathogenesis of schizophrenia

Epigenetic-genetic chromatin footprinting identifies novel and subject-specific genes active in prefrontal cortex neurons

Human prefrontal cortex (PFC) is associated with broad individual variabilities in functions linked to personality, social behaviors, and cognitive functions. The phenotype variabilities associated with brain functions can be caused by genetic or epigenetic factors. The interactions between these factors in human subjects is, as of yet, poorly understood. The heterogeneity of cerebral tissue, consisting of neuronal and nonneuronal cells, complicates the comparative analysis of gene activities in brain specimens. To approach the underlying neurogenomic determinants, we performed a deep analysis of open chromatin-associated histone methylation in PFC neurons sorted from multiple human individuals in conjunction with whole-genome and transcriptome sequencing. Integrative analyses produced novel unannotated neuronal genes and revealed individual-specific chromatin blueprints of neurons that, in part, relate to genetic background. Surprisingly, we observed gender-dependent epigenetic signals, implying that gender may contribute to the chromatin variabilities in neurons. Finally, we found epigenetic, allele-specific activation of the testis-specific gene nucleoporin 210 like (NUP210L) in brain in some individuals, which we link to a genetic variant occurring in \u3c 3% of the human population. Recently, the NUP210L locus has been associated with intelligence and mathematics ability. Our findings highlight the significance of epigenetic-genetic footprinting for exploring neurologic function in a subject-specific manner

The Interactive Effect of Genetic and Epigenetic Variations in FKBP5 and ApoE Genes on Anxiety and Brain EEG Parameters

FKBP51 is a key stress-responsive regulator of the hypothalamic–pituitary–adrenal axis. To elucidate the contribution of rs1360780 FKBP5 C/T alleles to aging and longevity, we genotyped FKBP5 in a cohort of 800 non-demented and Alzheimer’s disease (AD) subjects of different age, taking into account the allele state of ApoE ε4, the major risk factor for AD. Furthermore, we searched for the association of FKBP5 with subcohorts of non-demented subjects evaluated for anxiety and resting-state quantitative EEG characteristics, associated with cognitive, emotional, and functional brain activities. We observed that increased state anxiety scores depend on the combination of the FKBP5 and ApoE genotypes and on the DNA methylation state of the FKBP5 promoter and ApoE genotype. We also found a significant gender-dependent correlation between FKBP5 promoter methylation and alpha-, delta-, and theta-rhythms. Analysis of the FKBP5 expression in an independent cohort revealed a significant upregulation of FKBP5 in females versus males. Our data suggest a synergistic effect of the stress-associated (FKBP5) and neurodegeneration-associated (ApoE) gene alleles on anxiety and the gender-dependent effect of FKBP5 on neurophysiological brain activity

Whole-genome sequencing identifies a novel ABCB7 gene mutation for X-linked congenital cerebellar ataxia in a large family of Mongolian ancestry

X-linked congenital cerebellar ataxia is a heterogeneous nonprogressive neurodevelopmental disorder with onset in early childhood. We searched for a genetic cause of this condition, previously reported in a Buryat pedigree of Mongolian ancestry from southeastern Russia. Using whole-genome sequencing on Illumina HiSeq 2000 platform, we found a missense mutation in the ABCB7 (ABC-binding cassette transporter B7) gene, encoding a mitochondrial transporter, involved in heme synthesis and previously associated with sideroblastic anemia and ataxia. The mutation resulting in a substitution of a highly conserved glycine to serine in position 682 is apparently a major causative factor of the cerebellar hypoplasia/atrophy found in affected individuals of a Buryat family who had no evidence of sideroblastic anemia. Moreover, in these affected men we also found the genetic defects in two other genes closely linked to ABCB7 on chromosome X: a deletion of a genomic region harboring the second exon of copper-transporter gene (ATP7A) and a complete deletion of PGAM4 (phosphoglycerate mutase family member 4) retrogene located in the intronic region of the ATP7A gene. Despite the deletion, eliminating the first of six metal-binding domains in ATP7A, no signs for Menkes disease or occipital horn syndrome associated with ATP7A mutations were found in male carriers. The role of the PGAM4 gene has been previously implicated in human reproduction, but our data indicate that its complete loss does not disrupt male fertility. Our finding links cerebellar pathology to the genetic defect in ABCB7 and ATP7A structural variant inherited as X-linked trait, and further reveals the genetic heterogeneity of X-linked cerebellar disorders

The ctenophore genome and the evolutionary origins of neural systems

The origins of neural systems remain unresolved. In contrast to other basal metazoans, ctenophores (comb jellies) have both complex nervous and mesoderm-derived muscular systems. These holoplanktonic predators also have sophisticated ciliated locomotion, behaviour and distinct development. Here we present the draft genome of Pleurobrachia bachei, Pacific sea gooseberry, together with ten other ctenophore transcriptomes, and show that they are remarkably distinct from other animal genomes in their content of neurogenic, immune and developmental genes. Our integrative analyses place Ctenophora as the earliest lineage within Metazoa. This hypothesis is supported by comparative analysis of multiple gene families, including the apparent absence of HOX genes, canonical microRNA machinery, and reduced immune complement in ctenophores. Although two distinct nervous systems are well recognized in ctenophores, many bilaterian neuron-specific genes and genes of 'classical' neurotransmitter pathways either are absent or, if present, are not expressed in neurons. Our metabolomic and physiological data are consistent with the hypothesis that ctenophore neural systems, and possibly muscle specification, evolved independently from those in other animals.This work was supported by NSF (NSF-0744649 and NSF CNS-0821622 to L.L.M.; NSF CHE-1111705 to J.V.S.), NIH (1R01GM097502, R01MH097062, R21RR025699 and 5R21DA030118 to L.L.M.; P30 DA018310 to J.V.S.; R01 AG029360 and 1S10RR027052 to E.I.R.), NASA/nNNX13AJ31G (to K.M.H., L.L.M. and K.M.K.), NSERC 458115 and 211598 (J.P.R.), University of Florida Opportunity Funds/McKnight Brain Research and Florida Biodiversity Institute (L.L.M.), Rostock Inc./A.V. Chikunov (E.I.R.), grant from Russian Federation Government 14.B25.31.0033 (Resolution No.220) (E.I.R.). F.A.K., I.S.P. and R.D.were supported by HHMI(55007424),EMBO and MINECO(BFU2012-31329 and Sev-2012-0208). Contributions of AU Marine Biology Program 117 and Molette laboratory 22

Complete genomic and epigenetic maps of human centromeres

Existing human genome assemblies have almost entirely excluded repetitive sequences within and near centromeres, limiting our understanding of their organization, evolution, and functions, which include facilitating proper chromosome segregation. Now, a complete, telomere-to-telomere human genome assembly (T2T-CHM13) has enabled us to comprehensively characterize pericentromeric and centromeric repeats, which constitute 6.2% of the genome (189.9 megabases). Detailed maps of these regions revealed multimegabase structural rearrangements, including in active centromeric repeat arrays. Analysis of centromere-associated sequences uncovered a strong relationship between the position of the centromere and the evolution of the surrounding DNA through layered repeat expansions. Furthermore, comparisons of chromosome X centromeres across a diverse panel of individuals illuminated high degrees of structural, epigenetic, and sequence variation in these complex and rapidly evolving regions

Complete genomic and epigenetic maps of human centromeres.

Existing human genome assemblies have almost entirely excluded repetitive sequences within and near centromeres, limiting our understanding of their organization, evolution, and functions, which include facilitating proper chromosome segregation. Now, a complete, telomere-to-telomere human genome assembly (T2T-CHM13) has enabled us to comprehensively characterize pericentromeric and centromeric repeats, which constitute 6.2% of the genome (189.9 megabases). Detailed maps of these regions revealed multimegabase structural rearrangements, including in active centromeric repeat arrays. Analysis of centromere-associated sequences uncovered a strong relationship between the position of the centromere and the evolution of the surrounding DNA through layered repeat expansions. Furthermore, comparisons of chromosome X centromeres across a diverse panel of individuals illuminated high degrees of structural, epigenetic, and sequence variation in these complex and rapidly evolving regions