WED 139 Gene expression regulation in CD4+ t-cell dysfunction in ms

2018 ◽  
Vol 89 (10) ◽  
pp. A16.1-A16
Author(s):  
Hrastelj James ◽  
Bray Nicholas ◽  
Williams Nigel ◽  
Robertson Neil
Keyword(s):  
Gene Expression ◽  
T Lymphocytes ◽  
Gene Expression Regulation ◽  
Cell Types ◽  
Expression Data ◽  
Specific Expression ◽  
Complex Disorders ◽  
Risk Variants ◽  
Allele Specific ◽  
Regulatory Effects

BackgroundGenetic risk variants for complex disorders such as multiple sclerosis (MS) rarely encode protein. Growing evidence suggests risk variants regulate gene expression in specific disease-relevant cells by altering regulatory genetic sequences. This can be explored by correlating genotype at risk loci with expression of nearby genes (cis-regulation), with greatest sensitivity demonstrated in the most relevant cell types. Identifying genes under regulation by the MS risk variants could be a crucial step in identifying novel therapeutic targets.Aims1) Interrogate MS risk loci for cis-regulatory effects using allele-specific expression (ASE) analysis. 2) Establish a publicly available resource of genome-wide RNA-seq expression data in CSF-derived CD4 +T lymphocytes. 3) Correlate gene expression data with longitudinal clinical data to seek biomarkers of prognosis.Method and progressWe have extracted RNA from FACS-sorted CSF-derived CD4 +T lymphocytes from over 100 individuals. cDNA library preparation and sequencing for each sample is underway.Data analysisASE analysis makes use of a pre-selected transcribed SNP to differentiate maternal and paternal transcripts of each gene of interest. When an individual is heterozygous at an additional functional regulatory locus the ratio of maternal: paternal expression will deviate from 1:1. Each MS risk locus will be interrogated for this effect.

scholarly journals Genetic influences on cell type specific gene expression and splicing during neurogenesis elucidate regulatory mechanisms of brain traits

2020 ◽  
Author(s):  
Nil Aygün ◽  
Angela L. Elwell ◽  
Dan Liang ◽  
Michael J. Lafferty ◽  
Kerry E. Cheek ◽  
...  
Keyword(s):  
Gene Expression ◽  
Regulatory Elements ◽  
Regulatory Mechanisms ◽  
Specific Gene ◽  
Cell Type ◽  
Specific Expression ◽  
Risk Variants ◽  
Allele Specific ◽  
Cell Type Specific ◽  
Regulatory Effects

SummaryInterpretation of the function of non-coding risk loci for neuropsychiatric disorders and brain-relevant traits via gene expression and alternative splicing is mainly performed in bulk post-mortem adult tissue. However, genetic risk loci are enriched in regulatory elements of cells present during neocortical differentiation, and regulatory effects of risk variants may be masked by heterogeneity in bulk tissue. Here, we map e/sQTLs and allele specific expression in primary human neural progenitors (n=85) and their sorted neuronal progeny (n=74). Using colocalization and TWAS, we uncover cell-type specific regulatory mechanisms underlying risk for these traits.

scholarly journals Heritability enrichment of specifically expressed genes identifies disease-relevant tissues and cell types

2017 ◽  
Author(s):  
Hilary K. Finucane ◽  
Yakir A. Reshef ◽  
Verneri Anttila ◽  
Kamil Slowikowski ◽  
Alexander Gusev ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Data ◽  
Complex Disease ◽  
Genome Wide Association Study ◽  
Ex Vivo ◽  
Cell Types ◽  
Inhibitory Neurons ◽  
Biliary Cirrhosis ◽  
Expression Data ◽  
Specific Expression

ABSTRACTGenetics can provide a systematic approach to discovering the tissues and cell types relevant for a complex disease or trait. Identifying these tissues and cell types is critical for following up on non-coding allelic function, developing ex-vivo models, and identifying therapeutic targets. Here, we analyze gene expression data from several sources, including the GTEx and PsychENCODE consortia, together with genome-wide association study (GWAS) summary statistics for 48 diseases and traits with an average sample size of 169,331, to identify disease-relevant tissues and cell types. We develop and apply an approach that uses stratified LD score regression to test whether disease heritability is enriched in regions surrounding genes with the highest specific expression in a given tissue. We detect tissue-specific enrichments at FDR < 5% for 34 diseases and traits across a broad range of tissues that recapitulate known biology. In our analysis of traits with observed central nervous system enrichment, we detect an enrichment of neurons over other brain cell types for several brain-related traits, enrichment of inhibitory over excitatory neurons for bipolar disorder but excitatory over inhibitory neurons for schizophrenia and body mass index, and enrichments in the cortex for schizophrenia and in the striatum for migraine. In our analysis of traits with observed immunological enrichment, we identify enrichments of T cells for asthma and eczema, B cells for primary biliary cirrhosis, and myeloid cells for Alzheimer's disease, which we validated with independent chromatin data. Our results demonstrate that our polygenic approach is a powerful way to leverage gene expression data for interpreting GWAS signal.

scholarly journals Karyotype stability and unbiased fractionation in the paleo-allotetraploidCucurbitagenomes

2017 ◽  
Author(s):  
Honghe Sun ◽  
Shan Wu ◽  
Guoyu Zhang ◽  
Chen Jiao ◽  
Shaogui Guo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Agronomic Traits ◽  
Genetic Distances ◽  
Plant Genome ◽  
Specific Expression ◽  
Important Species ◽  
Allele Specific ◽  
Regulatory Effects ◽  
Karyotype Stability

AbstractTheCucurbitagenus contains several economically important species in the Cucurbitaceae family. Interspecific hybrids betweenC. maximaandC. moschataare widely used as rootstocks for other cucurbit crops. We report high-quality genome sequences ofC. maximaandC. moschataand provide evidence supporting an allotetraploidization event inCucurbita. We are able to partition the genome into two homoeologous subgenomes based on different genetic distances to melon, cucumber and watermelon in the Benincaseae tribe. We estimate that the two diploid progenitors successively diverged from Benincaseae around 31 and 26 million years ago (Mya), and the allotetraploidization happened earlier than 3 Mya, whenC. maximaandC. moschatadiverged. The subgenomes have largely maintained the chromosome structures of their diploid progenitors. Such long-term karyotype stability after polyploidization is uncommon in plant polyploids. The two subgenomes have retained similar numbers of genes, and neither subgenome is globally dominant in gene expression. Allele-specific expression analysis in theC. maxima×C. moschatainterspecific F1hybrid and the two parents indicates the predominance oftrans-regulatory effects underlying expression divergence of the parents, and detects transgressive gene expression changes in the hybrid correlated with heterosis in important agronomic traits. Our study provides insights into plant genome evolution and valuable resources for genetic improvement of cucurbit crops.

scholarly journals Cis-regulatory divergence in gene expression between two thermally divergent yeast species

2016 ◽  
Author(s):  
Xueying C. Li ◽  
Justin C. Fay
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Binding Sites ◽  
Small Subset ◽  
Regulatory Sequences ◽  
Promoter Regions ◽  
Specific Expression ◽  
Thermal Growth ◽  
Allele Specific ◽  
Regulatory Effects

AbstractGene regulation is a ubiquitous mechanism by which organisms respond to their environment. While organisms are often found to be adapted to the environments they experience, the role of gene regulation in environmental adaptation is not often known. In this study, we examine divergence in cis-regulatory effects between two Saccharomyces species, S. cerevisiae and S. uvarum, that have substantially diverged in their thermal growth profile. We measured allele specific expression (ASE) in the species’ hybrid at three temperatures, the highest of which is lethal to S. uvarum but not the hybrid or S. cerevisiae. We find that S. uvarum alleles can be expressed at the same level as S. cerevisiae alleles at high temperature and most cis-acting differences in gene expression are not dependent on temperature. While a small set of 136 genes show temperature-dependent ASE, we find no indication that signatures of directional cis-regulatory evolution are associated with temperature. Within promoter regions we find binding sites enriched upstream of temperature responsive genes, but only weak correlations between binding site and expression divergence. Our results indicate that temperature divergence between S. cerevisiae and S. uvarum has not caused widespread divergence in cis-regulatory activity, but point to a small subset of genes where the species’ alleles show differences in magnitude or opposite responses to temperature. The difficulty of explaining divergence in cis-regulatory sequences with models of transcription factor binding sites and nucleosome positioning highlights the importance of identifying mutations that underlie cis-regulatory divergence between species.

scholarly journals Parent of origin gene expression in a founder population identifies two new imprinted genes at known imprinted regions

2018 ◽  
Author(s):  
Sahar V. Mozaffari ◽  
Michelle M. Stein ◽  
Kevin M. Magnaye ◽  
Dan L. Nicolae ◽  
Carole Ober
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Gene Expression Data ◽  
Imprinted Genes ◽  
Genotype Data ◽  
Expression Data ◽  
Rna Seq ◽  
Specific Expression ◽  
Allele Specific ◽  
Parent Of Origin

AbstractGenomic imprinting is the phenomena that leads to silencing of one copy of a gene inherited from a specific parent. Mutations in imprinted regions have been involved in diseases showing parent of origin effects. Identifying genes with evidence of parent of origin expression patterns in family studies allows the detection of more subtle imprinting. Here, we use allele specific expression in lymphoblastoid cell lines from 306 Hutterites related in a single pedigree to provide formal evidence for parent of origin effects. We take advantage of phased genotype data to assign parent of origin to RNA-seq reads in individuals with gene expression data. Our approach identified known imprinted genes, two putative novel imprinted genes, and 14 genes with asymmetrical parent of origin gene expression. We used gene expression in peripheral blood leukocytes (PBL) to validate our findings, and then confirmed imprinting control regions (ICRs) using DNA methylation levels in the PBLs.Author SummaryLarge scale gene expression studies have identified known and novel imprinted genes through allele specific expression without knowing the parental origins of each allele. Here, we take advantage of phased genotype data to assign parent of origin to RNA-seq reads in 306 individuals with gene expression data. We identified known imprinted genes as well as two novel imprinted genes in lymphoblastoid cell line gene expression. We used gene expression in PBLs to validate our findings, and DNA methylation levels in PBLs to confirm previously characterized imprinting control regions that could regulate these imprinted genes.

scholarly journals A vast resource of allelic expression data spanning human tissues

2019 ◽  
Author(s):  
Stephane E. Castel ◽  
François Aguet ◽  
Pejman Mohammadi ◽  
Kristin G. Ardlie ◽  
Tuuli Lappalainen ◽  
...  
Keyword(s):  
Effect Sizes ◽  
Human Tissues ◽  
Expression Data ◽  
Specific Expression ◽  
Allele Specific Expression ◽  
Future Studies ◽  
Regulatory Variants ◽  
Level Data ◽  
Allele Specific ◽  
Regulatory Effects

AbstractAllele specific expression (ASE) analysis robustly measurescisregulatory effects. Here, we present a vast ASE resource generated from the GTEx v8 release, containing 15,253 samples spanning 54 human tissues for a total of 431 million measurements of ASE at the SNP-level and 153 million measurements at the haplotype-level. In addition, we developed an extension of our tool phASER that allows effect sizes ofcisregulatory variants to be estimated using haplotype-level ASE data. This ASE resource is the largest to date and we are able to make haplotype-level data publicly available. We anticipate that the availability of this resource will enable future studies of regulatory variation across human tissues.

scholarly journals Elimination of reference mapping bias reveals robust immune related allele-specific expression in crossbred sheep

2019 ◽  
Author(s):  
Mazdak Salavati ◽  
Stephen J. Bush ◽  
Sergio Palma-Vera ◽  
Mary E. B. McCulloch ◽  
David A. Hume ◽  
...  
Keyword(s):  
Gene Expression ◽  
Complex Traits ◽  
Allelic Imbalance ◽  
Cell Types ◽  
Rna Seq ◽  
Specific Expression ◽  
Allele Specific Expression ◽  
Gene Expression Atlas ◽  
Expression Atlas ◽  
Allele Specific

AbstractPervasive allelic variation at both gene and single nucleotide level (SNV) between individuals is commonly associated with complex traits in humans and animals. Allele-specific expression (ASE) analysis, using RNA-Seq, can provide a detailed annotation of allelic imbalance and infer the existence of cis-acting transcriptional regulation. However, variant detection in RNA-Seq data is compromised by biased mapping of reads to the reference DNA sequence. In this manuscript we describe an unbiased standardised computational pipeline for allele-specific expression analysis using RNA-Seq data, which we have adapted and developed using tools available under open licence. The analysis pipeline we present is designed to minimise reference bias while providing accurate profiling of allele-specific expression across tissues and cell types. Using this methodology, we were able to profile pervasive allelic imbalance across tissues and cell types, at both the gene and SNV level, in Texel x Scottish Blackface sheep, using the sheep gene expression atlas dataset. ASE profiles were pervasive in each sheep and across all tissue types investigated. However, ASE profiles shared across tissues were limited and instead they tended to be highly tissue-specific. These tissue-specific ASE profiles may underlie the expression of economically important traits and could be utilized as weighted SNVs, for example, to improve the accuracy of genomic selection in breeding programmes for sheep. An additional benefit of the pipeline is that it does not require parental genotypes and can therefore be applied to other RNA-Seq datasets for livestock, including those available on the Functional Annotation of Animal Genomes (FAANG) data portal. This study is the first global characterisation of moderate to extreme ASE in tissues and cell types from sheep. We have applied a robust methodology for ASE profiling, to provide both a novel analysis of the multi-dimensional sheep gene expression atlas dataset, and a foundation for identifying the regulatory and expressed elements of the genome that are driving complex traits in livestock.

scholarly journals Behavior-dependent cis regulation reveals genes and pathways associated with bower building in cichlid fishes

2018 ◽  
Vol 115 (47) ◽  
pp. E11081-E11090 ◽  
Author(s):  
Ryan A. York ◽  
Chinar Patil ◽  
Kawther Abdilleh ◽  
Zachary V. Johnson ◽  
Matthew A. Conte ◽  
...  
Keyword(s):  
Gene Expression ◽  
Neural Plasticity ◽  
Genetic Basis ◽  
Specific Expression ◽  
Preferential Expression ◽  
Cichlid Fishes ◽  
Brain Gene Expression ◽  
Genome Wide ◽  
Allele Specific ◽  
Genomic Regions

Many behaviors are associated with heritable genetic variation [Kendler and Greenspan (2006) Am J Psychiatry 163:1683–1694]. Genetic mapping has revealed genomic regions or, in a few cases, specific genes explaining part of this variation [Bendesky and Bargmann (2011) Nat Rev Gen 12:809–820]. However, the genetic basis of behavioral evolution remains unclear. Here we investigate the evolution of an innate extended phenotype, bower building, among cichlid fishes of Lake Malawi. Males build bowers of two types, pits or castles, to attract females for mating. We performed comparative genome-wide analyses of 20 bower-building species and found that these phenotypes have evolved multiple times with thousands of genetic variants strongly associated with this behavior, suggesting a polygenic architecture. Remarkably, F1 hybrids of a pit-digging and a castle-building species perform sequential construction of first a pit and then a castle bower. Analysis of brain gene expression in these hybrids showed that genes near behavior-associated variants display behavior-dependent allele-specific expression with preferential expression of the pit-digging species allele during pit digging and of the castle-building species allele during castle building. These genes are highly enriched for functions related to neurodevelopment and neural plasticity. Our results suggest that natural behaviors are associated with complex genetic architectures that alter behavior via cis-regulatory differences whose effects on gene expression are specific to the behavior itself.

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