scholarly journals Hemostatic Genes Exhibit a High Degree of Allele-Specific Regulation in Liver

2019 ◽  
Vol 119 (07) ◽  
pp. 1072-1083 ◽  
Author(s):  
Martina Olsson Lindvall ◽  
Lena Hansson ◽  
Sofia Klasson ◽  
Marcela Davila Lopez ◽  
Christina Jern ◽  
...  
Keyword(s):  
Human Liver ◽  
Genome Wide Association Study ◽  
University Hospital ◽  
Snp Analysis ◽  
Specific Expression ◽  
Human Liver Tissue ◽  
Expression Variability ◽  
Allele Specific ◽  
Specific Regulation ◽  
Hemostatic Genes

Objective Elucidating the genetic basis underlying hepatic hemostatic gene expression variability may contribute to unraveling genetic factors contributing to thrombotic or bleeding disorders. We aimed to identify novel cis-regulatory variants involved in regulating hemostatic genes by analyzing allele-specific expression (ASE) in human liver samples. Study Design Biopsies of human liver tissue and blood were collected from adults undergoing liver surgery at the Sahlgrenska University Hospital (n = 20). Genomic deoxyribonucleic acid (gDNA) and total ribonucleic acid (RNA) were isolated. A targeted approach was used to enrich and sequence 35 hemostatic genes for single nucleotide polymorphism (SNP) analysis (gDNAseq) and construct individualized genomes for transcript alignment. The allelic ratio of transcripts from targeted RNAseq was determined via ASE analysis. Public expression quantitative trait loci (eQTL) and genome-wide association study (GWAS) data were used to assess novelty and importance of the ASE SNPs (and proxies, r 2 ≥ 0.8) for relevant traits/diseases. Results Sixty percent of the genes studied showed allelic imbalance across 53 SNPs. Of these, 7 SNPs were previously validated in liver eQTL studies. For 32 with eQTLs in other cell/tissue types, this is the first time genotype-specific expression is demonstrated in liver, and for 14 ASE SNPs, this is the first ever reported genotype–expression association. A total of 29 ASE SNPs were previously associated with the respective plasma protein levels and 17 ASE SNPs to other relevant GWAS traits including venous thromboembolism, coronary artery disease, and stroke. Conclusion Our study provides a comprehensive ASE analysis of hemostatic genes and insights into the regulation of hemostatic genes in human liver.

scholarly journals A Comprehensive Sequencing-Based Analysis of Allelic Methylation Patterns in Hemostatic Genes in Human Liver

2019 ◽  
Vol 120 (02) ◽  
pp. 229-242 ◽  
Author(s):  
Martina Olsson Lindvall ◽  
Marcela Davila Lopez ◽  
Sofia Klasson ◽  
Lena Hansson ◽  
Staffan Nilsson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Liver Tissue ◽  
Human Liver ◽  
Genome Wide Association Study ◽  
Warfarin Dose ◽  
Sequencing Data ◽  
Human Liver Tissue ◽  
In Cis ◽  
Hemostatic Genes

AbstractCharacterizing the relationship between genetic, epigenetic (e.g., deoxyribonucleic acid [DNA] methylation), and transcript variation could provide insights into mechanisms regulating hemostasis and potentially identify new drug targets. Several hemostatic factors are synthesized in the liver, yet high-resolution DNA methylation data from human liver tissue is currently lacking for these genes. Single-nucleotide polymorphisms (SNPs) can influence DNA methylation in cis which can affect gene expression. This can be analyzed through allele-specific methylation (ASM) experiments. We performed targeted genomic DNA- and bisulfite-sequencing of 35 hemostatic genes in human liver samples for SNP and DNA methylation analysis, respectively, and integrated the data for ASM determination. ASM-associated SNPs (ASM-SNPs) were tested for association to gene expression in liver using in-house generated ribonucleic acid-sequencing data. We then assessed whether ASM-SNPs associated with gene expression, plasma proteins, or other traits relevant for hemostasis using publicly available data. We identified 112 candidate ASM-SNPs. Of these, 68% were associated with expression of their respective genes in human liver or in other human tissues and 54% were associated with the respective plasma protein levels, activity, or other relevant hemostatic genome-wide association study traits such as venous thromboembolism, coronary artery disease, stroke, and warfarin dose maintenance. Our study provides the first detailed map of the DNA methylation landscape and ASM analysis of hemostatic genes in human liver tissue, and suggests that methylation regulated by genetic variants in cis may provide a mechanistic link between noncoding SNPs and variation observed in circulating hemostatic proteins, prothrombotic diseases, and drug response.

scholarly journals Sequences required for paramutation of the maize b gene map to a region containing the promoter and upstream sequences.

Genetics ◽  
1995 ◽  
Vol 140 (4) ◽  
pp. 1389-1406 ◽  
Author(s):  
G I Patterson ◽  
K M Kubo ◽  
T Shroyer ◽  
V L Chandler
Keyword(s):  
Specific Interaction ◽  
Small Region ◽  
Regulatory Sequences ◽  
Specific Expression ◽  
Tissue Specific ◽  
Cis Acting ◽  
Gene Map ◽  
Transcriptional Regulatory ◽  
Allele Specific ◽  
Specific Regulation

Abstract The b gene encodes a transcriptional regulator of the maize anthocyanin biosynthetic pathway. Certain b alleles participate in paramutation, an allele-specific interaction that heritably alters transcription. The moderately transcribed B' allele heritably reduces the transcription of the highly transcribed B-I allele in a B'/B-I heterozygote, such that the B-I allele becomes B'. To identify the cis-acting sequences required for paramutation, we used B' or B-I alleles to isolate intragenic recombinants with B-Peru, an allele that is insensitive to paramutation and has distinct tissue-specific regulation. Physical mapping of the recombinant alleles showed that most of the crossovers were in a small region near the 5' end of the b-transcribed region. Analysis of the recombinant alleles revealed that the ability to cause and respond to paramutation and the control of tissue-specific expression both localize to the 5' region of the gene. The 3' boundary of these functions lies just upstream of the translation initiation codon. The 5' boundary has been estimated to be no more than 0.1 cM further upstream (1-150 kb). Thus, sequences critical for paramutation lie upstream of the b coding sequences and may include transcriptional regulatory sequences.

Genetic polymorphisms as the predictors of response to antiviral treatment in chronic hepatitis C virus infection

2011 ◽  
Vol 152 (22) ◽  
pp. 876-881
Author(s):  
Alajos Pár
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Genetic Polymorphisms ◽  
Chronic Hepatitis C ◽  
Genome Wide Association Study ◽  
Antiviral Treatment ◽  
Hcv Infection ◽  
Snp Analysis ◽  
Chronic Hcv

The review discusses the genetic polymorphisms involved in the pathogenesis of hepatitis C virus (HCV) infection, that may determine the outcome of disease. In this field earlier both certain major histocompatibility complex (MHC) alleles and some cytokine gene variants have also been studied. Recently, the genome-wide association study (GWAS) and targeted single nucleotide polymorphism (SNP) analysis have revealed that a variant in the promoter region of interleukin-28B (IL-28B) gene is strongly linked to viral clearance and it may be the strongest pretreatment predictor of treatment response in chronic hepatitis C. Last year it was shown that two genetic variants leading to inosine triphosphatase deficiency protect against haemolytic anemia in patients receiving ribavirin during antiviral treatment for chronic HCV infection. Orv. Hetil., 2011, 152, 876–881.

Human Liver-Specific Nanocarrier in a Novel Mouse Xenograft Model Bearing Noncancerous Human Liver Tissue

2011 ◽  
Vol 46 (2) ◽  
pp. 65-72 ◽  
Author(s):  
Yoshifumi Matsuura ◽  
Hiroshi Yagi ◽  
Sachiko Matsuda ◽  
Osamu Itano ◽  
Koichi Aiura ◽  
...  
Keyword(s):  
Liver Tissue ◽  
Human Liver ◽  
Xenograft Model ◽  
Human Liver Tissue ◽  
Mouse Xenograft ◽  
Mouse Xenograft Model

scholarly journals Investigation of allele specific expression in various tissues of broiler chickens using the detection tool VADT

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
M. Joseph Tomlinson ◽  
Shawn W. Polson ◽  
Jing Qiu ◽  
Juniper A. Lake ◽  
William Lee ◽  
...  
Keyword(s):  
Broiler Chickens ◽  
Nucleotide Polymorphisms ◽  
Rna Seq ◽  
Specific Expression ◽  
Single Nucleotide ◽  
Allele Specific Expression ◽  
Detection Tool ◽  
Commercial Broiler ◽  
Significant Phenomenon ◽  
Allele Specific

AbstractDifferential abundance of allelic transcripts in a diploid organism, commonly referred to as allele specific expression (ASE), is a biologically significant phenomenon and can be examined using single nucleotide polymorphisms (SNPs) from RNA-seq. Quantifying ASE aids in our ability to identify and understand cis-regulatory mechanisms that influence gene expression, and thereby assist in identifying causal mutations. This study examines ASE in breast muscle, abdominal fat, and liver of commercial broiler chickens using variants called from a large sub-set of the samples (n = 68). ASE analysis was performed using a custom software called VCF ASE Detection Tool (VADT), which detects ASE of biallelic SNPs using a binomial test. On average ~ 174,000 SNPs in each tissue passed our filtering criteria and were considered informative, of which ~ 24,000 (~ 14%) showed ASE. Of all ASE SNPs, only 3.7% exhibited ASE in all three tissues, with ~ 83% showing ASE specific to a single tissue. When ASE genes (genes containing ASE SNPs) were compared between tissues, the overlap among all three tissues increased to 20.1%. Our results indicate that ASE genes show tissue-specific enrichment patterns, but all three tissues showed enrichment for pathways involved in translation.

scholarly journals Replicate sequencing libraries are important for quantification of allelic imbalance

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Asia Mendelevich ◽  
Svetlana Vinogradova ◽  
Saumya Gupta ◽  
Andrey A. Mironov ◽  
Shamil R. Sunyaev ◽  
...  
Keyword(s):  
Allelic Imbalance ◽  
False Positive Rate ◽  
Error Rates ◽  
Differential Analysis ◽  
Rna Seq ◽  
Specific Expression ◽  
Technical Noise ◽  
Specific Analysis ◽  
Positive Rate ◽  
Allele Specific

AbstractA sensitive approach to quantitative analysis of transcriptional regulation in diploid organisms is analysis of allelic imbalance (AI) in RNA sequencing (RNA-seq) data. A near-universal practice in such studies is to prepare and sequence only one library per RNA sample. We present theoretical and experimental evidence that data from a single RNA-seq library is insufficient for reliable quantification of the contribution of technical noise to the observed AI signal; consequently, reliance on one-replicate experimental design can lead to unaccounted-for variation in error rates in allele-specific analysis. We develop a computational approach, Qllelic, that accurately accounts for technical noise by making use of replicate RNA-seq libraries. Testing on new and existing datasets shows that application of Qllelic greatly decreases false positive rate in allele-specific analysis while conserving appropriate signal, and thus greatly improves reproducibility of AI estimates. We explore sources of technical overdispersion in observed AI signal and conclude by discussing design of RNA-seq studies addressing two biologically important questions: quantification of transcriptome-wide AI in one sample, and differential analysis of allele-specific expression between samples.

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