Detection, validation, and downstream analysis of allelic variation in gene expression

Autoren

Daniel C Ciobanu
Lu Lu
Khyobeni Mozhui
Xusheng Wang
Manjunatha Jagalur
John A Morris
William L Taylor
Klaus Dietz
Perikles Simon
Robert W Williams

Autoren-URL

https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000281784000012&DestLinkType=FullRecord&DestApp=WOS_CPL

DOI

10.1534/genetics.109.107474

eISSN

1943-2631

Externe Identifier

Clarivate Analytics Document Solution ID: 649PH
PubMed Identifier: 19884314

ISSN

0016-6731

Ausgabe der Veröffentlichung

1

Zeitschrift

GENETICS

Paginierung

119 - 128

Datum der Veröffentlichung

2010

Status

Published

Titel

Detection, Validation, and Downstream Analysis of Allelic Variation in Gene Expression

Sub types

Article

Ausgabe der Zeitschrift

184

Datenquelle: Web of Science (Lite)

Abstract

AbstractCommon sequence variants within a gene often generate important differences in expression of corresponding mRNAs. This high level of local (allelic) control—or cis modulation—rivals that produced by gene targeting, but expression is titrated finely over a range of levels. We are interested in exploiting this allelic variation to study gene function and downstream consequences of differences in expression dosage. We have used several bioinformatics and molecular approaches to estimate error rates in the discovery of cis modulation and to analyze some of the biological and technical confounds that contribute to the variation in gene expression profiling. Our analysis of SNPs and alternative transcripts, combined with eQTL maps and selective gene resequencing, revealed that between 17 and 25% of apparent cis modulation is caused by SNPs that overlap probes rather than by genuine quantitative differences in mRNA levels. This estimate climbs to 40–50% when qualitative differences between isoform variants are included. We have developed an analytical approach to filter differences in expression and improve the yield of genuine cis-modulated transcripts to ∼80%. This improvement is important because the resulting variation can be successfully used to study downstream consequences of altered expression on higher-order phenotypes. Using a systems genetics approach we show that two validated cis-modulated genes, Stk25 and Rasd2, are likely to control expression of downstream targets and affect disease susceptibility.

Autoren

Daniel C Ciobanu
Lu Lu
Khyobeni Mozhui
Xusheng Wang
Manjunatha Jagalur
John A Morris
William L Taylor
Klaus Dietz
Perikles Simon
Robert W Williams

DOI

10.1534/genetics.109.107474

eISSN

1943-2631

Ausgabe der Veröffentlichung

1

Zeitschrift

Genetics

Sprache

en

Online publication date

2010

Paginierung

119 - 128

Datum der Veröffentlichung

2010

Status

Published

Herausgeber

Oxford University Press (OUP)

Herausgeber URL

http://dx.doi.org/10.1534/genetics.109.107474

Datum der Datenerfassung

2023

Titel

Detection, Validation, and Downstream Analysis of Allelic Variation in Gene Expression

Ausgabe der Zeitschrift

184

Datenquelle: Crossref

Abstract

Common sequence variants within a gene often generate important differences in expression of corresponding mRNAs. This high level of local (allelic) control-or cis modulation-rivals that produced by gene targeting, but expression is titrated finely over a range of levels. We are interested in exploiting this allelic variation to study gene function and downstream consequences of differences in expression dosage. We have used several bioinformatics and molecular approaches to estimate error rates in the discovery of cis modulation and to analyze some of the biological and technical confounds that contribute to the variation in gene expression profiling. Our analysis of SNPs and alternative transcripts, combined with eQTL maps and selective gene resequencing, revealed that between 17 and 25% of apparent cis modulation is caused by SNPs that overlap probes rather than by genuine quantitative differences in mRNA levels. This estimate climbs to 40-50% when qualitative differences between isoform variants are included. We have developed an analytical approach to filter differences in expression and improve the yield of genuine cis-modulated transcripts to approximately 80%. This improvement is important because the resulting variation can be successfully used to study downstream consequences of altered expression on higher-order phenotypes. Using a systems genetics approach we show that two validated cis-modulated genes, Stk25 and Rasd2, are likely to control expression of downstream targets and affect disease susceptibility.

Addresses

Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA. dciobanu2@unl.edu

Autoren

Daniel C Ciobanu
Lu Lu
Khyobeni Mozhui
Xusheng Wang
Manjunatha Jagalur
John A Morris
William L Taylor
Klaus Dietz
Perikles Simon
Robert W Williams

DOI

10.1534/genetics.109.107474

eISSN

1943-2631

Externe Identifier

PubMed Identifier: 19884314
PubMed Central ID: PMC2802080

Funding acknowledgements

NIAAA NIH HHS: U01 AA013499
NCI NIH HHS: U01CA105417
NIDA NIH HHS: P20 DA021131
NIAAA NIH HHS: U01 AA014425
NIAAA NIH HHS: U01AA013499
NIDA NIH HHS: P20-DA 21131
NCI NIH HHS: U01 CA105417
NINR NIH HHS: U01NR 105417
NIAAA NIH HHS: U01AA014425

Open access

false

ISSN

0016-6731

Ausgabe der Veröffentlichung

1

Zeitschrift

Genetics

Schlüsselwörter

Animals
Humans
Mice
RNA, Messenger
3' Untranslated Regions
Oligonucleotide Array Sequence Analysis
Reproducibility of Results
Gene Expression Profiling
Polymerase Chain Reaction
Sequence Analysis, DNA
Computational Biology
Gene Expression
Transcription, Genetic
Alternative Splicing
Polymorphism, Single Nucleotide
Alleles
Quantitative Trait Loci
Databases, Genetic

Sprache

eng

Medium

Print-Electronic

Online publication date

2009

Paginierung

119 - 128

Datum der Veröffentlichung

2010

Status

Published

Datum der Datenerfassung

2009

Titel

Detection, validation, and downstream analysis of allelic variation in gene expression.

Sub types

research-article
Journal Article
Research Support, N.I.H., Extramural

Ausgabe der Zeitschrift

184

Files

https://academic.oup.com/genetics/article-pdf/184/1/119/49429457/genetics0119.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19884314/pdf/?tool=EBI https://europepmc.org/articles/PMC2802080?pdf=render

Datenquelle: Europe PubMed Central

Abstract

Common sequence variants within a gene often generate important differences in expression of corresponding mRNAs. This high level of local (allelic) control-or cis modulation-rivals that produced by gene targeting, but expression is titrated finely over a range of levels. We are interested in exploiting this allelic variation to study gene function and downstream consequences of differences in expression dosage. We have used several bioinformatics and molecular approaches to estimate error rates in the discovery of cis modulation and to analyze some of the biological and technical confounds that contribute to the variation in gene expression profiling. Our analysis of SNPs and alternative transcripts, combined with eQTL maps and selective gene resequencing, revealed that between 17 and 25% of apparent cis modulation is caused by SNPs that overlap probes rather than by genuine quantitative differences in mRNA levels. This estimate climbs to 40-50% when qualitative differences between isoform variants are included. We have developed an analytical approach to filter differences in expression and improve the yield of genuine cis-modulated transcripts to approximately 80%. This improvement is important because the resulting variation can be successfully used to study downstream consequences of altered expression on higher-order phenotypes. Using a systems genetics approach we show that two validated cis-modulated genes, Stk25 and Rasd2, are likely to control expression of downstream targets and affect disease susceptibility.

Autoren

Daniel C Ciobanu
Lu Lu
Khyobeni Mozhui
Xusheng Wang
Manjunatha Jagalur
John A Morris
William L Taylor
Klaus Dietz
Perikles Simon
Robert W Williams

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/19884314

DOI

10.1534/genetics.109.107474

eISSN

1943-2631

Externe Identifier

PubMed Central ID: PMC2802080

Funding acknowledgements

NIDA NIH HHS: P20-DA 21131
NCI NIH HHS: U01CA105417
NIDA NIH HHS: P20 DA021131
NIAAA NIH HHS: U01AA014425
NIAAA NIH HHS: U01AA013499
NCI NIH HHS: U01 CA105417
NIAAA NIH HHS: U01 AA013499
NIAAA NIH HHS: U01 AA014425
NINR NIH HHS: U01NR 105417

Ausgabe der Veröffentlichung

1

Zeitschrift

Genetics

Schlüsselwörter

3' Untranslated Regions
Alleles
Alternative Splicing
Animals
Computational Biology
Databases, Genetic
Gene Expression
Gene Expression Profiling
Humans
Mice
Oligonucleotide Array Sequence Analysis
Polymerase Chain Reaction
Polymorphism, Single Nucleotide
Quantitative Trait Loci
RNA, Messenger
Reproducibility of Results
Sequence Analysis, DNA
Transcription, Genetic

Sprache

eng

Country

United States

Paginierung

119 - 128

PII

genetics.109.107474

Datum der Veröffentlichung

2010

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2010

Titel

Detection, validation, and downstream analysis of allelic variation in gene expression.

Sub types

Journal Article
Research Support, N.I.H., Extramural

Ausgabe der Zeitschrift

184

Datenquelle: PubMed

Detection, validation, and downstream analysis of allelic variation in gene expression

Files

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