Serious limitations of the QTL/Microarray approach for QTL gene discovery

Ricardo A. Verdugo, Charles R. Farber, Craig H Warden, Juan F. Medrano

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Background: It has been proposed that the use of gene expression microarrays in nonrecombinant parental or congenic strains can accelerate the process of isolating individual genes underlying quantitative trait loci (QTL). However, the effectiveness of this approach has not been assessed.Results: Thirty-seven studies that have implemented the QTL/microarray approach in rodents were reviewed. About 30% of studies showed enrichment for QTL candidates, mostly in comparisons between congenic and background strains. Three studies led to the identification of an underlying QTL gene. To complement the literature results, a microarray experiment was performed using three mouse congenic strains isolating the effects of at least 25 biometric QTL. Results show that genes in the congenic donor regions were preferentially selected. However, within donor regions, the distribution of differentially expressed genes was homogeneous once gene density was accounted for. Genes within identical-by-descent (IBD) regions were less likely to be differentially expressed in chromosome 2, but not in chromosomes 11 and 17. Furthermore, expression of QTL regulated in cis (cis eQTL) showed higher expression in the background genotype, which was partially explained by the presence of single nucleotide polymorphisms (SNP).Conclusions: The literature shows limited successes from the QTL/microarray approach to identify QTL genes. Our own results from microarray profiling of three congenic strains revealed a strong tendency to select cis-eQTL over trans-eQTL. IBD regions had little effect on rate of differential expression, and we provide several reasons why IBD should not be used to discard eQTL candidates. In addition, mismatch probes produced false cis-eQTL that could not be completely removed with the current strains genotypes and low probe density microarrays. The reviewed studies did not account for lack of coverage from the platforms used and therefore removed genes that were not tested. Together, our results explain the tendency to report QTL candidates as differentially expressed and indicate that the utility of the QTL/microarray as currently implemented is limited. Alternatives are proposed that make use of microarray data from multiple experiments to overcome the outlined limitations.

Original languageEnglish (US)
Article number96
JournalBMC Biology
Volume8
DOIs
StatePublished - Jul 12 2010

Fingerprint

Quantitative Trait Loci
Genetic Association Studies
Microarrays
quantitative trait loci
Genes
gene
genes
Chromosomes
chromosome
genotype
probe
Genotype
biometry
Congenic Mice
chromosomes
Biometrics
Polymorphism
Chromosomes, Human, Pair 11
Chromosomes, Human, Pair 17
Gene expression

ASJC Scopus subject areas

  • Physiology
  • Biotechnology
  • Structural Biology
  • Developmental Biology
  • Plant Science
  • Ecology, Evolution, Behavior and Systematics
  • Cell Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Serious limitations of the QTL/Microarray approach for QTL gene discovery. / Verdugo, Ricardo A.; Farber, Charles R.; Warden, Craig H; Medrano, Juan F.

In: BMC Biology, Vol. 8, 96, 12.07.2010.

Research output: Contribution to journalArticle

Verdugo, Ricardo A. ; Farber, Charles R. ; Warden, Craig H ; Medrano, Juan F. / Serious limitations of the QTL/Microarray approach for QTL gene discovery. In: BMC Biology. 2010 ; Vol. 8.
@article{d5bd700b23a5415599fbeedc5b614566,
title = "Serious limitations of the QTL/Microarray approach for QTL gene discovery",
abstract = "Background: It has been proposed that the use of gene expression microarrays in nonrecombinant parental or congenic strains can accelerate the process of isolating individual genes underlying quantitative trait loci (QTL). However, the effectiveness of this approach has not been assessed.Results: Thirty-seven studies that have implemented the QTL/microarray approach in rodents were reviewed. About 30{\%} of studies showed enrichment for QTL candidates, mostly in comparisons between congenic and background strains. Three studies led to the identification of an underlying QTL gene. To complement the literature results, a microarray experiment was performed using three mouse congenic strains isolating the effects of at least 25 biometric QTL. Results show that genes in the congenic donor regions were preferentially selected. However, within donor regions, the distribution of differentially expressed genes was homogeneous once gene density was accounted for. Genes within identical-by-descent (IBD) regions were less likely to be differentially expressed in chromosome 2, but not in chromosomes 11 and 17. Furthermore, expression of QTL regulated in cis (cis eQTL) showed higher expression in the background genotype, which was partially explained by the presence of single nucleotide polymorphisms (SNP).Conclusions: The literature shows limited successes from the QTL/microarray approach to identify QTL genes. Our own results from microarray profiling of three congenic strains revealed a strong tendency to select cis-eQTL over trans-eQTL. IBD regions had little effect on rate of differential expression, and we provide several reasons why IBD should not be used to discard eQTL candidates. In addition, mismatch probes produced false cis-eQTL that could not be completely removed with the current strains genotypes and low probe density microarrays. The reviewed studies did not account for lack of coverage from the platforms used and therefore removed genes that were not tested. Together, our results explain the tendency to report QTL candidates as differentially expressed and indicate that the utility of the QTL/microarray as currently implemented is limited. Alternatives are proposed that make use of microarray data from multiple experiments to overcome the outlined limitations.",
author = "Verdugo, {Ricardo A.} and Farber, {Charles R.} and Warden, {Craig H} and Medrano, {Juan F.}",
year = "2010",
month = "7",
day = "12",
doi = "10.1186/1741-7007-8-96",
language = "English (US)",
volume = "8",
journal = "BMC Biology",
issn = "1741-7007",
publisher = "BioMed Central",

}

TY - JOUR

T1 - Serious limitations of the QTL/Microarray approach for QTL gene discovery

AU - Verdugo, Ricardo A.

AU - Farber, Charles R.

AU - Warden, Craig H

AU - Medrano, Juan F.

PY - 2010/7/12

Y1 - 2010/7/12

N2 - Background: It has been proposed that the use of gene expression microarrays in nonrecombinant parental or congenic strains can accelerate the process of isolating individual genes underlying quantitative trait loci (QTL). However, the effectiveness of this approach has not been assessed.Results: Thirty-seven studies that have implemented the QTL/microarray approach in rodents were reviewed. About 30% of studies showed enrichment for QTL candidates, mostly in comparisons between congenic and background strains. Three studies led to the identification of an underlying QTL gene. To complement the literature results, a microarray experiment was performed using three mouse congenic strains isolating the effects of at least 25 biometric QTL. Results show that genes in the congenic donor regions were preferentially selected. However, within donor regions, the distribution of differentially expressed genes was homogeneous once gene density was accounted for. Genes within identical-by-descent (IBD) regions were less likely to be differentially expressed in chromosome 2, but not in chromosomes 11 and 17. Furthermore, expression of QTL regulated in cis (cis eQTL) showed higher expression in the background genotype, which was partially explained by the presence of single nucleotide polymorphisms (SNP).Conclusions: The literature shows limited successes from the QTL/microarray approach to identify QTL genes. Our own results from microarray profiling of three congenic strains revealed a strong tendency to select cis-eQTL over trans-eQTL. IBD regions had little effect on rate of differential expression, and we provide several reasons why IBD should not be used to discard eQTL candidates. In addition, mismatch probes produced false cis-eQTL that could not be completely removed with the current strains genotypes and low probe density microarrays. The reviewed studies did not account for lack of coverage from the platforms used and therefore removed genes that were not tested. Together, our results explain the tendency to report QTL candidates as differentially expressed and indicate that the utility of the QTL/microarray as currently implemented is limited. Alternatives are proposed that make use of microarray data from multiple experiments to overcome the outlined limitations.

AB - Background: It has been proposed that the use of gene expression microarrays in nonrecombinant parental or congenic strains can accelerate the process of isolating individual genes underlying quantitative trait loci (QTL). However, the effectiveness of this approach has not been assessed.Results: Thirty-seven studies that have implemented the QTL/microarray approach in rodents were reviewed. About 30% of studies showed enrichment for QTL candidates, mostly in comparisons between congenic and background strains. Three studies led to the identification of an underlying QTL gene. To complement the literature results, a microarray experiment was performed using three mouse congenic strains isolating the effects of at least 25 biometric QTL. Results show that genes in the congenic donor regions were preferentially selected. However, within donor regions, the distribution of differentially expressed genes was homogeneous once gene density was accounted for. Genes within identical-by-descent (IBD) regions were less likely to be differentially expressed in chromosome 2, but not in chromosomes 11 and 17. Furthermore, expression of QTL regulated in cis (cis eQTL) showed higher expression in the background genotype, which was partially explained by the presence of single nucleotide polymorphisms (SNP).Conclusions: The literature shows limited successes from the QTL/microarray approach to identify QTL genes. Our own results from microarray profiling of three congenic strains revealed a strong tendency to select cis-eQTL over trans-eQTL. IBD regions had little effect on rate of differential expression, and we provide several reasons why IBD should not be used to discard eQTL candidates. In addition, mismatch probes produced false cis-eQTL that could not be completely removed with the current strains genotypes and low probe density microarrays. The reviewed studies did not account for lack of coverage from the platforms used and therefore removed genes that were not tested. Together, our results explain the tendency to report QTL candidates as differentially expressed and indicate that the utility of the QTL/microarray as currently implemented is limited. Alternatives are proposed that make use of microarray data from multiple experiments to overcome the outlined limitations.

UR - http://www.scopus.com/inward/record.url?scp=77954393668&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954393668&partnerID=8YFLogxK

U2 - 10.1186/1741-7007-8-96

DO - 10.1186/1741-7007-8-96

M3 - Article

VL - 8

JO - BMC Biology

JF - BMC Biology

SN - 1741-7007

M1 - 96

ER -