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

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: T...

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Autores principales: Verdugo, Ricardo A, Farber, Charles R, Warden, Craig H, Medrano, Juan F
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919467/
https://www.ncbi.nlm.nih.gov/pubmed/20624276
http://dx.doi.org/10.1186/1741-7007-8-96
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author Verdugo, Ricardo A
Farber, Charles R
Warden, Craig H
Medrano, Juan F
author_facet Verdugo, Ricardo A
Farber, Charles R
Warden, Craig H
Medrano, Juan F
author_sort Verdugo, Ricardo A
collection PubMed
description 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.
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spelling pubmed-29194672010-08-11 Serious limitations of the QTL/Microarray approach for QTL gene discovery Verdugo, Ricardo A Farber, Charles R Warden, Craig H Medrano, Juan F BMC Biol Research Article 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. BioMed Central 2010-07-12 /pmc/articles/PMC2919467/ /pubmed/20624276 http://dx.doi.org/10.1186/1741-7007-8-96 Text en Copyright ©2010 Verdugo et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Verdugo, Ricardo A
Farber, Charles R
Warden, Craig H
Medrano, Juan F
Serious limitations of the QTL/Microarray approach for QTL gene discovery
title Serious limitations of the QTL/Microarray approach for QTL gene discovery
title_full Serious limitations of the QTL/Microarray approach for QTL gene discovery
title_fullStr Serious limitations of the QTL/Microarray approach for QTL gene discovery
title_full_unstemmed Serious limitations of the QTL/Microarray approach for QTL gene discovery
title_short Serious limitations of the QTL/Microarray approach for QTL gene discovery
title_sort serious limitations of the qtl/microarray approach for qtl gene discovery
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2919467/
https://www.ncbi.nlm.nih.gov/pubmed/20624276
http://dx.doi.org/10.1186/1741-7007-8-96
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