Bao et al.University of Tennessee Health Science Center, Memphis, TN
Human Molecular Genetics
April 11, 2007 [Pubmed]
This paper is largely a bioinformatic exercise. All of the biological data had been previously generated by others and conclusions from the work were not confirmed with any actual biology but the work is still interesting from a methodological standpoint. They use expression QTL mapping to extend the biologically significant finding of knockout mice and other mapped gene x phenotype interactions. This work was done using the recombinant inbred line BxD (B6xDBA) but the approach could easily be extended to inbred strains.
Bao et al. first used the Mammalian Phenotype Ontology to identify genes that had previously been shown to regulate neurological phenotypes. There were 630 genes from this list that were also present on the Affymetrix M430 microarray. Brain-wide expression variation across 42 BxD lines for these 630 genes were inspected for correlation with genetic variation genome-wide. Expression variation for 40 of these genes mapped back to 53 trans regulatory regions (some genes had more than one trans region. The association was most likely done (although the paper does not explicitly state this anywhere) with the WebQTL mapping tool. To identify candidate trans regulators, two methods were used.
One was searching the candidate region for genes known to have missense mutations between B6 and DBA strains. This points to Adcy2 as a regulator of Ntsr2 and there is literature that links them to the same biology, in this case nociception. Transcription factors within the trans peak with missense SNPs were of particular interest because they have direct method of modifying expression. Three of the initial 630 genes had a trans association with the region containing the Stat4 transcription factor and all three of those genes had Stat4 binging sites in their promoters likely confirming the association. The second method was to look for cis eQTLs within the trans region. The logic is that this will detect functional SNPs in the regulatory region of the gene and if the variation in expression of the cis gene matches the expression variation of the downstream gene that produced the original trans association, two genes are likely linked in the same pathway. This approach linked the expression of Myo7 to Myo6 and Ttc8 to Bbs4. There is literature that supports these associations.
As almost an afterthought, attempted to correlate gene expression variation with phenotypic variation using 67 behavioral or neurological phenotype that had previously been defined for BxD. One correlation, Ank2 with cocaine-induced activity in the open field, was corroborated by previously published data. This is type of association is not novel and has been done previously to a much better end.
Other useful items from the paper
Genetical Genomics - a term coined by Robert Williams to refer to the methods for the study of the genetics of gene expression on a genome wide scale.
Estimated that 25% of transcripts are highly heritable which they define as heritability > 0.5
Provides references for the public effort to generate a knock out mouse for every gene but I am not sure that they refer directly to the effort currently underway.
Recognize the difficulty of traditional QTL methods noting the phenotypes they used have not resulted in the identification of QTGs.
Paraphrasing Schadt et al give a nice break down on the reason on might see an association between gene expression and a phenotype. To quote from Bao et al,
Human Molecular Genetics
April 11, 2007 [Pubmed]
This paper is largely a bioinformatic exercise. All of the biological data had been previously generated by others and conclusions from the work were not confirmed with any actual biology but the work is still interesting from a methodological standpoint. They use expression QTL mapping to extend the biologically significant finding of knockout mice and other mapped gene x phenotype interactions. This work was done using the recombinant inbred line BxD (B6xDBA) but the approach could easily be extended to inbred strains.
Bao et al. first used the Mammalian Phenotype Ontology to identify genes that had previously been shown to regulate neurological phenotypes. There were 630 genes from this list that were also present on the Affymetrix M430 microarray. Brain-wide expression variation across 42 BxD lines for these 630 genes were inspected for correlation with genetic variation genome-wide. Expression variation for 40 of these genes mapped back to 53 trans regulatory regions (some genes had more than one trans region. The association was most likely done (although the paper does not explicitly state this anywhere) with the WebQTL mapping tool. To identify candidate trans regulators, two methods were used.
One was searching the candidate region for genes known to have missense mutations between B6 and DBA strains. This points to Adcy2 as a regulator of Ntsr2 and there is literature that links them to the same biology, in this case nociception. Transcription factors within the trans peak with missense SNPs were of particular interest because they have direct method of modifying expression. Three of the initial 630 genes had a trans association with the region containing the Stat4 transcription factor and all three of those genes had Stat4 binging sites in their promoters likely confirming the association. The second method was to look for cis eQTLs within the trans region. The logic is that this will detect functional SNPs in the regulatory region of the gene and if the variation in expression of the cis gene matches the expression variation of the downstream gene that produced the original trans association, two genes are likely linked in the same pathway. This approach linked the expression of Myo7 to Myo6 and Ttc8 to Bbs4. There is literature that supports these associations.
As almost an afterthought, attempted to correlate gene expression variation with phenotypic variation using 67 behavioral or neurological phenotype that had previously been defined for BxD. One correlation, Ank2 with cocaine-induced activity in the open field, was corroborated by previously published data. This is type of association is not novel and has been done previously to a much better end.
Other useful items from the paper
Genetical Genomics - a term coined by Robert Williams to refer to the methods for the study of the genetics of gene expression on a genome wide scale.
Estimated that 25% of transcripts are highly heritable which they define as heritability > 0.5
Provides references for the public effort to generate a knock out mouse for every gene but I am not sure that they refer directly to the effort currently underway.
Recognize the difficulty of traditional QTL methods noting the phenotypes they used have not resulted in the identification of QTGs.
Paraphrasing Schadt et al give a nice break down on the reason on might see an association between gene expression and a phenotype. To quote from Bao et al,
(i) causal model, where the common QTL acts on the gene expression trait and the gene regulates the phenotype trait; (ii) reactive model, where the common QTL acts on the phenotype trait and the gene expression trait is reactive to the phenotype and (iii) independent model, where the common QTL acts on the expression trait and phenotype trait independently.Whole proteome datasets are not yet available.
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