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Bimodal distribution of RNA expression levels in human skeletal muscle tissue.

Mason CC, Hanson RL, Ossowski V, Bian L, Baier LJ, Krakoff J, Bogardus C - BMC Genomics (2011)

Bottom Line: Association of expression with cis genetic variation in a subset of 149 individuals found all but one of the confirmed bimodal genes and nearly half of all potential ones to be highly significant expression quantitative trait loci (eQTL).The rare prevalence of these bimodally expressed genes found after controlling for batch effects was much lower than the prevalence reported in other studies.We conclude that the prevalence of bimodal gene expression is quite rare in healthy muscle tissue (<0.2%), and is much lower than limited reports from other studies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, 1550 E, Indian School Rd, Phoenix, AZ 85014, USA. masonclint@niddk.nih.gov

ABSTRACT

Background: Many human diseases and phenotypes are related to RNA expression, levels of which are influenced by a wide spectrum of genetic and exposure-related factors. In a large genome-wide study of muscle tissue expression, we found that some genes exhibited a bimodal distribution of RNA expression, in contrast to what is usually assumed in studies of a single healthy tissue. As bimodality has classically been considered a hallmark of genetic control, we assessed the genome-wide prevalence, cause, and association of this phenomenon with diabetes-related phenotypes in skeletal muscle tissue from 225 healthy Pima Indians using exon array expression chips.

Results: Two independent batches of microarrays were used for bimodal assessment and comparison. Of the 17,881 genes analyzed, eight (GSTM1, HLA-DRB1, ERAP2, HLA-DRB5, MAOA, ACTN3, NR4A2, and THNSL2) were found to have bimodal expression replicated in the separate batch groups, while 24 other genes had evidence of bimodality in only one group. Some bimodally expressed genes had modest associations with pre-diabetic phenotypes, of note ACTN3 with insulin resistance. Most of the other bimodal genes have been reported to be involved with various other diseases and characteristics. Association of expression with cis genetic variation in a subset of 149 individuals found all but one of the confirmed bimodal genes and nearly half of all potential ones to be highly significant expression quantitative trait loci (eQTL). The rare prevalence of these bimodally expressed genes found after controlling for batch effects was much lower than the prevalence reported in other studies. Additional validation in data from separate muscle expression studies confirmed the low prevalence of bimodality we observed.

Conclusions: We conclude that the prevalence of bimodal gene expression is quite rare in healthy muscle tissue (<0.2%), and is much lower than limited reports from other studies. The major cause of these clearly bimodal expression patterns in homogeneous tissue appears to be cis-polymorphisms, indicating that such bimodal genes are, for the most part, eQTL. The high frequency of disease associations reported with these genes gives hope that this unique feature may identify or actually be an underlying factor responsible for disease development.

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Histograms of the eight confirmed bimodal genes. Shown is the distribution of RNA expression values for the entire data set of n = 225. The 8 genes shown above correspond to: glutathione S-transferase mu 1 (GSTM1), major histocompatibility complex, class II, DR beta 1 (HLA-DRB1), endoplasmic reticulum aminopeptidase 2 (ERAP2), major histocompatibility complex, class II, DR beta 5 (HLA-DRB5), monoamine oxidase A (MAOA), actinin, alpha 3 (ACTN3), nuclear receptor subfamily 4, group A, member 2 (NR4A2), and threonine synthase-like 2 (THNSL2).
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Figure 2: Histograms of the eight confirmed bimodal genes. Shown is the distribution of RNA expression values for the entire data set of n = 225. The 8 genes shown above correspond to: glutathione S-transferase mu 1 (GSTM1), major histocompatibility complex, class II, DR beta 1 (HLA-DRB1), endoplasmic reticulum aminopeptidase 2 (ERAP2), major histocompatibility complex, class II, DR beta 5 (HLA-DRB5), monoamine oxidase A (MAOA), actinin, alpha 3 (ACTN3), nuclear receptor subfamily 4, group A, member 2 (NR4A2), and threonine synthase-like 2 (THNSL2).

Mentions: The total number of bimodally expressed genes estimated in each of the chip groups using different requirements for genuine bimodality is shown in Table 2. This analysis by group found only a small number of genes to be bimodally expressed with little overlap between the two components of the distribution, 19 in group A and 21 in group B, comprising a total of 32 unique genes (Table 3). Of these, 8 genes (GSTM1, HLA-DRB1, ERAP2, HLA-DRB5, MAOA, ACTN3, NR4A2, and THNSL2) were found to meet the stringent bimodal criterion in group A, group B, and the total study of 225 samples. Figure 2 shows the log2 expression level distributions for each of these confirmed bimodal genes. An additional 10 genes identified as bimodal had significant association with gender, of which 9 were located on the Y chromosome (Additional file 2).


Bimodal distribution of RNA expression levels in human skeletal muscle tissue.

Mason CC, Hanson RL, Ossowski V, Bian L, Baier LJ, Krakoff J, Bogardus C - BMC Genomics (2011)

Histograms of the eight confirmed bimodal genes. Shown is the distribution of RNA expression values for the entire data set of n = 225. The 8 genes shown above correspond to: glutathione S-transferase mu 1 (GSTM1), major histocompatibility complex, class II, DR beta 1 (HLA-DRB1), endoplasmic reticulum aminopeptidase 2 (ERAP2), major histocompatibility complex, class II, DR beta 5 (HLA-DRB5), monoamine oxidase A (MAOA), actinin, alpha 3 (ACTN3), nuclear receptor subfamily 4, group A, member 2 (NR4A2), and threonine synthase-like 2 (THNSL2).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3044673&req=5

Figure 2: Histograms of the eight confirmed bimodal genes. Shown is the distribution of RNA expression values for the entire data set of n = 225. The 8 genes shown above correspond to: glutathione S-transferase mu 1 (GSTM1), major histocompatibility complex, class II, DR beta 1 (HLA-DRB1), endoplasmic reticulum aminopeptidase 2 (ERAP2), major histocompatibility complex, class II, DR beta 5 (HLA-DRB5), monoamine oxidase A (MAOA), actinin, alpha 3 (ACTN3), nuclear receptor subfamily 4, group A, member 2 (NR4A2), and threonine synthase-like 2 (THNSL2).
Mentions: The total number of bimodally expressed genes estimated in each of the chip groups using different requirements for genuine bimodality is shown in Table 2. This analysis by group found only a small number of genes to be bimodally expressed with little overlap between the two components of the distribution, 19 in group A and 21 in group B, comprising a total of 32 unique genes (Table 3). Of these, 8 genes (GSTM1, HLA-DRB1, ERAP2, HLA-DRB5, MAOA, ACTN3, NR4A2, and THNSL2) were found to meet the stringent bimodal criterion in group A, group B, and the total study of 225 samples. Figure 2 shows the log2 expression level distributions for each of these confirmed bimodal genes. An additional 10 genes identified as bimodal had significant association with gender, of which 9 were located on the Y chromosome (Additional file 2).

Bottom Line: Association of expression with cis genetic variation in a subset of 149 individuals found all but one of the confirmed bimodal genes and nearly half of all potential ones to be highly significant expression quantitative trait loci (eQTL).The rare prevalence of these bimodally expressed genes found after controlling for batch effects was much lower than the prevalence reported in other studies.We conclude that the prevalence of bimodal gene expression is quite rare in healthy muscle tissue (<0.2%), and is much lower than limited reports from other studies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, 1550 E, Indian School Rd, Phoenix, AZ 85014, USA. masonclint@niddk.nih.gov

ABSTRACT

Background: Many human diseases and phenotypes are related to RNA expression, levels of which are influenced by a wide spectrum of genetic and exposure-related factors. In a large genome-wide study of muscle tissue expression, we found that some genes exhibited a bimodal distribution of RNA expression, in contrast to what is usually assumed in studies of a single healthy tissue. As bimodality has classically been considered a hallmark of genetic control, we assessed the genome-wide prevalence, cause, and association of this phenomenon with diabetes-related phenotypes in skeletal muscle tissue from 225 healthy Pima Indians using exon array expression chips.

Results: Two independent batches of microarrays were used for bimodal assessment and comparison. Of the 17,881 genes analyzed, eight (GSTM1, HLA-DRB1, ERAP2, HLA-DRB5, MAOA, ACTN3, NR4A2, and THNSL2) were found to have bimodal expression replicated in the separate batch groups, while 24 other genes had evidence of bimodality in only one group. Some bimodally expressed genes had modest associations with pre-diabetic phenotypes, of note ACTN3 with insulin resistance. Most of the other bimodal genes have been reported to be involved with various other diseases and characteristics. Association of expression with cis genetic variation in a subset of 149 individuals found all but one of the confirmed bimodal genes and nearly half of all potential ones to be highly significant expression quantitative trait loci (eQTL). The rare prevalence of these bimodally expressed genes found after controlling for batch effects was much lower than the prevalence reported in other studies. Additional validation in data from separate muscle expression studies confirmed the low prevalence of bimodality we observed.

Conclusions: We conclude that the prevalence of bimodal gene expression is quite rare in healthy muscle tissue (<0.2%), and is much lower than limited reports from other studies. The major cause of these clearly bimodal expression patterns in homogeneous tissue appears to be cis-polymorphisms, indicating that such bimodal genes are, for the most part, eQTL. The high frequency of disease associations reported with these genes gives hope that this unique feature may identify or actually be an underlying factor responsible for disease development.

Show MeSH
Related in: MedlinePlus