Limits...
Genetic networks in the mouse retina: growth associated protein 43 and phosphatase tensin homolog network.

Freeman NE, Templeton JP, Orr WE, Lu L, Williams RW, Geisert EE - Mol. Vis. (2011)

Bottom Line: For example, we define the genetic network regulating growth associated protein 43 (Gap43) and phosphatase tensin homolog (Pten).Two genes associated with axonal outgrowth (Gap43 and Pten) were used to display the power of this new retina database.The Gap43 and Pten network highlights the covariance of gene expression and forms a molecular network associated with axonal outgrowth in the adult retina.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Center for Vision Research, Memphis, TN, USA.

ABSTRACT

Purpose: The present study examines the structure and covariance of endogenous variation in gene expression across the recently expanded family of C57BL/6J (B) X DBA/2J (D) Recombinant Inbred (BXD RI) strains of mice. This work is accompanied by a highly interactive database that can be used to generate and test specific hypotheses. For example, we define the genetic network regulating growth associated protein 43 (Gap43) and phosphatase tensin homolog (Pten).

Methods: The Hamilton Eye Institute (HEI) Retina Database within GeneNetwork features the data analysis of 346 Illumina Sentrix BeadChip Arrays (mouse whole genome-6 version 2). Eighty strains of mice are presented, including 75 BXD RI strains, the parental strains (C57BL/6J and DBA/2J), the reciprocal crosses, and the BALB/cByJ mice. Independent biologic samples for at least two animals from each gender were obtained with a narrow age range (48 to 118 days). Total RNA was prepared followed by the production of biotinylated cRNAs, which were pipetted into the Mouse WG-6V2 arrays. The data was globally normalized with rank invariant and stabilization (2z+8).

Results: The HEI Retina Database is located on the GeneNetwork website. The database was used to extract unique transcriptome signatures for specific cell types in the retina (retinal pigment epithelial, amacrine, and retinal ganglion cells). Two genes associated with axonal outgrowth (Gap43 and Pten) were used to display the power of this new retina database. Bioinformatic tools located within GeneNetwork in conjunction with the HEI Retina Database were used to identify the unique signature Quantitative Trait Loci (QTLs) for Gap43 and Pten on chromosomes 1, 2, 12, 15, 16, and 19. Gap43 and Pten possess networks that are similar to ganglion cell networks that may be associated with axonal growth in the mouse retina. This network involves high correlations of transcription factors (SRY sex determining region Y-box 2 [Sox2], paired box gene 6 [Pax6], and neurogenic differentiation 1 [Neurod1]), and genes involved in DNA binding (proliferating cell nuclear antigen [Pcna] and zinc finger, BED-type containing 4 [Zbed4]), as well as an inhibitor of DNA binding (inhibitor of DNA binding 2, dominant negative helix-loop-helix protein [Id2]). Furthermore, we identified the potential upstream modifiers on chromosome 2 (teashirt zinc finger homeobox 2 [Tshz2], RNA export 1 homolog [Rae1] and basic helix-loop-helix domain contatining, class B4 [Bhlhb4]) on chromosome 15 (RAB, member of RAS oncogene family-like 2a [Rabl2a], phosphomannomutase 1 [Pmm1], copine VIII [Cpne8], and fibulin 1 [Fbln1]).

Conclusions: The endogenous variation in mRNA levels among BXD RI strains can be used to explore and test expression networks underlying variation in retina structure, function, and disease susceptibility. The Gap43 and Pten network highlights the covariance of gene expression and forms a molecular network associated with axonal outgrowth in the adult retina.

Show MeSH

Related in: MedlinePlus

A genome-wide graph displaying the quantitative trait loci (QTL) distribution across the Hamilton Eye Institute (HEI) Retina Database. Each point on the graph represents a single probe set. The x-axis plots the locations of the QTLs controlling the transcript expression. Positions are measured in mega bases (Mb) from chromosome 1 to chromosome X (1–2600 Mb). The y-axis plots the chromosomal location of each of the transcripts. The significant levels of individual QTLs are color-coded. The low genome wide p-value or high likelihood ratio statistic (LRS) are represented by red, the intermediate p-value/LRS values are green, and the high genome-wide p-value/low LRS values are presented in blue. The diagonal (red) band plots the large number of highly significant cis-acting QTLs and the vertical bands represent major trans-acting QTLs that co-regulate large numbers of downstream transcripts. These data were plotted from the HEI Retina Database with a false discovery rate of 0.2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3108897&req=5

f2: A genome-wide graph displaying the quantitative trait loci (QTL) distribution across the Hamilton Eye Institute (HEI) Retina Database. Each point on the graph represents a single probe set. The x-axis plots the locations of the QTLs controlling the transcript expression. Positions are measured in mega bases (Mb) from chromosome 1 to chromosome X (1–2600 Mb). The y-axis plots the chromosomal location of each of the transcripts. The significant levels of individual QTLs are color-coded. The low genome wide p-value or high likelihood ratio statistic (LRS) are represented by red, the intermediate p-value/LRS values are green, and the high genome-wide p-value/low LRS values are presented in blue. The diagonal (red) band plots the large number of highly significant cis-acting QTLs and the vertical bands represent major trans-acting QTLs that co-regulate large numbers of downstream transcripts. These data were plotted from the HEI Retina Database with a false discovery rate of 0.2.

Mentions: The HEI Retina Database presents the retinal transcriptome profiles of 75 BXD RI strains in a highly interactive website, GeneNetwork. The analytical tools within GeneNetwork allow for the a) systematic interrogation of the data set by identifying genetic variability across the BXD RI strains, b) constructing genetic networks controlling the development of the mouse retina, and c) defining the genomic loci underlying complex traits in the retina. To define genetic networks, quantitative trait analysis within GeneNetwork is used to reveal quantitative trait loci (QTLs) that modulate gene expression levels. Within the HEI Retina Database, there are a total of 11,141 probes with significant QTLs; 6,711 are trans-acting QTLs, while 4,078 QTLs are defined as cis-acting QTLs. The cis-acting QTLs are located at the same genomic locus as the gene of interest, while the trans-acting QTLs have genomic loci that modulate gene expression on a different location in the genome (for a complete discussion of trans-acting QTLs and cis-acting QTLs see [13]). The significant QTLs have a likelihood ratio statistic (LRS) over 15 (defined by GeneNetwork), which is the measurement of the linkage between the differences in mRNA expression and the differences in a particular DNA sequence. One way to visualize the total number of QTLs in the HEI Retina Database is to plot a genome-wide graph of all the QTLs, as shown in Figure 2. The graph displays the location of the best QTL for each probe set plotted against the corresponding location of the gene. The plot of the chromosomal location of each transcript with the corresponding position of the transcript’s largest QTL reveals the structure of the interactions of the transcripts within the BXD RI retina. The diagonal (red) band in Figure 2 represents the cis-acting QTLs, which are responsible for initiating the variations in gene expression. Generally, the cis-acting QTLs tend to have high LRS scores (>25). QTLs plotted away from this diagonal band represent the trans-acting QTLs and are most likely modulated by a cis-acting QTL at that genomic locus. On average, the LRS scores of the trans-acting QTLs tend to be lower than those of cis-acting QTLs. The co-regulated transcripts are represented as the vertical bands within the trans-acting QTLs. Thus, the retinal genome graph allows the visualization of the genetic sources of variation in the transcript expression of the retina at a global level.


Genetic networks in the mouse retina: growth associated protein 43 and phosphatase tensin homolog network.

Freeman NE, Templeton JP, Orr WE, Lu L, Williams RW, Geisert EE - Mol. Vis. (2011)

A genome-wide graph displaying the quantitative trait loci (QTL) distribution across the Hamilton Eye Institute (HEI) Retina Database. Each point on the graph represents a single probe set. The x-axis plots the locations of the QTLs controlling the transcript expression. Positions are measured in mega bases (Mb) from chromosome 1 to chromosome X (1–2600 Mb). The y-axis plots the chromosomal location of each of the transcripts. The significant levels of individual QTLs are color-coded. The low genome wide p-value or high likelihood ratio statistic (LRS) are represented by red, the intermediate p-value/LRS values are green, and the high genome-wide p-value/low LRS values are presented in blue. The diagonal (red) band plots the large number of highly significant cis-acting QTLs and the vertical bands represent major trans-acting QTLs that co-regulate large numbers of downstream transcripts. These data were plotted from the HEI Retina Database with a false discovery rate of 0.2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108897&req=5

f2: A genome-wide graph displaying the quantitative trait loci (QTL) distribution across the Hamilton Eye Institute (HEI) Retina Database. Each point on the graph represents a single probe set. The x-axis plots the locations of the QTLs controlling the transcript expression. Positions are measured in mega bases (Mb) from chromosome 1 to chromosome X (1–2600 Mb). The y-axis plots the chromosomal location of each of the transcripts. The significant levels of individual QTLs are color-coded. The low genome wide p-value or high likelihood ratio statistic (LRS) are represented by red, the intermediate p-value/LRS values are green, and the high genome-wide p-value/low LRS values are presented in blue. The diagonal (red) band plots the large number of highly significant cis-acting QTLs and the vertical bands represent major trans-acting QTLs that co-regulate large numbers of downstream transcripts. These data were plotted from the HEI Retina Database with a false discovery rate of 0.2.
Mentions: The HEI Retina Database presents the retinal transcriptome profiles of 75 BXD RI strains in a highly interactive website, GeneNetwork. The analytical tools within GeneNetwork allow for the a) systematic interrogation of the data set by identifying genetic variability across the BXD RI strains, b) constructing genetic networks controlling the development of the mouse retina, and c) defining the genomic loci underlying complex traits in the retina. To define genetic networks, quantitative trait analysis within GeneNetwork is used to reveal quantitative trait loci (QTLs) that modulate gene expression levels. Within the HEI Retina Database, there are a total of 11,141 probes with significant QTLs; 6,711 are trans-acting QTLs, while 4,078 QTLs are defined as cis-acting QTLs. The cis-acting QTLs are located at the same genomic locus as the gene of interest, while the trans-acting QTLs have genomic loci that modulate gene expression on a different location in the genome (for a complete discussion of trans-acting QTLs and cis-acting QTLs see [13]). The significant QTLs have a likelihood ratio statistic (LRS) over 15 (defined by GeneNetwork), which is the measurement of the linkage between the differences in mRNA expression and the differences in a particular DNA sequence. One way to visualize the total number of QTLs in the HEI Retina Database is to plot a genome-wide graph of all the QTLs, as shown in Figure 2. The graph displays the location of the best QTL for each probe set plotted against the corresponding location of the gene. The plot of the chromosomal location of each transcript with the corresponding position of the transcript’s largest QTL reveals the structure of the interactions of the transcripts within the BXD RI retina. The diagonal (red) band in Figure 2 represents the cis-acting QTLs, which are responsible for initiating the variations in gene expression. Generally, the cis-acting QTLs tend to have high LRS scores (>25). QTLs plotted away from this diagonal band represent the trans-acting QTLs and are most likely modulated by a cis-acting QTL at that genomic locus. On average, the LRS scores of the trans-acting QTLs tend to be lower than those of cis-acting QTLs. The co-regulated transcripts are represented as the vertical bands within the trans-acting QTLs. Thus, the retinal genome graph allows the visualization of the genetic sources of variation in the transcript expression of the retina at a global level.

Bottom Line: For example, we define the genetic network regulating growth associated protein 43 (Gap43) and phosphatase tensin homolog (Pten).Two genes associated with axonal outgrowth (Gap43 and Pten) were used to display the power of this new retina database.The Gap43 and Pten network highlights the covariance of gene expression and forms a molecular network associated with axonal outgrowth in the adult retina.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Center for Vision Research, Memphis, TN, USA.

ABSTRACT

Purpose: The present study examines the structure and covariance of endogenous variation in gene expression across the recently expanded family of C57BL/6J (B) X DBA/2J (D) Recombinant Inbred (BXD RI) strains of mice. This work is accompanied by a highly interactive database that can be used to generate and test specific hypotheses. For example, we define the genetic network regulating growth associated protein 43 (Gap43) and phosphatase tensin homolog (Pten).

Methods: The Hamilton Eye Institute (HEI) Retina Database within GeneNetwork features the data analysis of 346 Illumina Sentrix BeadChip Arrays (mouse whole genome-6 version 2). Eighty strains of mice are presented, including 75 BXD RI strains, the parental strains (C57BL/6J and DBA/2J), the reciprocal crosses, and the BALB/cByJ mice. Independent biologic samples for at least two animals from each gender were obtained with a narrow age range (48 to 118 days). Total RNA was prepared followed by the production of biotinylated cRNAs, which were pipetted into the Mouse WG-6V2 arrays. The data was globally normalized with rank invariant and stabilization (2z+8).

Results: The HEI Retina Database is located on the GeneNetwork website. The database was used to extract unique transcriptome signatures for specific cell types in the retina (retinal pigment epithelial, amacrine, and retinal ganglion cells). Two genes associated with axonal outgrowth (Gap43 and Pten) were used to display the power of this new retina database. Bioinformatic tools located within GeneNetwork in conjunction with the HEI Retina Database were used to identify the unique signature Quantitative Trait Loci (QTLs) for Gap43 and Pten on chromosomes 1, 2, 12, 15, 16, and 19. Gap43 and Pten possess networks that are similar to ganglion cell networks that may be associated with axonal growth in the mouse retina. This network involves high correlations of transcription factors (SRY sex determining region Y-box 2 [Sox2], paired box gene 6 [Pax6], and neurogenic differentiation 1 [Neurod1]), and genes involved in DNA binding (proliferating cell nuclear antigen [Pcna] and zinc finger, BED-type containing 4 [Zbed4]), as well as an inhibitor of DNA binding (inhibitor of DNA binding 2, dominant negative helix-loop-helix protein [Id2]). Furthermore, we identified the potential upstream modifiers on chromosome 2 (teashirt zinc finger homeobox 2 [Tshz2], RNA export 1 homolog [Rae1] and basic helix-loop-helix domain contatining, class B4 [Bhlhb4]) on chromosome 15 (RAB, member of RAS oncogene family-like 2a [Rabl2a], phosphomannomutase 1 [Pmm1], copine VIII [Cpne8], and fibulin 1 [Fbln1]).

Conclusions: The endogenous variation in mRNA levels among BXD RI strains can be used to explore and test expression networks underlying variation in retina structure, function, and disease susceptibility. The Gap43 and Pten network highlights the covariance of gene expression and forms a molecular network associated with axonal outgrowth in the adult retina.

Show MeSH
Related in: MedlinePlus