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Kinotypes: stable species- and individual-specific profiles of cellular kinase activity.

Trost B, Kindrachuk J, Scruten E, Griebel P, Kusalik A, Napper S - BMC Genomics (2013)

Bottom Line: Both humans and pigs also exhibited evidence for individual-specific kinome profiles that were independent of natural changes in blood cell populations.Species-specific kinotypes could have applications in disease research by facilitating the selection of appropriate animal models or by revealing a baseline kinomic signature to which treatment-induced profiles could be compared.Similarly, individual-specific kinotypes could have implications in personalized medicine, where the identification of molecular patterns or signatures within the kinome may depend on both the levels of kinome diversity and temporal stability across individuals.

View Article: PubMed Central - HTML - PubMed

Affiliation: Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Canada. scott.napper@usask.ca.

ABSTRACT

Background: Recently, questions have been raised regarding the ability of animal models to recapitulate human disease at the molecular level. It has also been demonstrated that cellular kinases, individually or as a collective unit (the kinome), play critical roles in regulating complex biology. Despite the intimate relationship between kinases and health, little is known about the variability, consistency and stability of kinome profiles across species and individuals.

Results: As a preliminary investigation of the existence of species- and individual-specific kinotypes (kinome signatures), peptide arrays were employed for the analysis of peripheral blood mononuclear cells collected weekly from human and porcine subjects (n = 6) over a one month period. The data revealed strong evidence for species-specific signalling profiles. Both humans and pigs also exhibited evidence for individual-specific kinome profiles that were independent of natural changes in blood cell populations.

Conclusions: Species-specific kinotypes could have applications in disease research by facilitating the selection of appropriate animal models or by revealing a baseline kinomic signature to which treatment-induced profiles could be compared. Similarly, individual-specific kinotypes could have implications in personalized medicine, where the identification of molecular patterns or signatures within the kinome may depend on both the levels of kinome diversity and temporal stability across individuals.

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Clustering of human and porcine kinome profiles. (a) Hierarchical clustering of human and porcine kinome profiles. The distance metric used was (1 – Pearson correlation), while McQuitty linkage was used as the linkage method. Rows correspond to probes (phosphorylation targets), and columns correspond to samples. The first character of each sample label identifies the species (“H” for human and “P” for pig), the second character identifies the individual from which the sample was taken, and the third indicates the time point. Colors indicate the average (over 9 intra-array replicates) normalized phosphorylation intensity of each target, with red indicating increased phosphorylation and green indicating decreased phosphorylation. The intensity of the color corresponds to the degree of increase or decrease [36]. (b) Distribution of random tree scores. The number of random trees having each random tree score is shown. For comparison, the score of the actual tree shown in part A is 97.9.
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Figure 1: Clustering of human and porcine kinome profiles. (a) Hierarchical clustering of human and porcine kinome profiles. The distance metric used was (1 – Pearson correlation), while McQuitty linkage was used as the linkage method. Rows correspond to probes (phosphorylation targets), and columns correspond to samples. The first character of each sample label identifies the species (“H” for human and “P” for pig), the second character identifies the individual from which the sample was taken, and the third indicates the time point. Colors indicate the average (over 9 intra-array replicates) normalized phosphorylation intensity of each target, with red indicating increased phosphorylation and green indicating decreased phosphorylation. The intensity of the color corresponds to the degree of increase or decrease [36]. (b) Distribution of random tree scores. The number of random trees having each random tree score is shown. For comparison, the score of the actual tree shown in part A is 97.9.

Mentions: All human and porcine kinome profiles were analyzed simultaneously using hierarchical clustering. There were significant differences in the profiles of humans and pigs, with nearly perfect species-specific separation of the samples (Figure 1a). Specifically, at the highest level of clustering, the samples separated into sample H2A (the first time point sample of human subject A) and all other samples (perhaps indicating that H2A was an outlier, as all the remaining samples for human subject A clustered exclusively with the other human samples). At the subsequent level, all remaining samples clustered into distinct, species-specific groups. To calculate the extent to which the samples clustered on the basis of species, the scoring metric T described in Methods was applied to the binary tree form of the dendrogram. The value of T was 97.9 out of 100, indicating near-perfect clustering by species. To determine whether T was greater than what would be expected by chance, the score was also calculated for 10,000 random trees. No random tree had a score >39.6 (Figure 1b), giving a P-value <0.0001. This supported the existence of species-specific patterns of kinome activity within human and porcine PBMCs.


Kinotypes: stable species- and individual-specific profiles of cellular kinase activity.

Trost B, Kindrachuk J, Scruten E, Griebel P, Kusalik A, Napper S - BMC Genomics (2013)

Clustering of human and porcine kinome profiles. (a) Hierarchical clustering of human and porcine kinome profiles. The distance metric used was (1 – Pearson correlation), while McQuitty linkage was used as the linkage method. Rows correspond to probes (phosphorylation targets), and columns correspond to samples. The first character of each sample label identifies the species (“H” for human and “P” for pig), the second character identifies the individual from which the sample was taken, and the third indicates the time point. Colors indicate the average (over 9 intra-array replicates) normalized phosphorylation intensity of each target, with red indicating increased phosphorylation and green indicating decreased phosphorylation. The intensity of the color corresponds to the degree of increase or decrease [36]. (b) Distribution of random tree scores. The number of random trees having each random tree score is shown. For comparison, the score of the actual tree shown in part A is 97.9.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3924188&req=5

Figure 1: Clustering of human and porcine kinome profiles. (a) Hierarchical clustering of human and porcine kinome profiles. The distance metric used was (1 – Pearson correlation), while McQuitty linkage was used as the linkage method. Rows correspond to probes (phosphorylation targets), and columns correspond to samples. The first character of each sample label identifies the species (“H” for human and “P” for pig), the second character identifies the individual from which the sample was taken, and the third indicates the time point. Colors indicate the average (over 9 intra-array replicates) normalized phosphorylation intensity of each target, with red indicating increased phosphorylation and green indicating decreased phosphorylation. The intensity of the color corresponds to the degree of increase or decrease [36]. (b) Distribution of random tree scores. The number of random trees having each random tree score is shown. For comparison, the score of the actual tree shown in part A is 97.9.
Mentions: All human and porcine kinome profiles were analyzed simultaneously using hierarchical clustering. There were significant differences in the profiles of humans and pigs, with nearly perfect species-specific separation of the samples (Figure 1a). Specifically, at the highest level of clustering, the samples separated into sample H2A (the first time point sample of human subject A) and all other samples (perhaps indicating that H2A was an outlier, as all the remaining samples for human subject A clustered exclusively with the other human samples). At the subsequent level, all remaining samples clustered into distinct, species-specific groups. To calculate the extent to which the samples clustered on the basis of species, the scoring metric T described in Methods was applied to the binary tree form of the dendrogram. The value of T was 97.9 out of 100, indicating near-perfect clustering by species. To determine whether T was greater than what would be expected by chance, the score was also calculated for 10,000 random trees. No random tree had a score >39.6 (Figure 1b), giving a P-value <0.0001. This supported the existence of species-specific patterns of kinome activity within human and porcine PBMCs.

Bottom Line: Both humans and pigs also exhibited evidence for individual-specific kinome profiles that were independent of natural changes in blood cell populations.Species-specific kinotypes could have applications in disease research by facilitating the selection of appropriate animal models or by revealing a baseline kinomic signature to which treatment-induced profiles could be compared.Similarly, individual-specific kinotypes could have implications in personalized medicine, where the identification of molecular patterns or signatures within the kinome may depend on both the levels of kinome diversity and temporal stability across individuals.

View Article: PubMed Central - HTML - PubMed

Affiliation: Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, Canada. scott.napper@usask.ca.

ABSTRACT

Background: Recently, questions have been raised regarding the ability of animal models to recapitulate human disease at the molecular level. It has also been demonstrated that cellular kinases, individually or as a collective unit (the kinome), play critical roles in regulating complex biology. Despite the intimate relationship between kinases and health, little is known about the variability, consistency and stability of kinome profiles across species and individuals.

Results: As a preliminary investigation of the existence of species- and individual-specific kinotypes (kinome signatures), peptide arrays were employed for the analysis of peripheral blood mononuclear cells collected weekly from human and porcine subjects (n = 6) over a one month period. The data revealed strong evidence for species-specific signalling profiles. Both humans and pigs also exhibited evidence for individual-specific kinome profiles that were independent of natural changes in blood cell populations.

Conclusions: Species-specific kinotypes could have applications in disease research by facilitating the selection of appropriate animal models or by revealing a baseline kinomic signature to which treatment-induced profiles could be compared. Similarly, individual-specific kinotypes could have implications in personalized medicine, where the identification of molecular patterns or signatures within the kinome may depend on both the levels of kinome diversity and temporal stability across individuals.

Show MeSH