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Identification of 2R-ohnologue gene families displaying the same mutation-load skew in multiple cancers.

Tinti M, Dissanayake K, Synowsky S, Albergante L, MacKintosh C - Open Biol (2014)

Bottom Line: The complexity of signalling pathways was boosted at the origin of the vertebrates, when two rounds of whole genome duplication (2R-WGD) occurred.The non-mutated 2R-ohnologues are therefore potential therapeutic targets.These include proteins linked to growth factor signalling, neurotransmission and ion channels.

View Article: PubMed Central - PubMed

Affiliation: Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.

ABSTRACT
The complexity of signalling pathways was boosted at the origin of the vertebrates, when two rounds of whole genome duplication (2R-WGD) occurred. Those genes and proteins that have survived from the 2R-WGD-termed 2R-ohnologues-belong to families of two to four members, and are enriched in signalling components relevant to cancer. Here, we find that while only approximately 30% of human transcript-coding genes are 2R-ohnologues, they carry 42-60% of the gene mutations in 30 different cancer types. Across a subset of cancer datasets, including melanoma, breast, lung adenocarcinoma, liver and medulloblastoma, we identified 673 2R-ohnologue families in which one gene carries mutations at multiple positions, while sister genes in the same family are relatively mutation free. Strikingly, in 315 of the 322 2R-ohnologue families displaying such a skew in multiple cancers, the same gene carries the heaviest mutation load in each cancer, and usually the second-ranked gene is also the same in each cancer. Our findings inspire the hypothesis that in certain cancers, heterogeneous combinations of genetic changes impair parts of the 2R-WGD signalling networks and force information flow through a limited set of oncogenic pathways in which specific non-mutated 2R-ohnologues serve as effectors. The non-mutated 2R-ohnologues are therefore potential therapeutic targets. These include proteins linked to growth factor signalling, neurotransmission and ion channels.

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Related in: MedlinePlus

MLs of 2R-ohnologue genes in melanoma. (a) For the melanoma dataset [15], the figure plots the ML distribution for 2R-ohnologues within families of 2, 3 and 4 members. Only families in which at least one gene carries carried 10 or more different mutations are included. The ML is computed by summing the total number of mutations identified for a gene divided by the total number of mutations in all members of the same 2R-ohnologue family. The y-axes give the number of genes, with the ML scores indicated on the x-axes. Each histogram set indicates the medians (red lines), interquartile ranges (rectangular boxes) and outliers (green diamonds) for the ML distributions. Note that for families of 2 members, the median will always be 0.5 by construction, regardless of the ML distribution profile. Data file S1 in the electronic supplementary material presents the corresponding histograms for 30 cancer types, and its legend contains a discussion note about statistics. (b) The distribution of mutations in melanoma is given for the HECW E3 ubiquitin ligase family (as an example of even ML distribution) and the type II PAK family (an example with a skewed ML where the PAK7 gene accumulates most of the family mutations). Illustrations were created with Domain Graph, v. 1.0.5 [26]. CDS is coding sequence, UTR refers to 3′ and 5′ UTRs, and mutations are indicated by vertical black lines. Data file S2 in the electronic supplementary material gives similar diagrams for the distributions of mutations in other 2R-ohnologue families in melanoma.
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RSOB140029F2: MLs of 2R-ohnologue genes in melanoma. (a) For the melanoma dataset [15], the figure plots the ML distribution for 2R-ohnologues within families of 2, 3 and 4 members. Only families in which at least one gene carries carried 10 or more different mutations are included. The ML is computed by summing the total number of mutations identified for a gene divided by the total number of mutations in all members of the same 2R-ohnologue family. The y-axes give the number of genes, with the ML scores indicated on the x-axes. Each histogram set indicates the medians (red lines), interquartile ranges (rectangular boxes) and outliers (green diamonds) for the ML distributions. Note that for families of 2 members, the median will always be 0.5 by construction, regardless of the ML distribution profile. Data file S1 in the electronic supplementary material presents the corresponding histograms for 30 cancer types, and its legend contains a discussion note about statistics. (b) The distribution of mutations in melanoma is given for the HECW E3 ubiquitin ligase family (as an example of even ML distribution) and the type II PAK family (an example with a skewed ML where the PAK7 gene accumulates most of the family mutations). Illustrations were created with Domain Graph, v. 1.0.5 [26]. CDS is coding sequence, UTR refers to 3′ and 5′ UTRs, and mutations are indicated by vertical black lines. Data file S2 in the electronic supplementary material gives similar diagrams for the distributions of mutations in other 2R-ohnologue families in melanoma.

Mentions: The ML distributions for the melanoma dataset are graphed in figure 2a and for other cancers in the electronic supplementary material, data file S1 (with statistical note in legend). In melanoma and other tumour types, there were 2R-ohnologue families in which the MLs were evenly distributed among family members, such as the HECW family of two E3 ubiquitin ligases (figure 2b). However, in most cancers, including melanoma, there were also 2R-ohnologue families with a ‘skewed ML’, meaning that one gene carried most of the ML. For example, in the melanoma dataset PAK7 carries 95 of the 114 mutated sites in the family of three type II PAK protein kinases (figure 2b).Figure 2.


Identification of 2R-ohnologue gene families displaying the same mutation-load skew in multiple cancers.

Tinti M, Dissanayake K, Synowsky S, Albergante L, MacKintosh C - Open Biol (2014)

MLs of 2R-ohnologue genes in melanoma. (a) For the melanoma dataset [15], the figure plots the ML distribution for 2R-ohnologues within families of 2, 3 and 4 members. Only families in which at least one gene carries carried 10 or more different mutations are included. The ML is computed by summing the total number of mutations identified for a gene divided by the total number of mutations in all members of the same 2R-ohnologue family. The y-axes give the number of genes, with the ML scores indicated on the x-axes. Each histogram set indicates the medians (red lines), interquartile ranges (rectangular boxes) and outliers (green diamonds) for the ML distributions. Note that for families of 2 members, the median will always be 0.5 by construction, regardless of the ML distribution profile. Data file S1 in the electronic supplementary material presents the corresponding histograms for 30 cancer types, and its legend contains a discussion note about statistics. (b) The distribution of mutations in melanoma is given for the HECW E3 ubiquitin ligase family (as an example of even ML distribution) and the type II PAK family (an example with a skewed ML where the PAK7 gene accumulates most of the family mutations). Illustrations were created with Domain Graph, v. 1.0.5 [26]. CDS is coding sequence, UTR refers to 3′ and 5′ UTRs, and mutations are indicated by vertical black lines. Data file S2 in the electronic supplementary material gives similar diagrams for the distributions of mutations in other 2R-ohnologue families in melanoma.
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Related In: Results  -  Collection

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RSOB140029F2: MLs of 2R-ohnologue genes in melanoma. (a) For the melanoma dataset [15], the figure plots the ML distribution for 2R-ohnologues within families of 2, 3 and 4 members. Only families in which at least one gene carries carried 10 or more different mutations are included. The ML is computed by summing the total number of mutations identified for a gene divided by the total number of mutations in all members of the same 2R-ohnologue family. The y-axes give the number of genes, with the ML scores indicated on the x-axes. Each histogram set indicates the medians (red lines), interquartile ranges (rectangular boxes) and outliers (green diamonds) for the ML distributions. Note that for families of 2 members, the median will always be 0.5 by construction, regardless of the ML distribution profile. Data file S1 in the electronic supplementary material presents the corresponding histograms for 30 cancer types, and its legend contains a discussion note about statistics. (b) The distribution of mutations in melanoma is given for the HECW E3 ubiquitin ligase family (as an example of even ML distribution) and the type II PAK family (an example with a skewed ML where the PAK7 gene accumulates most of the family mutations). Illustrations were created with Domain Graph, v. 1.0.5 [26]. CDS is coding sequence, UTR refers to 3′ and 5′ UTRs, and mutations are indicated by vertical black lines. Data file S2 in the electronic supplementary material gives similar diagrams for the distributions of mutations in other 2R-ohnologue families in melanoma.
Mentions: The ML distributions for the melanoma dataset are graphed in figure 2a and for other cancers in the electronic supplementary material, data file S1 (with statistical note in legend). In melanoma and other tumour types, there were 2R-ohnologue families in which the MLs were evenly distributed among family members, such as the HECW family of two E3 ubiquitin ligases (figure 2b). However, in most cancers, including melanoma, there were also 2R-ohnologue families with a ‘skewed ML’, meaning that one gene carried most of the ML. For example, in the melanoma dataset PAK7 carries 95 of the 114 mutated sites in the family of three type II PAK protein kinases (figure 2b).Figure 2.

Bottom Line: The complexity of signalling pathways was boosted at the origin of the vertebrates, when two rounds of whole genome duplication (2R-WGD) occurred.The non-mutated 2R-ohnologues are therefore potential therapeutic targets.These include proteins linked to growth factor signalling, neurotransmission and ion channels.

View Article: PubMed Central - PubMed

Affiliation: Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.

ABSTRACT
The complexity of signalling pathways was boosted at the origin of the vertebrates, when two rounds of whole genome duplication (2R-WGD) occurred. Those genes and proteins that have survived from the 2R-WGD-termed 2R-ohnologues-belong to families of two to four members, and are enriched in signalling components relevant to cancer. Here, we find that while only approximately 30% of human transcript-coding genes are 2R-ohnologues, they carry 42-60% of the gene mutations in 30 different cancer types. Across a subset of cancer datasets, including melanoma, breast, lung adenocarcinoma, liver and medulloblastoma, we identified 673 2R-ohnologue families in which one gene carries mutations at multiple positions, while sister genes in the same family are relatively mutation free. Strikingly, in 315 of the 322 2R-ohnologue families displaying such a skew in multiple cancers, the same gene carries the heaviest mutation load in each cancer, and usually the second-ranked gene is also the same in each cancer. Our findings inspire the hypothesis that in certain cancers, heterogeneous combinations of genetic changes impair parts of the 2R-WGD signalling networks and force information flow through a limited set of oncogenic pathways in which specific non-mutated 2R-ohnologues serve as effectors. The non-mutated 2R-ohnologues are therefore potential therapeutic targets. These include proteins linked to growth factor signalling, neurotransmission and ion channels.

Show MeSH
Related in: MedlinePlus