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The role of positive selection in determining the molecular cause of species differences in disease.

Vamathevan JJ, Hasan S, Emes RD, Amrine-Madsen H, Rajagopalan D, Topp SD, Kumar V, Word M, Simmons MD, Foord SM, Sanseau P, Yang Z, Holbrook JD - BMC Evol. Biol. (2008)

Bottom Line: Thus we investigate whether biomedical disease differences between species can be attributed to positively selected genes.This is the first such evidence to be detected widely among mammalian genes and may be important in identifying molecular pathways causative of species differences.We conclude that studying the evolution of functional and biomedical disease differences between species is an important way to gain insight into their molecular causes and may provide a method to predict when animal models do not mirror human biology.

View Article: PubMed Central - HTML - PubMed

Affiliation: 1Department of Biology, University College London, Darwin Bldg, Gower Street, London WC1E 6BT, UK. j.vamathevan@ucl.ac.uk

ABSTRACT

Background: Related species, such as humans and chimpanzees, often experience the same disease with varying degrees of pathology, as seen in the cases of Alzheimer's disease, or differing symptomatology as in AIDS. Furthermore, certain diseases such as schizophrenia, epithelial cancers and autoimmune disorders are far more frequent in humans than in other species for reasons not associated with lifestyle. Genes that have undergone positive selection during species evolution are indicative of functional adaptations that drive species differences. Thus we investigate whether biomedical disease differences between species can be attributed to positively selected genes.

Results: We identified genes that putatively underwent positive selection during the evolution of humans and four mammals which are often used to model human diseases (mouse, rat, chimpanzee and dog). We show that genes predicted to have been subject to positive selection pressure during human evolution are implicated in diseases such as epithelial cancers, schizophrenia, autoimmune diseases and Alzheimer's disease, all of which differ in prevalence and symptomatology between humans and their mammalian relatives. In agreement with previous studies, the chimpanzee lineage was found to have more genes under positive selection than any of the other lineages. In addition, we found new evidence to support the hypothesis that genes that have undergone positive selection tend to interact with each other. This is the first such evidence to be detected widely among mammalian genes and may be important in identifying molecular pathways causative of species differences.

Conclusion: Our dataset of genes predicted to have been subject to positive selection in five species serves as an informative resource that can be consulted prior to selecting appropriate animal models during drug target validation. We conclude that studying the evolution of functional and biomedical disease differences between species is an important way to gain insight into their molecular causes and may provide a method to predict when animal models do not mirror human biology.

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Biological Process ontologies over-represented by PSGs. Biological Process ontology terms which had an over-representation of PSGs (p < 0.05). Ontology terms are grouped by functional protein PANTHER Biological Process families.
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Figure 2: Biological Process ontologies over-represented by PSGs. Biological Process ontology terms which had an over-representation of PSGs (p < 0.05). Ontology terms are grouped by functional protein PANTHER Biological Process families.

Mentions: A one-sided binomial test was used to test if the PSGs from each lineage were over-represented among the Biological Process (BP) class of the PANTHER ontology database [32]. The terms that showed the most enrichment were then grouped into BP families (Figure 2) as defined by the PANTHER classification system [33]. Thirty-two BP ontology terms which belong to fourteen BP families were enriched for PSGs (p < 0.05, binomial test). After multiple correction, four BP terms were significant at p < 0.05. The ontologies that had the most representation by PSGs from the primate lineages were nucleic acid metabolism, neuronal activities, and immunity and defence. Primate PSGs also showed enrichment in functional categories such as development processes or signal transduction, which can be associated with species differences. PSGs from the murid lineages showed over-representation mostly in the functional categories immunity and defence and signal transduction. A significantly high proportion of the chimpanzee PSGs had undefined or unknown biological function (see Additional File 2 'Functional Classification of Chimpanzee PSGs').


The role of positive selection in determining the molecular cause of species differences in disease.

Vamathevan JJ, Hasan S, Emes RD, Amrine-Madsen H, Rajagopalan D, Topp SD, Kumar V, Word M, Simmons MD, Foord SM, Sanseau P, Yang Z, Holbrook JD - BMC Evol. Biol. (2008)

Biological Process ontologies over-represented by PSGs. Biological Process ontology terms which had an over-representation of PSGs (p < 0.05). Ontology terms are grouped by functional protein PANTHER Biological Process families.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2576240&req=5

Figure 2: Biological Process ontologies over-represented by PSGs. Biological Process ontology terms which had an over-representation of PSGs (p < 0.05). Ontology terms are grouped by functional protein PANTHER Biological Process families.
Mentions: A one-sided binomial test was used to test if the PSGs from each lineage were over-represented among the Biological Process (BP) class of the PANTHER ontology database [32]. The terms that showed the most enrichment were then grouped into BP families (Figure 2) as defined by the PANTHER classification system [33]. Thirty-two BP ontology terms which belong to fourteen BP families were enriched for PSGs (p < 0.05, binomial test). After multiple correction, four BP terms were significant at p < 0.05. The ontologies that had the most representation by PSGs from the primate lineages were nucleic acid metabolism, neuronal activities, and immunity and defence. Primate PSGs also showed enrichment in functional categories such as development processes or signal transduction, which can be associated with species differences. PSGs from the murid lineages showed over-representation mostly in the functional categories immunity and defence and signal transduction. A significantly high proportion of the chimpanzee PSGs had undefined or unknown biological function (see Additional File 2 'Functional Classification of Chimpanzee PSGs').

Bottom Line: Thus we investigate whether biomedical disease differences between species can be attributed to positively selected genes.This is the first such evidence to be detected widely among mammalian genes and may be important in identifying molecular pathways causative of species differences.We conclude that studying the evolution of functional and biomedical disease differences between species is an important way to gain insight into their molecular causes and may provide a method to predict when animal models do not mirror human biology.

View Article: PubMed Central - HTML - PubMed

Affiliation: 1Department of Biology, University College London, Darwin Bldg, Gower Street, London WC1E 6BT, UK. j.vamathevan@ucl.ac.uk

ABSTRACT

Background: Related species, such as humans and chimpanzees, often experience the same disease with varying degrees of pathology, as seen in the cases of Alzheimer's disease, or differing symptomatology as in AIDS. Furthermore, certain diseases such as schizophrenia, epithelial cancers and autoimmune disorders are far more frequent in humans than in other species for reasons not associated with lifestyle. Genes that have undergone positive selection during species evolution are indicative of functional adaptations that drive species differences. Thus we investigate whether biomedical disease differences between species can be attributed to positively selected genes.

Results: We identified genes that putatively underwent positive selection during the evolution of humans and four mammals which are often used to model human diseases (mouse, rat, chimpanzee and dog). We show that genes predicted to have been subject to positive selection pressure during human evolution are implicated in diseases such as epithelial cancers, schizophrenia, autoimmune diseases and Alzheimer's disease, all of which differ in prevalence and symptomatology between humans and their mammalian relatives. In agreement with previous studies, the chimpanzee lineage was found to have more genes under positive selection than any of the other lineages. In addition, we found new evidence to support the hypothesis that genes that have undergone positive selection tend to interact with each other. This is the first such evidence to be detected widely among mammalian genes and may be important in identifying molecular pathways causative of species differences.

Conclusion: Our dataset of genes predicted to have been subject to positive selection in five species serves as an informative resource that can be consulted prior to selecting appropriate animal models during drug target validation. We conclude that studying the evolution of functional and biomedical disease differences between species is an important way to gain insight into their molecular causes and may provide a method to predict when animal models do not mirror human biology.

Show MeSH
Related in: MedlinePlus