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

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.

journal_name

BMC Evol Biol

journal_title

BMC evolutionary biology

authors

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

doi

10.1186/1471-2148-8-273

subject

Has Abstract

pub_date

2008-10-06 00:00:00

pages

273

issn

1471-2148

pii

1471-2148-8-273

journal_volume

pub_type

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