Exploring the potential relevance of human-specific genes to complex disease

David N Cooper,Hildegard Kehrer-Sawatzki

doi:10.1186/1479-7364-5-2-99

Abstract

Although human disease genes generally tend to be evolutionarily more ancient than non-disease genes, complex disease genes appear to be represented more frequently than Mendelian disease genes among genes of more recent evolutionary origin. It is therefore proposed that the analysis of human-specific genes might provide new insights into the genetics of complex disease. Cross-comparison with the Human Gene Mutation Database (http://www.hgmd.org) revealed a number of examples of disease-causing and disease-associated mutations in putatively human-specific genes. A sizeable proportion of these were missense polymorphisms associated with complex disease. Since both human-specific genes and genes associated with complex disease have often experienced particularly rapid rates of evolutionary change, either due to weaker purifying selection or positive selection, it is proposed that a significant number of human-specific genes may play a role in complex disease.

Highlights

Human ‘disease genes’ have been known for some time to differ significantly from ‘non-disease genes’ in terms of their higher degree of evolutionary conservation.[1,2,3] Further, with respect to their evolutionary age, human disease genes appear not to be a random subset of all genes in the genome but are instead biased toward being of ancient origin.[4]
‘young’, the term ‘middle-aged’ was employed to describe those genes whose origin went back to the bony fish, and genes that emerged at some stage between yeast and Ciona were ascribed the term ‘old-aged’. Using these fairly crude descriptors of gene age, Cai et al.[5] confirmed that there was a tendency for Mendelian disease genes to be of more ancient evolutionary origin than nondisease genes
Both Mendelian and complex disease genes were found to be under-represented in the ‘young’ category, the frequency of complex disease genes in this category was found to be more than twice that exhibited by the Mendelian disease genes.[5]

Summary

Kawasaki disease

Chronic hepatitis C infection, susceptibility to FOXD4 Forkhead box 9p24.3 Missense (Trp148Arg) CM073074 DM. The numbers involved are clearly small, it would appear that there is at least a tendency for human-specific genes to harbour a greater-than-expected number of examples of polymorphisms associated with complex disease by comparison with the number of mutations causing Mendelian disease (bearing in mind that disease-associated polymorphisms constitute only a small minority of the lesions logged in the HGMD; see legend to Table 3)

Associated disease Reference state

Chronic granulomatous disease

MHC class I polypeptiderelated sequence A