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

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 [1-3]. Further, with respect to their evolutionary age, human disease genes appear not to be simply a random subset of all genes in the genome but are instead biased toward being of ancient (early metazoan) origin [4]. Concomitantly, a pronounced paucity of human lineage-specific genes is also evident among disease genes [4]. These initial findings were subsequently confirmed and elaborated upon by Cai et al.,[5] who determined the approximate age of evolutionary emergence of all human genes and then proceeded to compare disease genes with non-disease genes with respect to whether they were 'young', 'middle-aged' or 'old-aged'. For the purposes of their study, the origin of a given gene was determined by retracing its orthologues back to the species most distantly related to human. Genes that originated during the period since the adaptive radiation of the Laurasiatheria were described as '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 (a tunicate) 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 (ie those genes underlying single gene disorders) to be of more ancient evolutionary origin than non-disease genes. With Mendelian disease genes, the 'old-aged' genes were in the majority, closely followed by the 'middle-aged' genes. By contrast, most genes involved in the aetiology of complex disease were found to reside in the 'middle-aged' category. Although 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 dise