The expansion of gene families implicated in cancer and other genetic diseases is an evolutionary oddity from a natural selection perspective.This expansion of "dangerous" gene families in vertebrates is correlated with other genomic properties such as their connectivity within protein complexes,gene divergence rates,gene expression levels,etc.Yet,many of these correlations are in fact mediated through the indirect effect of a third property and only provide partial insights on evolutionary origin of this expansion of "dangerous" gene families.To go beyond such simple statistical associations and quantify their direct and indirect effects on the expansion of "cancer" gene families,we have used the Mediation framework developped by Pearl.It demonstrates the central role of two rounds of whole genome duplication at the origin of vertebrates in their enhanced susceptibility to genetic disorders and cancers.These results are also supported by a simple population genetics model that rationalizes,from an evolutionary perspective,this expansion of gene families frequently implicated in genetic disorders and cancers.