Phylostratigraphic tracking of cancer genes suggests a link to the emergence of multicellularity in metazoa

Abstract

Background: Phylostratigraphy is a method used to correlate the evolutionary origin of founder genes (that is, functional founder protein domains) of gene families with particular macroevolutionary transitions. It is based on a model of genome evolution that suggests that the origin of complex phenotypic innovations will be accompanied by the emergence of such founder genes, the descendants of which can still be traced in extant organisms. The origin of multicellularity can be considered to be a macroevolutionary transition, for which new gene functions would have been required. Cancer should be tightly connected to multicellular life since it can be viewed as a malfunction of interaction between cells in a multicellular organism. A phylostratigraphic tracking of the origin of cancer genes should, therefore, also provide insights into the origin of multicellularity.

Results: We find two strong peaks of the emergence of cancer related protein domains, one at the time of the origin of the first cell and the other around the time of the evolution of the multicellular metazoan organisms. These peaks correlate with two major classes of cancer genes, the 'caretakers', which are involved in general functions that support genome stability and the 'gatekeepers', which are involved in cellular signalling and growth processes. Interestingly, this phylogenetic succession mirrors the ontogenetic succession of tumour progression, where mutations in caretakers are thought to precede mutations in gatekeepers.

Conclusions: A link between multicellularity and formation of cancer has often been predicted. However, this has not so far been explicitly tested. Although we find that a significant number of protein domains involved in cancer predate the origin of multicellularity, the second peak of cancer protein domain emergence is, indeed, connected to a phylogenetic level where multicellular animals have emerged. The fact that we can find a strong and consistent signal for this second peak in the phylostratigraphic map implies that a complex multi-level selection process has driven the transition to multicellularity.

Figure 1

Phylogeny used in the search for the evolutionary origin of human genes. Taxa represented in the databases with complete genomes or a substantial amount of TRACE and expressed sequence tag data are in bold. Taxa in italics are represented in the databases only with small numbers of highly conserved genes: their exclusion from the analysis does not influence the results. The phylogeny is based on the results of the most recent phylogenomic analyses [15-19].

Figure 2

Statistical analysis of the cancer datasets on the phylostratigraphic map. Phylostratigraphic representation of log-odds statistics of human cancer genes, based on four different compilations (see inset on top right). Arrows designate the strongest significant over-representations. Statistical significance of the deviations were tested by a two-tailed hypergeometric test corrected for multiple comparison by a false discovery rate at 0.05 level (* P < 0.05; ** P < 0.01; *** P < 0.001). Significant over-representations and under-representations are shaded in red and blue, respectively.

Figure 3

Statistical analysis of caretakers and gatekeepers on the phylostratigraphic map. Phylostratigraphic representation of log-odds statistics of human caretaker and gatekeeper cancer genes following the annotations in Entrez are shown. Arrows designate the strongest significant over-representation. Squares denote the caretaker dataset (green line, N = 224) and circles denote the gatekeeper dataset (red line, N = 900). The gatekeeper dataset is further subdivided into tumour suppressor genes (solid black line, N = 601) and oncogenes (dashed line, N = 380). Statistical significances of the deviations were tested as described in the legend of Figure 2.

Figure 4

Colinearity between evolutionary age of cancer genes and their role in tumour progression. Parallels between the macroevolutionary origin of the global pathways leading to neoplasia and the developmental timing of mutations in these pathways are shown. The upper part of the figure is adapted from reference [11].