Molecular Evolution of Human Cancer Genes MDS2 and TCL6

2 1. Introduction 1.1. Aim of the thesis Our lab recently identified systemic properties of human cancer genes when compared to the rest of human genes 1 . These results were the starting point of an evolutionary study to identify the origin of cancer genes: for this purpose, several model organisms were used to assign orthology. Our analysis revealed that cancer genes tended to appear in evolution earlier than the rest of human genes. Only two cancer genes had no orthologs besides primates, implying a recent appearance: MDS2 and TCL6. The aim of this work is to investigate origin and evolution of these two primate-specific hu- man cancer genes. 1.2. Systemic properties of Cancer Genes Cancer genes can be defined as genes whose alteration by mutation contributes to the process of tumorigenesis. The negative or lethal effects of a single mutation can be recovered by different maintenance systems within the mammalian biological machinery. Only when several cancer genes suffer mutation events at once, causing a multiple loss of functionality, the development of cancer can arise. Cancer genes can be classified as oncogenes, tumor suppressor genes or stability genes 2 . Oncogenes include mutated cancer genes that become constitutionally or conditionally active in situations where the wild-type gene would not be. Their activation can derive from chromosomal translocations, gene amplifications or intragenic mutations in regulatory regions. A monoallelic mutation is usually enough to give a cell selective growth advantage. The activity of tumor suppressor genes instead is reduced upon mutation. This can be due to missense substitutions altering codons corresponding to residues that are essential for the protein functionality or even premature stop codons that result in a truncated peptide sequences. Generally, these genes must be mutated in both alleles to give the cell a selective growth advantage. Com- 2