GENOME EVOLUTION

Our laboratory asks how cancers develop by researching how the genome adapts to environmental change, ageing, and damage. Such genetic changes occur at two levels:

• Germline (heritable) changes that affect families or species; and
• Somatic (acquired) changes that affect the ageing tissues of individuals.

As such, we view the human genome not as a fixed genetic blueprint, but as a fluid organelle that is constantly responding to environmental change. The net outcome of this genomic-environmental interaction reflects the balance of two evolutionary selective pressures:

• Negative selection, which involves genetic retention of essential functionalities; and
• Positive selection, which involves (rare) gain of genetically advantageous traits.

The term 'cancer' denotes a heterogeneous group of disorders in which a critical sequence of genetic changes in somatic cells triggers a breakdown of normal intercellular regulation. Again, there are two main functional gene groups responsible for preventing such cancers:

• 'Caretaker' tumour suppressor genes which maintain genetic repair and stability; and
• 'Gatekeeper' tumour suppressor genes that regulate normal cell growth and death.

Our work supports the view that this dynamic interplay between the human genome and its environment is primarily mediated by the epigenetic modification of DNA (CpG dinucleotide) methylation - an evolutionary masterstroke that can reversibly transform local gene regions from being highly stable to highly unstable. In this sense we regard sporadic age-related cancer as representing a human 'price paid' for maintaining germline evolutionary plasticity, a paradigm which we have termed programmed genetic instability. At present we are directly testing this hypothesis by experimentally creating novel 'cancer-proof' (i.e., mutation-resistant) tumour suppressor genes via synonymous substitution of CpG-variable sequences within the coding region of the critical pro-apoptotic anticancer gatekeeper gene TP53.