Duplicate copies of genes are commonly found in the genomes of living things from bacteria to humans. Duplicate genes are important in disease, are a hugely important source of evolutionary novelty, and for many years we thought we understood them. We thought that duplicates were an 'extra' copy that can be modified or lost with no consequence. We thought that any gene, no matter its importance, had an equal chance to be duplicated, and that that duplicate copy is (at least initially) unimportant owing to its redundancy. We thought that a duplicate is a duplicate is a duplicate. In recent years evidence has accumulated challenging this view. Rather than being the result of an unbiased process, the genes that tend to duplicate are quickly evolving, non-essential genes, irrespective of current duplication status. Conversely, when the duplication is not of an individual gene, but of an entire genome (whole genome duplication; WGD) the patterns are flipped. After WGD many duplicates are lost, reverting to the original copy number. The genes that tend to be retained are the slowly evolving, important genes. Furthermore, rather than being redundant copies, the WGD duplicates are both required, and disruption to them often results in disease. This striking difference between the products of the two alternative mechanisms of duplication requires an explanation.
In this project we are exploring and testing a hypothesis that different resolution of the evolutionary constraints imposed by the demands of gene expression (how high or low a gene is turned on) can explain these contrasting relationships. We are testing our idea that the opposing constraints on gene-by-gene duplications as compared to WGD channel these different sets of genes into remarkably different evolutionary trajectories. We propose a common mechanism of pathogenicity for many duplication events independent of the biochemical function of the encoded genes, namely competition for cellular resources. We have also begun testing the relationship of genome duplication to stress resilience - an exciting hypothesis that was suggested by the disproportionate survival of genome duplicated organisms through periods of otherwise mass extinction. Our work using the microscopic worm C. elegant, has shown a strong causative link between genome duplication and temperature stress resilience.
With the availability of abundant high-quality genomics data, now is an opportune time to address these questions. This project is important because it aims to deepen our understanding of the genome, and uncover links between evolutionary patterns and human genetic disease. These are fundamental insights which can be applied across all areas of genomics.
