ARE WE MERELY HOPEFUL MONSTERS: THE ROLE OF GENE AND GENOME DUPLICATION IN EVOLUTION AND GENETIC DISEASE

Abstract

In 1933 the German geneticist Richard Goldschmidt presented his theory that major evolutionary events have been driven, not by the slow accumulation of small variants, in line with Darwinian thought, but instead large-scale mutations which he called macromutations. His theory was called The hopeful monsters hypothesis, as any species arising from such an event would often result in evolutionary dead end. This theory was, however, by and large rejected due to its stark contrast with that of Darwins theory of evolution. 86 years on, thanks to tremendous advancements in genomic technologies and evolutionary analysis, we are aware of the existence of a myriad of what could be considered macromutations (large-scale duplications) in the human genome, and the significant role they have played in our evolution. Whilst beneficial in the process of shaping who we are as a species, these large-scale mutations are not always benevolent, having been found to have significant links with a plethora of human diseases. Using evolutionary data, alongside important biological features of human genes, we explore the links between large-scale mutations, particularly whole genome duplications, introgressed genes, and heritable, parasitic, and viral disease. We find that there are strong links between ancient fragility, exposed by divergence between duplicated genes, and heritable disease; that co-evolution between humans and the soil borne helminth parasite Trichuris trichura has been facilitated by strong selective pressures exerted on the ancient genes of the TGFb superfamily; and that viruses target ancient and important gene families and functions. It is clear that large-scale mutations, in particular gene and genome duplications, have provided the genetic redundancy that contributed to the evolution of the complex species we are today. However, given the fragility and propensity of genes of this kind to be associated with disease of all varieties, our future evolvability, and ability to adapt is in question. We must, therefore, readdress Goldschmidts theory as a question -Are we merely the descendants of hopeful monsters?

Date of Award	1 Aug 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	David Robertson (Supervisor) & Sam Griffiths-Jones (Supervisor)