Purging of deleterious retroviral integrations at the earliest stages of genomic invasion

• Applicant: Professor Dr. Alex Greenwood, Ph.D.
• Subject Area: Evolutionary Cell and Developmental Biology (Zoology) ; Evolution, Anthropology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 429450856

In humans, about 8% of the genome consists of endogenous retrovirus-like elements, comprising a larger proportion of the genome than the coding regions of genes. Humans are not unique in this respect as many vertebrates have equal or proportionally more viral like DNA in their genomes. Therefore, a large component of the vertebrate genome reflects the process of viral invasion whereby host and virus adapt to one another. The evolutionary dynamics of this portion of the genome differs substantially from that of gene coding regions. However, the rate of this adaptive process and the underlying mechanisms remain obscure. In most vertebrates the reason for this obscurity is that the process completed millions of years ago such that the critical adaptive changes are indistinguishable from subsequent non-adaptive mutations. For example, most endogenous retroviruses are highly degraded, particularly in the retroviral envelope gene involved in viral host cell entry. However, it is unclear how and how quickly this degradation occurs during the co-evolution of host and virus. Similarly, many endogenous retroviruses exhibit signs of recombination. However, it is unclear if these are variants that occurred after endogenization and were selected for or were early events responsible for allowing endogenization to occur. An important exception among mammals to ancient endogenization is observed in the koala (Phascolarctos cinereus) which is currently undergoing a genomic retroviral invasion by the koala retrovirus, KoRV. We have preliminary evidence from studying KoRV that suggests that the rate of retroviral adaptation to the host is very rapid and largely mediated at the earliest stages by recombination with already established endogenous retroviruses in the host genome. These elements disrupt the invading retroviruses while simultaneously remobilizing themselves leading to the proliferation of replication defective viral copies in the genome and thus taming the exogenous retroviruses. Therefore, already resident endogenous retroviruses may play a defensive role against newly invading viruses. In large populations the taming process is hard to observe directly. However, on island populations subject to founder events, the fixation of KoRVs, the purging of deleterious mutants (or retroviruses) and genetic drift can be observed at a greatly accelerated rate. Using a population genetics approach on island populations of koalas established in the early 20th century from a few individual koalas (St. Bees Island, Queensland), we will examine directly the process of recombination mediated taming of retroviruses during an ongoing genomic retroviral invasion and determine the roles of genetic drift and selection in shaping almost 10% of the vertebrate genome. We will also demonstrate that the selective force is likely KoRV driven cancer.

• DFG Programme: Research Grants