Computational analysis of host/pathogen coevolution

Thesis

In this thesis, I present my research on host/pathogen coevolution in several different systems and on different time scales. The thesis comprises multiple parts and shows how advances in computational methods can be applied to a broad range of questions, from basic research to issues of immediate clinical relevance.

Chapter 1 examines this host pathogen coevolution in a nonhuman system, looking at giant viruses, satellite viruses, related transposable elements found in eukaryotes and giant viruses, and individual 'jumping' homing endonuclease genes (HEGs) found in all three. Unfortunately, due to enormous amounts of time over which some of the elements involved have diverged, it is difficult to draw reliable conclusions here. However, the novel identification of HEGs in satellite and giant viruses shows a likely solution to the question of the mechanism for the horizontal gene transfer of HEGs between dissimilar phyla.

Chapter 2 focuses on the coevolution of humans with pathogens. This can be seen in the influence of archaic hominid immune genes on the modern immune system, and what appears to be the introgression of archaic hominids' granular adaptation to local pathogens when modern humans expanded out of Africa. The fact that these archaic HLAs have retained this regional granular adaptation for tens of thousands of years suggests some sort of survival advantage. While previous work has shown that there is different selective pressures acting on different class I HLAs, this chapter shows that this relationship is retained when looking exclusively at archaic derived HLAs. Selective pressures acting on HLA-A but not HLA-B have not previously been described, and Chapter 2 identifies the suppression of endogenous retroviruses as possibly being one such selective pressure.

Chapter 3 examines the granular adaptation of HIV-1M to humans in Sub-Saharan Africa by looking at correlations between human genetic diversity and HIV diversity. Unfortunately, widespread genotyping of HIV patients in Sub-Saharan Africa is not available, but linguistic diversity has previously been specifically shown to correlate with human genetic diversity in Sub-Saharan Africa, providing a useful proxy with which to make comparisons. My results show that linguistic diversity, and by extension human genetic diversity, does indeed correlate with both HIV subtype and amino acid sequence diversity in the region. This runs contrary to the dominant paradigm that HIV subtypes are artefacts of founder effects and may explain some of the difficulties in creating an HIV vaccine despite over 30 years of research on the subject.

Authors: Campbell, S

• DOI: 10.5287/ora-erx2bvrvk
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: virophage; Denisovans; homing endonuclease gene; phylogenetics; HLA; polinton; HIV; Neanderthals; linguistics
• Subjects: HIV (Viruses); HLA histocompatibility antigens; Biology; Neanderthals; Virology