Introduction to my research
We know that a person’s genes can predispose them to particular diseases. However, why do human genetic differences exist at all? Natural selection from pathogens is an important selective force maintaining genetic diversity in human populations. I use mathematical models and computational simulations of evolution to understand this process. Understanding how pathogen selection drives genetic diversity in humans will offer mechanistic insights into functional differences between variants of human genes, and will also teach us new ways that we can combat infectious disease.
For all of my publications, please see my Publication list. For my current projects at the Zeeman Institute, please see this page. Below I describe my major areas of research interest.
Genes responsible for parts of our immune system include the two most diverse gene families in the human genome: the human leukocyte antigens (HLAs, also known as major histocompatibility complex genes MHCs) and the Killer-cell Immunglobulin-like Receptors (KIRs). I have used mathematical and computational models to show that pathogen selection can account for the genomic organisation of HLAs (Penman et al 2013), and that a combination of pathogen selection and reproductive selection could have shaped the population genetics of human KIRs (Penman et al 2016). Connor White and I recently showed how the combined effects of HLA diversity and pathogen diversity may mean we miss important HLA effects in case control studies (White et al 2020).
Malaria and human genetics
Malaria has had a profound effect on human genetics. Malaria protective genetic variants have evolved and spread in sub Saharan Africa, much of Asia, and the region around the Mediterranean. We see malaria protective variants in populations living in countries which eradicated malaria decades ago. These malaria protective genetic variants can impact people’s health. One famous example of such a variant is the mutation responsible for the blood disorder sickle cell anaemia. Malaria can thus impact public health long after malaria parasites have been eradicated from a region.
My work on malaria and human genetics focuses on why different populations have evolved different solutions to the problem of malaria. I have shown that interactions amongst malaria protective disorders of haemoglobin can account for the relative rarity of sickle cell in the Mediterranean region (Penman et al, 2009), and for the exclusion of sickle cell from certain populations in south Asia (Penman et al 2011). I have also demonstrated that the sheer diversity of adaptations to malaria could reduce the sensitivity of public health screens for the presence of disorders such as beta thalassaemia (Penman et al 2014).
There is a striking contrast between the way that humans have adapted to the two major species of human malaria parasite (Plasmodium falciparum and Plasmodium vivax). I recently showed that adaptations which block malaria infection in the first place (such as the Duffy negative adaptation against P. vivax) are unlikely to emerge if adaptive immunity against malaria virulence is gained quickly. Penman and Gandon, 2020, press release. This could account for why there are no widespread P. falciparum blocking adaptations.
Comparing human malaria adaptations with those of non-human species
Malaria is not just a problem for humans, and comparing human and non-human adaptations to malaria can deliver important mechanistic insights. In collaboration with my former colleagues at the University of Oxford I am investigating how malaria has shaped the evolutionary history of the long-tailed macaque. We have recently archived a preprint (Faust et al 2020) demonstrating that long-tailed macaque alpha globin is under malaria selection.