Biology subjects

Penman, B. S.

Publications and source records attributed to Penman, B. S..

4 recordsLinked to original sources

bioRxiv2022

The erythrocyte membrane properties of beta thalassaemia heterozygotes and their consequences for Plasmodium falciparum invasion

Malaria parasites such as Plasmodium falciparum have exerted formidable selective pressures on the human genome. Of the human genetic variants associated with malaria protection, beta thalassaemia (a haemoglobinopathy) was the earliest to be associated with malaria prevalence. However, the malaria protective properties of beta thalassaemic erythrocytes remain unclear. Here we studied the mechanics and surface protein expression of beta thalassaemia heterozygous erythrocytes, measured their susceptibility to P. falciparum invasion, and calculated the energy required for merozoites to invade them. We found invasion-relevant differences in beta thalassaemic cells versus matched controls, specifically: elevated membrane tension, reduced bending modulus, and higher levels of expression of the major invasion receptor basigin. However, these differences acted in opposition to each other with respect to their likely impact on invasion, and overall we did not observe beta thalassaemic cells to have lower P. falciparum invasion efficiency for any of the strains tested.

microbiology↗

bioRxiv2020

Alpha globin variation in the long-tailed macaque suggests malaria selection

Human haemoglobin variants, such as sickle, confer protection against death from malaria; consequently, frequencies of such variants are often greatly elevated in humans from malaria endemic regions. Among non-human primates, the long-tailed macaque, Macaca fascicularis, also displays substantial haemoglobin variation. Almost all M. fascicularis haemoglobin variation is in the alpha globin chain, encoded by two linked genes: HBA1 and HBA2. We demonstrate that alpha globin variation in M. fascicularis correlates with the strength of malaria selection. We identify a range of missense mutations in M. fascicularis alpha globin and demonstrate that some of these exhibit a striking HBA1 or HBA2 specificity, a pattern consistent with computational simulations of selection on genes exhibiting copy number variation. We propose that M. fascicularis accumulated amino acid substitutions in its alpha globin genes under malaria selection, in a process that closely mirrors, but does not entirely converge with, human malaria adaptation.

evolutionary biology↗

bioRxiv2018

Estimating the burden of α-thalassaemia in Thailand using a comprehensive prevalence database for Southeast Asia

Severe forms of -thalassaemia, haemoglobin H disease and haemoglobin Barts hydrops fetalis, are an important public health concern in Southeast Asia. Yet information on the prevalence, genetic diversity and health burden of -thalassaemia in the region remains limited. We compiled a geodatabase of -thalassaemia prevalence and genetic diversity surveys and, using geostatistical modelling methods, generated the first continuous maps of -thalassaemia mutations in Thailand and sub-national estimates of the number of newborns with severe forms in 2020. We also summarised the current evidence-base for -thalassaemia prevalence and diversity for the region. We estimate that 3,595 (95% credible interval 1,717 - 6,199) newborns will be born with severe -thalassaemia in Thailand in 2020, which is considerably higher than previous estimates. Accurate, fine-scale epidemiological data are necessary to guide sustainable national and regional health policies for -thalassaemia control. Our maps and newborn estimates are an important first step towards this aim.\n\nFundingThis work was supported by European Unions Seventh Framework Programme (FP7//2007-2013)/European Research Council [268904 - DIVERSITY]

epidemiology↗

bioRxiv2017

Reverse immunodynamics: a new method to identifying targets of protective immunity.

Despite a dramatic increase in our ability to catalogue variation among pathogen genomes, we have made far fewer advances in using this information to identify targets of protective immunity. We propose a novel methodology that combines predictions from epidemiological models with phylogenetic and structural analyses to identify such targets. Epidemiological models predict that strong immune selection can cause antigenic variants to exist in non-overlapping combinations. A corollary of this theory is that targets of immunity may be identified by searching for non-overlapping associations among antigenic variants. We applied this concept to the AMA-1 protein of the malaria parasite Plasmodium falciparum and found strong signatures of immune selection among certain regions of low variability which could render them ideal vaccine candidates.

epidemiology↗