Biology subjects

Amenga-Etego, L. N.

Publications and source records attributed to Amenga-Etego, L. N..

6 recordsLinked to original sources

bioRxiv2025

Geographical variation drives adaptive equilibrium of the P. falciparum sickle-associated mutations

The recent discovery of genetic mutations in Plasmodium falciparum--the most lethal malaria parasite--that enable it to overcome the protective effects of sickle cell trait, raises fundamental questions about the underlying biological and evolutionary interactions. Here we develop a geostatistical model to compare sickle haemoglobin genotype frequencies to the Plasmodium falciparum sickle-associated alleles across global populations, and find a robust association at multiple geographical scales, implying that sickle drives positive selection for these parasite mutations. A model of parasite evolution and an analysis of local haplotype patterns suggest that key features of these mutations - that they are polymorphic in all African populations and are mutually correlated despite lying in different genome regions - are caused by geographical variation in selection pressure, and that the alleles may have been maintained by balancing selection over timescales comparable to the age of the sickle mutation itself. The predicted impact of this host-parasite interaction on disease outcomes varies widely across populations, and functional data are needed to discover the biological mechanisms involved.

genetics↗

bioRxiv2024

Addressing pandemic-wide systematic errors in the SARS-CoV-2 phylogeny

The SARS-CoV-2 genome occupies a unique place in infection biology - it is the most highly sequenced genome on earth (making up over 20% of public sequencing datasets) with fine scale information on sampling date and geography, and has been subject to unprecedented intense analysis. As a result, these phylogenetic data are an incredibly valuable resource for science and public health. However, the vast majority of the data was sequenced by tiling amplicons across the full genome, with amplicon schemes that changed over the pandemic as mutations in the viral genome interacted with primer binding sites. In combination with the disparate set of genome assembly workflows and lack of consistent quality control (QC) processes, the current genomes have many systematic errors that have evolved with the virus and amplicon schemes. These errors have significant impacts on the phylogeny, and therefore over the last few years, many thousands of hours of researchers time has been spent in "eyeballing" trees, looking for artefacts, and then patching the tree. Given the huge value of this dataset, we therefore set out to reprocess the complete set of public raw sequence data in a rigorous amplicon-aware manner, and build a cleaner phylogeny. Here we provide a global tree of 4,471,579 samples, built from a consistently assembled set of high quality consensus sequences from all available public data as of June 2024, viewable at https://viridian.taxonium.org. Each genome was constructed using a novel assembly tool called Viridian (https://github.com/iqbal-lab-org/viridian), developed specifically to process amplicon sequence data, eliminating artefactual errors and mask the genome at low quality positions. We provide simulation and empirical validation of the methodology, and quantify the improvement in the phylogeny. We hope the tree, consensus sequences and Viridian will be a valuable resource for researchers.

bioinformatics↗

bioRxiv2024

A complex Plasmodium falciparum cryptotype circulating at low frequency across the African continent

The population structure of the malaria parasite Plasmodium falciparum can reveal underlying demographic and adaptive evolutionary processes. Here, we analyse population structure in 4,376 P. falciparum genomes from 21 countries across Africa. We identified a strongly differentiated cluster of parasites, comprising [~]1.2% of samples analysed, geographically distributed over 13 countries across the continent. Members of this cluster, named AF1, carry a genetic background consisting of a large number of highly differentiated variants, rarely observed outside this cluster, at a multitude of genomic loci distributed across most chromosomes. At these loci, the AF1 haplotypes appear to have common ancestry, irrespective of the sampling location; outside the shared loci, however, AF1 members are genetically similar to their sympatric parasites. AF1 parasites sharing up to 23 genomic co-inherited regions were found in all major regions of Africa, at locations over 7,000 km apart. We coined the term cryptotype to describe a complex common background which is geographically widespread, but concealed by genomic regions of local origin. Most AF1 differentiated variants are functionally related, comprising structural variations and single nucleotide polymorphisms in components of the MSP1 complex and several other genes involved in interactions with red blood cells, including invasion and erythrocyte antigen export. We propose that AF1 parasites have adapted to some as yet unidentified evolutionary niche, by acquiring a complex compendium of interacting variants that rarely circulate separately in Africa. As the cryptotype spread across the continent, it appears to have been maintained mostly intact in spite of recombination events, suggesting a selective advantage. It is possible that other cryptotypes circulate in Africa, and new analysis methods may be needed to identify them.

genomics↗

bioRxiv2023

A fourth locus in the Plasmodium falciparum genome associated with sickle haemoglobin

BackgroundHeterozygosity for sickle haemoglobin (HbS) confers protection against severe malaria caused by the parasite Plasmodium falciparum. Recent work has suggested that this protective effect can depend on the parasite genotype: P. falciparum sickle-associated (Pfsa) variants were found disproportionately in individuals with severe malaria carrying HbS alleles in The Gambia and Kenya. Interactions between the P. falciparum genome and HbS have not previously been investigated in mild malaria cases or in Ghana. MethodsWe performed a genome-wide association analysis of P. falciparum against human {beta}-globin genotypes in a sample of 1,368 people with mild malaria in northern Ghana. ResultsWe replicated the previously identified associations with HbS at two parasite loci (Pfsa1 and Pfsa3). Pfsa2 was absent from this population. A candidate newly identified locus within the serine/ threonine kinase FIKK4.2, which we putatively term Pfsa4, was also associated with HbS; this finding replicated in a published sample from Mali. The Pfsa1-4 mutations vary widely in frequencies across Africa, are absent or very low frequency in Asia, and are highly correlated with each-other across multiple populations. We found no strong associations with haemoglobin C. ConclusionsThis study replicates previously reported sickle-associated loci in the P. falciparum genome and has produced new evidence of a potential association with sickle haemoglobin at a fourth parasite locus. Further research is needed to validate the tentative fourth locus. These findings add new complexity to the emerging picture of association between human and co-evolving malaria parasite genomes, suggesting new avenues for functional exploration.

microbiology↗

bioRxiv2022

Nanopore sequencing for real-time genomic surveillance of Plasmodium falciparum

Malaria is a global public health priority causing over 600,000 deaths annually, mostly young children living in Sub-Saharan Africa. Molecular surveillance can provide key information for malaria control, such as the prevalence and distribution of antimalarial drug resistance. However, genome sequencing capacity in endemic countries can be limited. Here, we have implemented an end-to-end workflow for P. falciparum genomic surveillance in Ghana using Oxford Nanopore Technologies, targeting antimalarial resistance markers and the leading vaccine antigen circumsporozoite protein (csp). The workflow was rapid, robust, accurate, affordable and straightforward to implement, and could be deployed using readily collected dried blood spot samples. We found that P. falciparum parasites in Ghana had become largely susceptible to chloroquine, with persistent sulfadoxine-pyrimethamine (SP) resistance, and no evidence of artemisinin resistance. Multiple Single Nucleotide Polymorphism (SNP) differences from the vaccine csp sequence were identified, though their significance is uncertain. This study demonstrates the potential utility and feasibility of malaria genomic surveillance in endemic settings using Nanopore sequencing.

genomics↗

bioRxiv2019

New insights into malaria susceptibility from the genomes of 17,000 individuals from Africa, Asia, and Oceania

We conducted a genome-wide association study of host resistance to severe Plasmodium falciparum malaria in over 17,000 individuals from 11 malaria-endemic countries, undertaking a wide ranging analysis which identifies five replicable associations with genome-wide levels of evidence. Our findings include a newly implicated variant on chromosome 6 associated with risk of cerebral malaria, and the discovery of an erythroid-specific transcription start site underlying the association in ATP2B4. Previously reported HLA associations cannot be replicated in this dataset. We estimate substantial heritability of severe malaria (h2 ~ 23%), of which around 10% is explained by the currently identified associations. Our dataset will provide a major building block for future research on the genetic determinants of disease in these diverse human populations.

genetics↗