Genome-wide scans provide evidence for positive selection of genes implicated in Lassa fever

Rapidly evolving viruses and other pathogens can have an immense impact on human evolution as natural selection acts to increase the prevalence of genetic variants providing resistance to disease. With the emergence of large datasets of human genetic variation, we can search for signatures of natural selection in the human genome driven by such disease-causing microorganisms. Based on this approach, we have previously hypothesized that Lassa virus (LASV) may have been a driver of natural selection in West African populations where Lassa haemorrhagic fever is endemic. In this study, we provide further evidence for this notion. By applying tests for selection to genome-wide data from the International Haplotype Map Consortium and the 1000 Genomes Consortium, we demonstrate evidence for positive selection in LARGE and interleukin 21 (IL21), two genes implicated in LASV infectivity and immunity. We further localized the signals of selection, using the recently developed composite of multiple signals method, to introns and putative regulatory regions of those genes. Our results suggest that natural selection may have targeted variants giving rise to alternative splicing or differential gene expression of LARGE and IL21. Overall, our study supports the hypothesis that selective pressures imposed by LASV may have led to the emergence of particular alleles conferring resistance to Lassa fever, and opens up new avenues of research pursuit

Genetic Signatures of Strong Recent Positive Selection at the Lactase Gene

In most human populations, the ability to digest lactose contained in milk usually disappears in childhood, but in European-derived populations, lactase activity frequently persists into adulthood (Scrimshaw and Murray 1988). It has been suggested (Cavalli-Sforza 1973; Hollox et al. 2001; Enattah et al. 2002; Poulter et al. 2003) that a selective advantage based on additional nutrition from dairy explains these genetically determined population differences (Simoons 1970; Kretchmer 1971; Scrimshaw and Murray 1988; Enattah et al. 2002), but formal population-genetics–based evidence of selection has not yet been provided. To assess the population-genetics evidence for selection, we typed 101 single-nucleotide polymorphisms covering 3.2 Mb around the lactase gene. In northern European–derived populations, two alleles that are tightly associated with lactase persistence (Enattah et al. 2002) uniquely mark a common (∼77%) haplotype that extends largely undisrupted for >1 Mb. We provide two new lines of genetic evidence that this long, common haplotype arose rapidly due to recent selection: (1) by use of the traditional FST measure and a novel test based on pexcess, we demonstrate large frequency differences among populations for the persistence-associated markers and for flanking markers throughout the haplotype, and (2) we show that the haplotype is unusually long, given its high frequency—a hallmark of recent selection. We estimate that strong selection occurred within the past 5,000–10,000 years, consistent with an advantage to lactase persistence in the setting of dairy farming; the signals of selection we observe are among the strongest yet seen for any gene in the genome

Reporter Assays for Ebola Virus Nucleoprotein Oligomerization, Virion-Like Particle Budding, and Minigenome Activity Reveal the Importance of Nucleoprotein Amino Acid Position 111

For highly pathogenic viruses, reporter assays that can be rapidly performed are critically needed to identify potentially functional mutations for further study under maximal containment (e.g., biosafety level 4 [BSL-4]). The Ebola virus nucleoprotein (NP) plays multiple essential roles during the viral life cycle, yet few tools exist to study the protein under BSL-2 or equivalent containment. Therefore, we adapted reporter assays to measure NP oligomerization and virion-like particle (VLP) production in live cells and further measured transcription and replication using established minigenome assays. As a proof-of-concept, we examined the NP-R111C substitution, which emerged during the 20132016 Western African Ebola virus disease epidemic and rose to high frequency. NP-R111C slightly increased NP oligomerization and VLP budding but slightly decreased transcription and replication. By contrast, a synthetic charge-reversal mutant, NP-R111E, greatly increased oligomerization but abrogated transcription and replication. These results are intriguing in light of recent structures of NP oligomers, which reveal that the neighboring residue, K110, forms a salt bridge with E349 on adjacent NP molecules. By developing and utilizing multiple reporter assays, we find that the NP-111 position mediates a complex interplay between NP\u27s roles in protein structure, virion budding, and transcription and replication

Correction: Lassa hemorrhagic fever in a late term pregnancy from northern Sierra Leone with a positive maternal outcome: case report

Lassa fever (LF) is a devastating viral disease prevalent in West Africa. Efforts to take on this public health crisis have been hindered by lack of infrastructure and rapid field deployable diagnosis in areas where the disease is prevalent. Recent capacity building at the Kenema Government Hospital Lassa Fever Ward (KGH LFW) in Sierra Leone has lead to a major turning point in the diagnosis, treatment and study of LF. Herein we present the first comprehensive rapid diagnosis and real time characterization of an acute hemorrhagic LF case at KGH LFW. This case report focuses on a third trimester pregnant Sierra Leonean woman from the historically non-endemic Northern district of Tonkolili who survived the illness despite fetal demise. Employed in this study were newly developed recombinant LASV Antigen Rapid Test cassettes and dipstick lateral flow immunoassays (LFI) that enabled the diagnosis of LF within twenty minutes of sample collection. Deregulation of overall homeostasis, significant hepatic and renal system involvement, and immunity profiles were extensively characterized during the course of hospitalization. Rapid diagnosis, prompt treatment with a full course of intravenous (IV) ribavirin, IV fluids management, and real time monitoring of clinical parameters resulted in a positive maternal outcome despite admission to the LFW seven days post onset of symptoms, fetal demise, and a natural still birth delivery. These studies solidify the growing rapid diagnostic, treatment, and surveillance capabilities at the KGH LF Laboratory, and the potential to significantly improve the current high mortality rate caused by LF. As a result of the growing capacity, we were also able to isolate Lassa virus (LASV) RNA from the patient and perform Sanger sequencing where we found significant genetic divergence from commonly circulating Sierra Leonean strains, showing potential for the discovery of a newly emerged LASV strain with expanded geographic distribution. Furthermore, recent emergence of LF cases in Northern Sierra Leone highlights the need for superior diagnostics to aid in the monitoring of LASV strain divergence with potentially increased geographic expansion.Organismic and Evolutionary BiologyOther Research Uni