ABSTRACT
Infection with Lassa virus (LASV) can cause Lassa fever, a haemorrhagic illness with an estimated fatality rate of 29.7%, but causes no or mild symptoms in many individuals. Here, to investigate whether human genetic variation underlies the heterogeneity of LASV infection, we carried out genome-wide association studies (GWAS) as well as seroprevalence surveys, human leukocyte antigen typing and high-throughput variant functional characterization assays. We analysed Lassa fever susceptibility and fatal outcomes in 533 cases of Lassa fever and 1,986 population controls recruited over a 7 year period in Nigeria and Sierra Leone. We detected genome-wide significant variant associations with Lassa fever fatal outcomes near GRM7 and LIF in the Nigerian cohort. We also show that a haplotype bearing signatures of positive selection and overlapping LARGE1, a required LASV entry factor, is associated with decreased risk of Lassa fever in the Nigerian cohort but not in the Sierra Leone cohort. Overall, we identified variants and genes that may impact the risk of severe Lassa fever, demonstrating how GWAS can provide insight into viral pathogenesis.
Subject(s)
Lassa Fever , Humans , Lassa Fever/genetics , Lassa Fever/diagnosis , Lassa Fever/epidemiology , Genome-Wide Association Study , Seroepidemiologic Studies , Lassa virus/genetics , Fever , Human GeneticsABSTRACT
Most approaches that capture signatures of selective sweeps in population genomics data do not identify the specific mutation favored by selection. We present iSAFE (for "integrated selection of allele favored by evolution"), a method that enables researchers to accurately pinpoint the favored mutation in a large region (â¼5 Mbp) by using a statistic derived solely from population genetics signals. iSAFE does not require knowledge of demography, the phenotype under selection, or functional annotations of mutations.
Subject(s)
Genomics , Nucleic Acid Amplification Techniques , Nucleic Acid Hybridization/methods , Alleles , Biological Evolution , Haplotypes , Humans , MutationABSTRACT
The 2013-2015 West African epidemic of Ebola virus disease (EVD) reminds us of how little is known about biosafety level 4 viruses. Like Ebola virus, Lassa virus (LASV) can cause hemorrhagic fever with high case fatality rates. We generated a genomic catalog of almost 200 LASV sequences from clinical and rodent reservoir samples. We show that whereas the 2013-2015 EVD epidemic is fueled by human-to-human transmissions, LASV infections mainly result from reservoir-to-human infections. We elucidated the spread of LASV across West Africa and show that this migration was accompanied by changes in LASV genome abundance, fatality rates, codon adaptation, and translational efficiency. By investigating intrahost evolution, we found that mutations accumulate in epitopes of viral surface proteins, suggesting selection for immune escape. This catalog will serve as a foundation for the development of vaccines and diagnostics. VIDEO ABSTRACT.
Subject(s)
Genome, Viral , Lassa Fever/virology , Lassa virus/genetics , RNA, Viral/genetics , Africa, Western/epidemiology , Animals , Biological Evolution , Disease Reservoirs , Ebolavirus/genetics , Genetic Variation , Glycoproteins/genetics , Hemorrhagic Fever, Ebola/virology , Humans , Lassa Fever/epidemiology , Lassa Fever/transmission , Lassa virus/classification , Lassa virus/physiology , Murinae/genetics , Mutation , Nigeria/epidemiology , Viral Proteins/genetics , Zoonoses/epidemiology , Zoonoses/virologyABSTRACT
The past fifty years have seen the development and application of numerous statistical methods to identify genomic regions that appear to be shaped by natural selection. These methods have been used to investigate the macro- and microevolution of a broad range of organisms, including humans. Here, we provide a comprehensive outline of these methods, explaining their conceptual motivations and statistical interpretations. We highlight areas of recent and future development in evolutionary genomics methods and discuss ongoing challenges for researchers employing such tests. In particular, we emphasize the importance of functional follow-up studies to characterize putative selected alleles and the use of selection scans as hypothesis-generating tools for investigating evolutionary histories.
Subject(s)
Genomics , Selection, Genetic/genetics , Adaptation, Physiological/genetics , Alleles , Amino Acid Substitution , Animals , Evolution, Molecular , Forecasting , Gene Frequency , Genetics, Population/methods , Genotyping Techniques , Humans , Linkage Disequilibrium , Models, Genetic , Multifactorial Inheritance/genetics , Mutation , Mutation Rate , Phenotype , Sequence Analysis, DNAABSTRACT
Genome-wide computational studies can now identify targets of natural selection. The unique information about humans these studies reveal, and the media attention they attract, indicate the need for caution and precision in communicating results. This need is exacerbated by ways in which evolutionary and genetic considerations have been misapplied to support discriminatory policies, by persistent misconceptions of these fields and by the social sensitivity surrounding discussions of racial ancestry. We discuss the foundations, accomplishments and future directions of human evolutionary genomics, attending to ways in which the interpretation of good science can go awry, and offer suggestions for researchers to prevent misapplication of their work.
