RESUMEN
Hosts are continually selected to evolve new defenses against an ever-changing array of pathogens. To understand this process, we examined the genetic basis of resistance to the Drosophila A virus in Drosophila melanogaster. In a natural population, we identified a polymorphic transposable element (TE) insertion that was associated with an â¼19,000-fold reduction in viral titers, allowing flies to largely escape the harmful effects of infection by this virulent pathogen. The insertion occurs in the protein-coding sequence of the gene Veneno, which encodes a Tudor domain protein. By mutating Veneno with CRISPR-Cas9 in flies and expressing it in cultured cells, we show that the ancestral allele of the gene has no effect on viral replication. Instead, the TE insertion is a gain-of-function mutation that creates a gene encoding a novel resistance factor. Viral titers remained reduced when we deleted the TE sequence from the transcript, indicating that resistance results from the TE truncating the Veneno protein. This is a novel mechanism of virus resistance and a new way by which TEs can contribute to adaptation.
Asunto(s)
Elementos Transponibles de ADN , Dicistroviridae , Drosophila melanogaster , Interacciones Huésped-Patógeno , Dominio Tudor , Animales , Elementos Transponibles de ADN/genética , Drosophila melanogaster/genética , Drosophila melanogaster/virología , Mutación con Ganancia de Función , Interacciones Huésped-Patógeno/genética , Eliminación de SecuenciaRESUMEN
The burden of several common diseases including obesity, diabetes, hypertension, asthma, and depression is increasing in most world populations. However, the mechanisms underlying the numerous epidemiological and genetic correlations among these disorders remain largely unknown. We investigated whether common polymorphic inversions underlie the shared genetic influence of these disorders. We performed an inversion association analysis including 21 inversions and 25 obesity-related traits on a total of 408,898 Europeans and validated the results in 67,299 independent individuals. Seven inversions were associated with multiple diseases while inversions at 8p23.1, 16p11.2, and 11q13.2 were strongly associated with the co-occurrence of obesity with other common diseases. Transcriptome analysis across numerous tissues revealed strong candidate genes for obesity-related traits. Analyses in human pancreatic islets indicated the potential mechanism of inversions in the susceptibility of diabetes by disrupting the cis-regulatory effect of SNPs from their target genes. Our data underscore the role of inversions as major genetic contributors to the joint susceptibility to common complex diseases.
Asunto(s)
Inversión Cromosómica/genética , Diabetes Mellitus/genética , Predisposición Genética a la Enfermedad , Hipertensión/genética , Obesidad/complicaciones , Obesidad/genética , Polimorfismo Genético , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Cromosomas Humanos Par 16/genética , Cromosomas Humanos Par 8/genética , Conjuntos de Datos como Asunto/normas , Diabetes Mellitus/patología , Europa (Continente)/etnología , Femenino , Perfilación de la Expresión Génica , Haplotipos , Humanos , Hipertensión/complicaciones , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
Polymorphic inversions contribute to adaptation and phenotypic variation. However, large multi-centric association studies of inversions remain challenging. We present scoreInvHap, a method to genotype inversions from SNP data for genome-wide association studies (GWASs), overcoming important limitations of current methods and outperforming them in accuracy and applicability. scoreInvHap calls individual inversion-genotypes from a similarity score to the SNPs of experimentally validated references. It can be used on different sources of SNP data, including those with low SNP coverage such as exome sequencing, and is easily adaptable to genotype new inversions, either in humans or in other species. We present 20 human inversions that can be reliably and easily genotyped with scoreInvHap to discover their role in complex human traits, and illustrate a first genome-wide association study of experimentally-validated human inversions. scoreInvHap is implemented in R and it is freely available from Bioconductor.
Asunto(s)
Estudio de Asociación del Genoma Completo/métodos , Inversión de Secuencia , Técnicas de Genotipaje , Humanos , Polimorfismo de Nucleótido Simple , Programas InformáticosRESUMEN
Wolbachia is a common heritable bacterial symbiont in insects. Its evolutionary success lies in the diverse phenotypic effects it has on its hosts coupled to its propensity to move between host species over evolutionary timescales. In a survey of natural host-symbiont associations in a range of Drosophila species, we found that 10 of 16 Wolbachia strains protected their hosts against viral infection. By moving Wolbachia strains between host species, we found that the symbiont genome had a much greater influence on the level of antiviral protection than the host genome. The reason for this was that the level of protection depended on the density of the symbiont in host tissues, and Wolbachia rather than the host-controlled density. The finding that virus resistance and symbiont density are largely under the control of symbiont genes in this system has important implications both for the evolution of these traits and for public health programmes using Wolbachia to prevent mosquitoes from transmitting disease.
Asunto(s)
Resistencia a la Enfermedad , Drosophila/microbiología , Simbiosis , Wolbachia/genética , Animales , Drosophila/genética , Drosophila/virología , Genoma Bacteriano , Genoma de los Insectos , Fenotipo , Virus/patogenicidadRESUMEN
It is common to find considerable genetic variation in susceptibility to infection in natural populations. We have investigated whether natural selection increases this variation by testing whether host populations show more genetic variation in susceptibility to pathogens that they naturally encounter than novel pathogens. In a large cross-infection experiment involving four species of Drosophila and four host-specific viruses, we always found greater genetic variation in susceptibility to viruses that had coevolved with their host. We went on to examine the genetic architecture of resistance in one host species, finding that there are more major-effect genetic variants in coevolved host-pathogen interactions. We conclude that selection by pathogens has increased genetic variation in host susceptibility, and much of this effect is caused by the occurrence of major-effect resistance polymorphisms within populations.