Biology subjects

Pedergnana, V.

Publications and source records attributed to Pedergnana, V..

7 recordsLinked to original sources

bioRxiv2026

MutaPhy: A clade-based framework to detect genotype-phenotype associations on phylogenetic trees

Understanding how genetic variation in pathogens influences clinical phenotypes observed in infected hosts is a fundamental challenge in evolutionary genomics and public health. Phenotypic traits such as infection severity are often non-randomly distributed within the pathogens phylogeny, suggesting the existence of evolutionary determinants but also violating the independence assumption underlying classical genome-wide association studies and potentially leading to inflated false positive rates. We present MutaPhy, a phylogeny-based method aimed at detecting correlations between a binary host phenotype and the corresponding pathogen genome by directly utilizing the hierarchical structure of phylogenetic trees. MutaPhy encompasses three different scales: (i) a subtree scale, on which relevant clades over-representing the phenotype of interest are detected using permutation-based tests; (ii) a tree scale, which agglomerates local signals into a global association statistics; and (iii) a site scale, whereby candidate mutational events on branches leading to significant clades are examined using ancestral sequence reconstruction. We evaluate the statistical behavior and detection performance of MutaPhy using simulations under diverse evolutionary scenarios. We also compare this tool to several existing phylogenetic association methods. As illustrative applications, we apply MutaPhy to dengue virus and hepatitis C virus datasets associated to clinical phenotypes in human hosts. Our results highlight the ability of the proposed approach to detect viral lineages associated to over-represented phenotypes while revealing limited evidence for robust mutation-level associations in these particular datasets. Altogether, MutaPhy provides a framework for guiding genotype-phenotype association analyses by leveraging phylogenetic structure, thereby reducing false positive findings and improving the interpretability of association signals.

evolutionary biology↗

bioRxiv2023

Mitochondrial variation in Anopheles gambiae and An. coluzzii: phylogeographic legacy of species isolation and mito-nuclear associations with metabolic resistance to pathogens and insecticides

Mitochondrial DNA (mtDNA) has been a popular marker in phylogeography, phylogeny, and molecular ecology, but its complex evolution is increasingly recognized. Here, we investigated mtDNA variation in An. gambiae and An. coluzzii, in perspective with other species in the Anopheles gambiae complex (AGC), by assembling the mitogenomes of 1219 mosquitoes across Africa. The mtDNA phylogeny of the AGC was consistent with a previously reported highly reticulated evolutionary history, revealing important discordances with the species tree. The three most widespread species (An. gambiae, An. coluzzii, An. arabiensis), known for extensive historical introgression, could not be discriminated based on mitogenomes. Furthermore, a monophyletic clustering of the three salt-water tolerant species (An. merus, An. melas, An. bwambae) in the AGC also suggested that introgression and possibly selection shaped mtDNA evolution. MtDNA variation in An. gambiae and An. coluzzii across Africa revealed significant partitioning among populations and species. A peculiar mtDNA lineage found predominantly in An. coluzzii and in the hybrid taxon of the African "far-west" exhibited divergence comparable to the inter-species divergence in the AGC, with a geographic distribution matching closely An. coluzziis geographic range. This phylogeographic relict of the An. coluzzii and An. gambiae split was associated with population and species structuration, but not with Wolbachia occurrence. The lineage was significantly associated with SNPs in the nuclear genome, particularly in genes associated with pathogen and insecticide resistance. These findings underline the mito-nuclear coevolution history and the role played by mitochondria in shaping metabolic responses to pathogens and insecticide in Anopheles.

evolutionary biology↗

bioRxiv2023

Inference of host-pathogen interaction matrices from genome-wide polymorphism data

Coevolution is defined as the evolutionary change in one antagonist (host) in response to changes in the other antagonist (pathogen). At the genetic level, these changes are determined by genotype x genotype (GxG) interactions. We build on a general theoretical model of a host-pathogen interaction to derive four indices to retrieve key features of GxG interactions. The four developed indices extract relevant information from polymorphism data of randomly sampled uninfected hosts as well as infected hosts and their respective pathogen strains. Using these indices as summary statistics in an Approximate Bayesian Computation method, we can show their power to discriminate between GxG interaction matrices. Second, we apply our ABC method to a SNP data set of 451 European humans and their infecting Hepatitis C Virus (HCV) strains supplemented by polymorphism data of 503 individuals from the 1,000 genomes project. As our indices encompass and extend previous natural co-GWAs we recover many of the associations previously reported for this dataset and infer their underlying interaction matrix. We reveal a new candidate gene for resistance to HCV in the human genome, and two groups of significant GxG associations exhibiting gene-for-gene interactions. We suggest that the inferred types of GxG interactions result from the recent expansion, adaptation and low prevalence of the HCV virus population in Europe. Significance statementWhy are some host individuals susceptible/resistant to infection by certain pathogen genotypes and others not? Understanding the genetic characteristics of genes driving host-pathogen interactions is crucial to predict epidemics. We develop four indices based on a mathematical model and build a Bayesian statistical method computing these indices on full genome data of infected hosts and their infecting pathogen strains and data of non-infected hosts. We can pinpoint the genes underlying host-pathogen interactions and infer their characteristics. Applying our framework to data from European humans and the Hepatitis C virus, we discover a new potential resistance gene in humans and reveal how the virus has adapted in the last 150 years to match the genetic diversity of the European human population.

evolutionary biology↗

bioRxiv2021

Global spread and evolutionary history of HCV subtype 3a

Studies have shown that HCV subtype 3a had likely been circulating in South Asia before its global spread. However, the time and route of this dissemination remain unclear. For the first time, we generated host and virus genome-wide data for more than 500 patients infected with HCV subtype 3a from the UK, North America, Australia and New Zealand. We used the host genomic data to infer the ancestry of the patients and used this information to investigate the epidemic history of HCV subtype 3a. We observed that viruses from hosts of South Asian ancestry clustered together near the root of the tree, irrespective of the sampling country and that they were more diverse than viruses from other host ancestries. We also inferred that three independent transmission events resulted in the spread of the virus from South Asia to the UK, North America and the Australian continent. This initial spread happened during or soon after the end of the second world war. This was followed by an exponential growth in the effective population size of HCV subtype 3a worldwide and many independent transmissions between the UK, North America and Australian continent. Using both host and virus genomic information can be highly informative in studying the virus epidemic history especially in the context of chronic infections.

evolutionary biology↗

bioRxiv2020

Viral genome wide association study identifies novel hepatitis C virus polymorphisms associated with sofosbuvir treatment failure

Chronic hepatitis C virus (HCV) infection is a major cause of chronic liver disease, cirrhosis and hepatocellular carcinoma worldwide. With the recent development of direct acting antivirals (DAA), treatment of chronically infected patients has become highly effective although a subset of patients do not respond to therapy. Sofosbuvir is a common component of current de novo or salvage combination therapies. We used pre-treatment whole genome sequencing of HCV from 507 patients infected with HCV subtype 3a and treated with sofosbuvir containing regimens to detect viral polymorphisms associated with response to treatment. We found that three common polymorphisms present in HCV NS2 and NS3 proteins (not direct targets of sofosbuvir) were associated with reduced treatment response. These polymorphisms were enriched in post-treatment HCV sequences of patients unresponsive to treatment; they were also associated with lower reductions in viral load in the first week of therapy. The finding of polymorphisms in NS2 and NS3 proteins associated with poor treatment outcomes emphasises the value of more systematic genome-wide analyses of HCV in uncovering indirect but clinically relevant mechanisms of antiviral resistance.

microbiology↗

bioRxiv2018

Genome sequencing analysis identifies high-risk Epstein-Barr virus subtypes for nasopharyngeal carcinoma

Epstein-Barr virus (EBV) infection is ubiquitous worldwide and associated with multiple cancers including nasopharyngeal carcinoma (NPC). The role of EBV viral genomic variation in NPC development and its striking endemicity in southern China has been poorly explored. Through large-scale genome sequencing and association study of EBV isolates from China, we identified two non-synonymous EBV variants within BALF2 strongly associated with NPC risk (conditional P value 1.75x10-6 for SNP162476_C and 3.23x10-13 for SNP163364_T), whose cumulative effects contributed to 83% of the overall risk in southern China. Phylogenetic analysis of the risk variants revealed a unique origin in southern China followed by clonal expansion. EBV BALF2 haplotype carrying the risk variants were shown to reduce viral lytic DNA replication, as a result potentially promoting viral latency. Our discovery has not only provided insight to the unique endemic pattern of NPC occurrence in southern China, but also paved the way for the identification of individuals at high risk of NPC and effective intervention program to reduce the disease burden in southern China.

genetics↗

bioRxiv2018

Interferon lambda 4 impacts broadly on hepatitis C virus diversity.

Type III interferons (IFN-{lambda}) are part of the innate immune response to hepatitis C virus (HCV) infection however the specific role of IFN-{lambda}4 and the nature of the viral adaption to this pressure have not been defined. Here we use paired genome-wide human and viral genetic data in 485 patients infected with HCV genotype 3a to explore the role of IFN-{lambda}4 on HCV evolution during chronic infection. We show that genetic variations within the host IFNL4 locus have a broad and systematic impact on HCV amino acid diversity. We also demonstrate that this impact is larger in patients producing a more active form of IFN-{lambda}4 protein compared to the less active form. A similar observation was noted for viral load. We conclude that IFN-{lambda}4 protein is a likely causal agent driving widespread HCV amino acid changes and associated with viral load and possibly other clinical and biological outcomes of HCV infection.

genomics↗