European genetic diversity and susceptibility to pathogens

Infectious diseases, both in their endemic and epidemic forms, have shaped the human genome. Ecology has also contributed to geographically constrained pressures on human populations. There are now multiple examples of population-specific genetic variants that modulate susceptibility to infection - several of which have been observed solely in Europeans. The pathogen genome also mutates and adapts to individuals and common alleles in populations. The current understanding has benefited from genome-wide association studies as well as from rapid progress in the genetic characterization of Mendelian immunodeficiencies that are defined by susceptibility to specific pathogens. It is expected that current efforts to characterize rare human genetic variants will contribute to the understanding of severe manifestations of common infections in European and other human groups.

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Jacques Fellay, Amalio Telenti
2013
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https://infoscience.epfl.ch/record/202777?ln=fr

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Étude d'association pangénomique

Une étude d'association pangénomique (en anglais genome-wide association study, GWAS) est une analyse de nombreuses variations génétiques chez de nombreux individus, afin d'étudier leurs corrélations

Human genetic variation

Human genetic variation is the genetic differences in and among populations. There may be multiple variants of any given gene in the human population (alleles), a situation called polymorphism. No

Human genome

The human genome is a complete set of nucleic acid sequences for humans, encoded as DNA within the 23 chromosome pairs in cell nuclei and in a small DNA molecule found within individual mitochondria.

Human genomics of acute liver failure due to hepatitis B virus infection: An exome sequencing study in liver transplant recipients

Samira Asgari, Nimisha Chaturvedi, Jacques Fellay, Christian Hammer, Petar Scepanovic

Acute liver failure (ALF) or fulminant hepatitis is a rare, yet severe outcome of infection with hepatitis B virus (HBV) that carries a high mortality rate. The occurrence of a life-threatening condition upon infection with a prevalent virus in individuals without known risk factors is suggestive of pathogen-specific immune dysregulation. In the absence of established differences in HBV virulence, we hypothesized that ALF upon primary infection with HBV could be due to rare deleterious variants in the human genome. To search for such variants, we performed exome sequencing in 21 previously healthy adults who required liver transplantation upon fulminant HBV infection and 172 controls that were positive for anti-HBc and anti-HBs but had no clinical history of jaundice or liver disease. After a series of hypothesis-driven filtering steps, we searched for putatively pathogenic variants that were significantly associated with case-control status. We did not find any causal variant or gene, a result that does not support the hypothesis of a shared monogenic basis for human susceptibility to HBV-related ALF in adults. This study represents a first attempt at deciphering the human genetic contribution to the most severe clinical presentation of acute HBV infection in previously healthy individuals.

2019

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GuavaH: a compendium of host genomic data in HIV biology and disease

Istvan Bartha, Jacques Fellay, Amalio Telenti

Background: There is an ever-increasing volume of data on host genes that are modulated during HIV infection, influence disease susceptibility or carry genetic variants that impact HIV infection. We created GuavaH (Genomic Utility for Association and Viral Analyses in HIV, http://www.GuavaH.org), a public resource that supports multipurpose analysis of genome-wide genetic variation and gene expression profile across multiple phenotypes relevant to HIV biology. Findings: We included original data from 8 genome and transcriptome studies addressing viral and host responses in and ex vivo. These studies cover phenotypes such as HIV acquisition, plasma viral load, disease progression, viral replication cycle, latency and viral-host genome interaction. This represents genome-wide association data from more than 4,000 individuals, exome sequencing data from 392 individuals, in vivo transcriptome microarray data from 127 patients/conditions, and 60 sets of RNA-seq data. Additionally, GuavaH allows visualization of protein variation in similar to 8,000 individuals from the general population. The publicly available GuavaH framework supports queries on (i) unique single nucleotide polymorphism across different HIV related phenotypes, (ii) gene structure and variation, (iii) in vivo gene expression in the setting of human infection (CD4+ T cells), and (iv) in vitro gene expression data in models of permissive infection, latency and reactivation. Conclusions: The complexity of the analysis of host genetic influences on HIV biology and pathogenesis calls for comprehensive motors of research on curated data. The tool developed here allows queries and supports validation of the rapidly growing body of host genomic information pertinent to HIV research.

BioMed Central2014

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Exploring the interactions between the human and viral genomes

Jacques Fellay

Over the last decade, genome-wide association studies led to major advances in identifying human genetic variants associated with infectious disease susceptibility. On the pathogen side, comparable methods are now applied to identify disease-modulating pathogen variants. As host and pathogen variants jointly determine disease outcomes, the most recent development has been to explore simultaneously host and pathogen genomes, through so-called genome-to-genome studies. In this review, we provide some background on the development of genome-to-genome analysis and we detail the first wave of studies in this emerging field, which focused on patients chronically infected with HIV and hepatitis C virus. We also discuss the need for novel statistical methods to better tackle the issues of population stratification and multiple testing. Finally, we speculate on future research areas where genome-to-genome analysis may prove to be particularly effective.

SPRINGER2020

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