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Understanding Disease Susceptibility through Population Genomics.

ABSTRACT: Genetic epidemiology studies have established that the natural variation of gene expression profiles is heritable and has genetic bases. A number of proximal and remote DNA variations, known as expression quantitative trait loci (eQTLs), that are associated with the expression phenotypes have been identified, first in Epstein-Barr virus-transformed lymphoblastoid cell lines and later expanded to other cell and tissue types. Integration of the eQTL information and the network analysis of transcription modules may lead to a better understanding of gene expression regulation. As these network modules have relevance to biological or disease pathways, these findings may be useful in predicting disease susceptibility.

SUBMITTER: Han S

PROVIDER: S-EPMC3543923 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Understanding Disease Susceptibility through Population Genomics.

Han Seonggyun S Lee Junnam J Kim Sangsoo S

Genomics & informatics 20121231 4

Genetic epidemiology studies have established that the natural variation of gene expression profiles is heritable and has genetic bases. A number of proximal and remote DNA variations, known as expression quantitative trait loci (eQTLs), that are associated with the expression phenotypes have been identified, first in Epstein-Barr virus-transformed lymphoblastoid cell lines and later expanded to other cell and tissue types. Integration of the eQTL information and the network analysis of transcri ...[more]

PMID: 23346035

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Project description:The increased prevalence of vancomycin-intermediate Staphylococcus aureus (VISA) is an emerging health care threat. Genome-based comparative methods hold great promise to uncover the genetic basis of the VISA phenotype, which remains obscure. S. aureus isolates were collected from a single individual that presented with recurrent staphylococcal bacteremia at three time points, and the isolates showed successively reduced levels of vancomycin susceptibility. A population genomic approach was taken to compare patient S. aureus isolates with decreasing vancomycin susceptibility across the three time points. To do this, patient isolates were sequenced to high coverage (~500×), and sequence reads were used to model site-specific allelic variation within and between isolate populations. Population genetic methods were then applied to evaluate the overall levels of variation across the three time points and to identify individual variants that show anomalous levels of allelic change between populations. A successive reduction in the overall levels of population genomic variation was observed across the three time points, consistent with a population bottleneck resulting from antibiotic treatment. Despite this overall reduction in variation, a number of individual mutations were swept to high frequency in the VISA population. These mutations were implicated as potentially involved in the VISA phenotype and interrogated with respect to their functional roles. This approach allowed us to identify a number of mutations previously implicated in VISA along with allelic changes within a novel class of genes, encoding LPXTG motif-containing cell-wall-anchoring proteins, which shed light on a novel mechanistic aspect of vancomycin resistance. IMPORTANCE The emergence and spread of antibiotic resistance among bacterial pathogens are two of the gravest threats to public health facing the world today. We report the development and application of a novel population genomic technique aimed at uncovering the evolutionary dynamics and genetic determinants of antibiotic resistance in Staphylococcus aureus. This method was applied to S. aureus cultures isolated from a single patient who showed decreased susceptibility to the vancomycin antibiotic over time. Our approach relies on the increased resolution afforded by next-generation genome-sequencing technology, and it allowed us to discover a number of S. aureus mutations, in both known and novel gene targets, which appear to have evolved under adaptive pressure to evade vancomycin mechanisms of action. The approach we lay out in this work can be applied to resistance to any number of antibiotics across numerous species of bacterial pathogens.

Project description:BackgroundThe presence of Bacillus in very diverse environments reflects the versatile metabolic capabilities of a widely distributed genus. Traditional phylogenetic analysis based on limited gene sampling is not adequate for resolving the genus evolutionary relationships. By distinguishing between core and pan-genome, we determined the evolutionary and functional relationships of known Bacillus.ResultsOur analysis is based upon twenty complete and draft Bacillus genomes, including a newly sequenced Bacillus isolate from an aquatic environment that we report for the first time here. Using a core genome, we were able to determine the phylogeny of known Bacilli, including aquatic strains whose position in the phylogenetic tree could not be unambiguously determined in the past. Using the pan-genome from the sequenced Bacillus, we identified functional differences, such as carbohydrate utilization and genes involved in signal transduction, which distinguished the taxonomic groups. We also assessed the genetic architecture of the defining traits of Bacillus, such as sporulation and competence, and showed that less than one third of the B. subtilis genes are conserved across other Bacilli. Most variation was shown to occur in genes that are needed to respond to environmental cues, suggesting that Bacilli have genetically specialized to allow for the occupation of diverse habitats and niches.ConclusionsThe aquatic Bacilli are defined here for the first time as a group through the phylogenetic analysis of 814 genes that comprise the core genome. Our data distinguished between genomic components, especially core vs. pan-genome to provide insight into phylogeny and function that would otherwise be difficult to achieve. A phylogeny may mask the diversity of functions, which we tried to uncover in our approach. The diversity of sporulation and competence genes across the Bacilli was unexpected based on previous studies of the B. subtilis model alone. The challenge of uncovering the novelties and variations among genes of the non-subtilis groups still remains. This task will be best accomplished by directing efforts toward understanding phylogenetic groups with similar ecological niches.

Dataset Information

Understanding Disease Susceptibility through Population Genomics.

Publications

Understanding Disease Susceptibility through Population Genomics.

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