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Finding the needles in the metagenome haystack.

ABSTRACT: In the collective genomes (the metagenome) of the microorganisms inhabiting the Earth's diverse environments is written the history of life on this planet. New molecular tools developed and used for the past 15 years by microbial ecologists are facilitating the extraction, cloning, screening, and sequencing of these genomes. This approach allows microbial ecologists to access and study the full range of microbial diversity, regardless of our ability to culture organisms, and provides an unprecedented access to the breadth of natural products that these genomes encode. However, there is no way that the mere collection of sequences, no matter how expansive, can provide full coverage of the complex world of microbial metagenomes within the foreseeable future. Furthermore, although it is possible to fish out highly informative and useful genes from the sea of gene diversity in the environment, this can be a highly tedious and inefficient procedure. Microbial ecologists must be clever in their pursuit of ecologically relevant, valuable, and niche-defining genomic information within the vast haystack of microbial diversity. In this report, we seek to describe advances and prospects that will help microbial ecologists glean more knowledge from investigations into metagenomes. These include technological advances in sequencing and cloning methodologies, as well as improvements in annotation and comparative sequence analysis. More significant, however, will be ways to focus in on various subsets of the metagenome that may be of particular relevance, either by limiting the target community under study or improving the focus or speed of screening procedures. Lastly, given the cost and infrastructure necessary for large metagenome projects, and the almost inexhaustible amount of data they can produce, trends toward broader use of metagenome data across the research community coupled with the needed investment in bioinformatics infrastructure devoted to metagenomics will no doubt further increase the value of metagenomic studies in various environments.

SUBMITTER: Kowalchuk GA

PROVIDER: S-EPMC1915608 | biostudies-other | 2007 Apr

REPOSITORIES: biostudies-other

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Project description:Genetic adaptation to future environmental conditions is crucial to help species persist as the climate changes. Genome scans are powerful tools to understand adaptive landscapes, enabling us to correlate genetic diversity with environmental gradients while disentangling neutral from adaptive variation. However, low gene flow can lead to both local adaptation and highly structured populations, and is a major confounding factor for genome scans, resulting in an inflated number of candidate loci. Here, we compared candidate locus detection in a marine mollusc (Onithochiton neglectus), taking advantage of a natural geographical contrast in the levels of genetic structure between its populations. O. neglectus is endemic to New Zealand and distributed throughout an environmental gradient from the subtropical north to the subantarctic south. Due to a brooding developmental mode, populations tend to be locally isolated. However, adult hitchhiking on rafting kelp increases connectivity among southern populations. We applied two genome scans for outliers (Bayescan and PCAdapt) and two genotype-environment association (GEA) tests (BayeScEnv and RDA). To limit issues with false positives, we combined results using the geometric mean of q-values and performed association tests with random environmental variables. This novel approach is a compromise between stringent and relaxed approaches widely used before, and allowed us to classify candidate loci as low confidence or high confidence. Genome scans for outliers detected a large number of significant outliers in strong and moderately structured populations. No high-confidence GEA loci were detected in the context of strong population structure. However, 86 high-confidence loci were associated predominantly with latitudinally varying abiotic factors in the less structured southern populations. This suggests that the degree of connectivity driven by kelp rafting over the southern scale may be insufficient to counteract local adaptation in this species. Our study supports the expectation that genome scans may be prone to errors in highly structured populations. Nonetheless, it also empirically demonstrates that careful statistical controls enable the identification of candidate loci that invite more detailed investigations. Ultimately, genome scans are valuable tools to help guide further research aiming to determine the potential of non-model species to adapt to future environments.

Project description:The human cortex encodes information in complex networks that can be anatomically dispersed and variable in their microstructure across individuals. Using simulations with neural network models, we show that contemporary statistical methods for functional brain imaging-including univariate contrast, searchlight multivariate pattern classification, and whole-brain decoding with L1 or L2 regularization-each have critical and complementary blind spots under these conditions. We then introduce the sparse-overlapping-sets (SOS) LASSO-a whole-brain multivariate approach that exploits structured sparsity to find network-distributed information-and show in simulation that it captures the advantages of other approaches while avoiding their limitations. When applied to fMRI data to find neural responses that discriminate visually presented faces from other visual stimuli, each method yields a different result, but existing approaches all support the canonical view that face perception engages localized areas in posterior occipital and temporal regions. In contrast, SOS LASSO uncovers a network spanning all four lobes of the brain. The result cannot reflect spurious selection of out-of-system areas because decoding accuracy remains exceedingly high even when canonical face and place systems are removed from the dataset. When used to discriminate visual scenes from other stimuli, the same approach reveals a localized signal consistent with other methods-illustrating that SOS LASSO can detect both widely distributed and localized representational structure. Thus, structured sparsity can provide an unbiased method for testing claims of functional localization. For faces and possibly other domains, such decoding may reveal representations more widely distributed than previously suspected.SIGNIFICANCE STATEMENT Brain systems represent information as patterns of activation over neural populations connected in networks that can be widely distributed anatomically, variable across individuals, and intermingled with other networks. We show that four widespread statistical approaches to functional brain imaging have critical blind spots in this scenario and use simulations with neural network models to illustrate why. We then introduce a new approach designed specifically to find radically distributed representations in neural networks. In simulation and in fMRI data collected in the well studied domain of face perception, the new approach discovers extensive signal missed by the other methods-suggesting that prior functional imaging work may have significantly underestimated the degree to which neurocognitive representations are distributed and variable across individuals.

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Finding the needles in the metagenome haystack.

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