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PubMed2003

Exploiting genome data to understand the function, regulation, and evolutionary origins of toxicologically relevant genes.

The wealth of new information coming from the many genome sequencing projects is providing unprecedented opportunities for major advances in all areas of biology, including the environmental health sciences. To facilitate this discovery process, experts in the fields of functional genomics and informatics and the emerging field of toxicogenomics recently gathered at the Mount Desert Island Biological Laboratory in Salisbury Cove, Maine, site of a National Institute of Environmental Health Sciences Marine and Freshwater Biomedical Science Center, to share their ideas and latest research findings. The goal of the symposium was to highlight approaches that may be used to identify and characterize toxicologically relevant genes being discovered in the genome sequencing projects. Many of the approaches rely heavily on comparative models as a way of identifying gene homology, ontology, and physiologic function, and on the availability of databases that facilitate storage, analysis, interpretation, and widespread dissemination of relevant data.

Animals↗
PubMed2005

Mining nematode genome data for novel drug targets.

Expressed sequence tag projects have currently produced over 400 000 partial gene sequences from more than 30 nematode species and the full genomic sequences of selected nematodes are being determined. In addition, functional analyses in the model nematode Caenorhabditis elegans have addressed the role of almost all genes predicted by the genome sequence. This recent explosion in the amount of available nematode DNA sequences, coupled with new gene function data, provides an unprecedented opportunity to identify pre-validated drug targets through efficient mining of nematode genomic databases. This article describes the various information sources available and strategies that can expedite this process.

Animals↗
PubMed2005

Retrieval of first genome data for rice cluster I methanogens by a combination of cultivation and molecular techniques.

We report first insights into a representative genome of rice cluster I (RC-I), a major group of as-yet uncultured methanogens. The starting point of our study was the methanogenic consortium MRE50 that had been stably maintained for 3 years by consecutive transfers to fresh medium and anaerobic incubation at 50 degrees C. Process-oriented measurements provided evidence for hydrogenotrophic CO(2)-reducing methanogenesis. Assessment of the diversity of consortium MRE50 suggested members of the families Thermoanaerobacteriaceae and Clostridiaceae to constitute the major bacterial component, while the archaeal population was represented entirely by RC-I. The RC-I population amounted to more than 50% of total cells, as concluded from fluorescence in situ hybridization using specific probes for either Bacteria or Archaea. The high enrichment status of RC-I prompted construction of a large insert fosmid library from consortium MRE50. Comparative sequence analysis of internal transcribed spacer (ITS) regions revealed that three different RC-I rrn operon variants were present in the fosmid library. Three, approximately 40-kb genomic fragments, each representative for one of the three different rrn operon variants, were recovered and sequenced. Computational analysis of the sequence data resulted in two major findings: (i) consortium MRE50 most likely harbours only a single RC-I genotype, which is characterized by multiple rrn operon copies; (ii) seven genes were identified to possess a strong phylogenetic signal (eIF2a, dnaG, priA, pcrA, gatD, gatE, and a gene encoding a putative RNA-binding protein). Trees exemplarily computed for the deduced amino acid sequences of eIF2a, dnaG, and priA corroborated a specific phylogenetic association of RC-I with the Methanosarcinales.

Agriculture↗
PubMed2004

Conserved spatially interacting motifs of protein superfamilies: application to fold recognition and function annotation of genome data.

Limitations in techniques for the elucidation of protein function have led to an increasing gap between the annotated proteins and those encoded in a genome. The functional selection and three-dimensional structural constraints of proteins in nature often relate to the retention of significant sequence similarity between proteins of similar fold and function despite poor sequence identity. We identify spatially interacting conserved regions, or motifs, within protein superfamilies that are critical for structure and/or function. A search in sequence databases using these descriptors as additional constraints is an approach to identifying putative additional members of superfamilies. Such constrained searches have been tested against proteins of known structure to demonstrate high percentage specificity (93) with a low error rate of 0.0004. This approach has been compared with other sensitive sequence search methods (e.g., PSI-BLAST, HMMsearch, and IMPALA). It has been extended to analyze the distribution of 11 superfamilies in 93 genomes, including the human genome.

Amino Acid Motifs↗
PubMed2025

Causal Inference for Genomic Data with Multiple Heterogeneous Outcomes.

With the evolution of single-cell RNA sequencing techniques into a standard approach in genomics, it has become possible to conduct cohort-level causal inferences based on single-cell-level measurements. However, the individual gene expression levels of interest are not directly observable; instead, only repeated proxy measurements from each individual's cells are available, providing a derived outcome to estimate the underlying outcome for each of many genes. In this paper, we propose a generic semiparametric inference framework for doubly robust estimation with multiple derived outcomes, which also encompasses the usual setting of multiple outcomes when the response of each unit is available. To reliably quantify the causal effects of heterogeneous outcomes, we specialize the analysis to standardized average treatment effects and quantile treatment effects. Through this, we demonstrate the use of the semiparametric inferential results for doubly robust estimators derived from both Von Mises expansions and estimating equations. A multiple testing procedure based on Gaussian multiplier bootstrap is tailored for doubly robust estimators to control the false discovery exceedance rate. Applications in single-cell CRISPR perturbation analysis and individual-level differential expression analysis demonstrate the utility of the proposed methods and offer insights into the usage of different estimands for causal inference in genomics.

Derived outcomes↗
PubMed2002

Immunity as a function of the unicellular state: implications of emerging genomic data.

Instead of being greeted as supporting the growing corpus of immunological theory, recent advances in the bioinformatic analysis of genomes have often surprised the discoverers and failed to attract the attention of immunologists. In fact, the view that multicellular immune systems are adaptations of already highly evolved unicellular immune systems that are capable of self/not-self discrimination can assist our comprehension of phenomena, such as 'junk' DNA, genetic polymorphism and the ubiquity of repetitive elements. For instance, the 'hidden transcriptome', revealed by run-on transcription of genes or repetitive elements, contains a diverse repertoire of RNA 'immune receptors' with the potential to form double-stranded RNA with viral RNA 'antigens', thus triggering intracellular alarms.

Alu Elements↗
PubMed2002

Sequence variations in the public human genome data reflect a bottlenecked population history.

Single-nucleotide polymorphisms (SNPs) constitute the great majority of variations in the human genome, and as heritable variable landmarks they are useful markers for disease mapping and resolving population structure. Redundant coverage in overlaps of large-insert genomic clones, sequenced as part of the Human Genome Project, comprises a quarter of the genome, and it is representative in terms of base compositional and functional sequence features. We mined these regions to produce 500,000 high-confidence SNP candidates as a uniform resource for describing nucleotide diversity and its regional variation within the genome. Distributions of marker density observed at different overlap length scales under a model of recombination and population size change show that the history of the population represented by the public genome sequence is one of collapse followed by a recent phase of mild size recovery. The inferred times of collapse and recovery are Upper Paleolithic, in agreement with archaeological evidence of the initial modern human colonization of Europe.

Databases, Nucleic Acid↗
PubMed2001

Integration of genome data and protein structures: prediction of protein folds, protein interactions and "molecular phenotypes" of single nucleotide polymorphisms.

With the massive amount of sequence and structural data being produced, new avenues emerge for exploiting the information therein for applications in several fields. Fold distributions can be mapped onto entire genomes to learn about the nature of the protein universe and many of the interactions between proteins can now be predicted solely on the basis of the genomic context of their genes. Furthermore, by utilising the new incoming data on single nucleotide polymorphisms by mapping them onto three-dimensional structures of proteins, problems concerning population, medical and evolutionary genetics can be addressed.

Apolipoproteins E↗
PubMed2005

Privacy protection for clinical and genomic data. The use of privacy-enhancing techniques in medicine.

Privacy includes the right of individuals and organisations to determine for themselves when, how and to what extent information about them is communicated to others. The growing need of managing large amounts of both clinical and genetic data raises important legal and ethical challenges. This paper introduces some of the privacy-protection problems related to classical and genomic medicine, and highlights the relevance of trusted third parties and of privacy-enhancing techniques (PETs) in the context of data collection, e.g., for research. Practical approaches based on two pseudonymisation models, for both batch data collection and interactive data storage, are presented. The actual application of the described techniques today proves the possible benefits for medicine that innovative privacy-enhancing techniques can provide. Technical PET solutions can unlock valuable data sources, otherwise not available.

Belgium↗
PubMed2002

Evidence for sequence-independent evolutionary traces in genomics data.

Sequence conservation during evolution is the foundation for the functional classification of the enormous number of new protein sequences being discovered in the current era of genome sequencing. Conventional methods to detect homologous proteins are not always able to distinguish between true homologs and false positive hits in the twilight zone of sequence similarity. Several different approaches have been proposed to improve the sensitivity of these methods. Among the most successful are sequence profiles, multi-linked alignment, and threading. However, evolution might offer up other clues about a protein's ancestry that are sequence independent. Here we report the discovery of two such traces of evolution that could potentially be used to help infer the fold of a protein and hence improve the ability to predict the biochemical function. The first such evolutionary trace is a conservation of fold along the genome, i.e. nearby genes tend to share a fold more often than expected by chance alone--a not unexpected observation, but one which holds true even when no pair of genes being examined share appreciable homology. The second such evolutionary trace is, surprisingly, present in expression data: genes that are correlated in expression are more apt to share a fold than two randomly chosen genes. This result is surprising because correlations in expression have previously only been considered useful for determining biological function (e.g. what pathway a particular gene fits into), yet the observed fold enrichment in the expression data permits us to say something about biochemical function since fold corresponds strongly with biochemical function. Again, the fold enrichment observed in the expression data is apparent even when no pair of genes being examined share appreciable homology.

Arabidopsis↗
PubMed2000

Ty3/Gypsy retrotransposons: description of new Arabidopsis thaliana elements and evolutionary perspectives derived from comparative genomic data.

We performed a comprehensive analysis of the evolution of the Ty3/GYPSY: group of long-terminal-repeat retrotransposons (also known as METAVIRIDAE:). Exhaustive database searches allowed us to detect novel elements of this group. In particular, the Arabidopsis thaliana and Drosophila melanogaster genome sequencing projects have recently disclosed a large number of new Ty3/GYPSY: sequences. So far, elements of three different Ty3/GYPSY: lineages had been described for A. thaliana. Here, we describe six new lineages, which we have called Tit-for-tat1, Tit-for-tat2, Gimli, Gloin, Legolas, and Little Athila. We confirm that plant Ty3/GYPSY: elements form two main monophyletic groups. Moreover, our results suggest that at least four independent ancestral lineages existed before the monocot-dicot split, about 200 MYA. Twelve sequences from D. melanogaster that may correspond to new elements are also described. Some of these sequences are similar to those of OSVALDO: and Ulysses, two elements of the OSVALDO: clade that had never before been described for D. melanogaster. Comparative analyses of multiple organisms, some of them with completely sequenced genomes, show that the number of lineages of Ty3/GYPSY: elements is very variable. Thus, while only 1 lineage is present in Saccharomyces cerevisiae, at least 6 exist in Caenorhabditis elegans, at least 9 are present in the A. thaliana, and perhaps 20 are present in D. melanogaster. Finally, we suggest that the presence of a chromodomain-containing integrase, a feature of some closely related Ty3/GYPSY: elements of fungi, plants, and animals, may be used to define a new METAVIRIDAE: genus.

Amino Acid Sequence↗