Modeling DNA methylation dynamics with approaches from phylogenetics

Methylation of CpG dinucleotides is a prevalent epigenetic modification that is required for proper development in vertebrates, and changes in CpG methylation are essential to cellular differentiation. Genome-wide DNA methylation assays have become increasingly common, and recently distinct stages across differentiating cellular lineages have been assayed. How- ever, current methods for modeling methylation dynamics do not account for the dependency structure between precursor and dependent cell types. We developed a continuous-time Markov chain approach, based on the observation that changes in methylation state over tissue differentiation can be modeled similarly to DNA nucleotide changes over evolutionary time. This model explicitly takes precursor to descendant relationships into account and enables inference of CpG methylation dynamics. To illustrate our method, we analyzed a high-resolution methylation map of the differentiation of mouse stem cells into several blood cell types. Our model can successfully infer unobserved CpG methylation states from observations at the same sites in related cell types (90% correct), and this approach more accurately reconstructs missing data than imputation based on neighboring CpGs (84% correct). Additionally, the single CpG resolution of our methylation dynamics estimates enabled us to show that DNA sequence context of CpG sites is informative about methylation dynamics across tissue differentiation. Finally, we identified genomic regions with clusters of highly dynamic CpGs and present a likely functional example. Our work establishes a framework for inference and modeling that is well-suited to DNA methylation data, and our success suggests that other methods for analyzing DNA nucleotide substitutions will also translate to the modeling of epigenetic phenomena.Comment: 8 pages, 5 figure

Microarray Based Diagnosis Profits from Better Documentation of Gene Expression Signatures

Microarray gene expression signatures hold great promise to improve diagnosis and prognosis of disease. However, current documentation standards of such signatures do not allow for an unambiguous application to study-external patients. This hinders independent evaluation, effectively delaying the use of signatures in clinical practice. Data from eight publicly available clinical microarray studies were analyzed and the consistency of study-internal with study-external diagnoses was evaluated. Study-external classifications were based on documented information only. Documenting a signature is conceptually different from reporting a list of genes. We show that even the exact quantitative specification of a classification rule alone does not define a signature unambiguously. We found that discrepancy between study-internal and study-external diagnoses can be as frequent as 30% (worst case) and 18% (median). By using the proposed documentation by value strategy, which documents quantitative preprocessing information, the median discrepancy was reduced to 1%. The process of evaluating microarray gene expression diagnostic signatures and bringing them to clinical practice can be substantially improved and made more reliable by better documentation of the signatures

Noncoding Sequences Near Duplicated Genes Evolve Rapidly

Gene expression divergence and chromosomal rearrangements have been put forward as major contributors to phenotypic differences between closely related species. It has also been established that duplicated genes show enhanced rates of positive selection in their amino acid sequences. If functional divergence is largely due to changes in gene expression, it follows that regulatory sequences in duplicated loci should also evolve rapidly. To investigate this hypothesis, we performed likelihood ratio tests (LRTs) on all noncoding loci within 5 kb of every transcript in the human genome and identified sequences with increased substitution rates in the human lineage since divergence from Old World Monkeys. The fraction of rapidly evolving loci is significantly higher nearby genes that duplicated in the common ancestor of humans and chimps compared with nonduplicated genes. We also conducted a genome-wide scan for nucleotide substitutions predicted to affect transcription factor binding. Rates of binding site divergence are elevated in noncoding sequences of duplicated loci with accelerated substitution rates. Many of the genes associated with these fast-evolving genomic elements belong to functional categories identified in previous studies of positive selection on amino acid sequences. In addition, we find enrichment for accelerated evolution nearby genes involved in establishment and maintenance of pregnancy, processes that differ significantly between humans and monkeys. Our findings support the hypothesis that adaptive evolution of the regulation of duplicated genes has played a significant role in human evolution

A Model-Based Analysis of GC-Biased Gene Conversion in the Human and Chimpanzee Genomes

GC-biased gene conversion (gBGC) is a recombination-associated process that favors the fixation of G/C alleles over A/T alleles. In mammals, gBGC is hypothesized to contribute to variation in GC content, rapidly evolving sequences, and the fixation of deleterious mutations, but its prevalence and general functional consequences remain poorly understood. gBGC is difficult to incorporate into models of molecular evolution and so far has primarily been studied using summary statistics from genomic comparisons. Here, we introduce a new probabilistic model that captures the joint effects of natural selection and gBGC on nucleotide substitution patterns, while allowing for correlations along the genome in these effects. We implemented our model in a computer program, called phastBias, that can accurately detect gBGC tracts about 1 kilobase or longer in simulated sequence alignments. When applied to real primate genome sequences, phastBias predicts gBGC tracts that cover roughly 0.3% of the human and chimpanzee genomes and account for 1.2% of human-chimpanzee nucleotide differences. These tracts fall in clusters, particularly in subtelomeric regions; they are enriched for recombination hotspots and fast-evolving sequences; and they display an ongoing fixation preference for G and C alleles. They are also significantly enriched for disease-associated polymorphisms, suggesting that they contribute to the fixation of deleterious alleles. The gBGC tracts provide a unique window into historical recombination processes along the human and chimpanzee lineages. They supply additional evidence of long-term conservation of megabase-scale recombination rates accompanied by rapid turnover of hotspots. Together, these findings shed new light on the evolutionary, functional, and disease implications of gBGC. The phastBias program and our predicted tracts are freely available. © 2013 Capra et al

A high-resolution map of human evolutionary constraint using 29 mammals.

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease

Nested effects models for high-dimensional phenotyping screens

Motivation: In high-dimensional phenotyping screens, a large number of cellular features is observed after perturbing genes by knockouts or RNA interference. Comprehensive analysis of perturbation effects is one of the most powerful techniques for attributing functions to genes, but not much work has been done so far to adapt statistical and computational methodology to the specific needs of large-scale and high-dimensional phenotyping screens. Results: We introduce and compare probabilistic methods to efficiently infer a genetic hierarchy from the nested structure of observed perturbation effects. These hierarchies elucidate the structures of signaling pathways and regulatory networks. Our methods achieve two goals: (1) they reveal clusters of genes with highly similar phenotypic profiles, and (2) they order (clusters of) genes according to subset relationships between phenotypes. We evaluate our algorithms in the controlled setting of simulation studies and show their practical use in two experimental scenarios: (1) a data set investigating the response to microbial challenge in Drosophila melanogaster, and (2) a compendium of expression profiles of Saccharomyces cerevisiae knockout strains. We show that our methods identify biologically justified genetic hierarchies of perturbation effects. Availability: The software used in our analysis is freely available in the R package ‘nem’ from www.bioconductor.or

Search for displaced vertices arising from decays of new heavy particles in 7 TeV pp collisions at ATLAS

We present the results of a search for new, heavy particles that decay at a significant distance from their production point into a final state containing charged hadrons in association with a high-momentum muon. The search is conducted in a pp-collision data sample with a center-of-mass energy of 7 TeV and an integrated luminosity of 33 pb^-1 collected in 2010 by the ATLAS detector operating at the Large Hadron Collider. Production of such particles is expected in various scenarios of physics beyond the standard model. We observe no signal and place limits on the production cross-section of supersymmetric particles in an R-parity-violating scenario as a function of the neutralino lifetime. Limits are presented for different squark and neutralino masses, enabling extension of the limits to a variety of other models.Comment: 8 pages plus author list (20 pages total), 8 figures, 1 table, final version to appear in Physics Letters

Measurement of the polarisation of W bosons produced with large transverse momentum in pp collisions at sqrt(s) = 7 TeV with the ATLAS experiment

This paper describes an analysis of the angular distribution of W->enu and W->munu decays, using data from pp collisions at sqrt(s) = 7 TeV recorded with the ATLAS detector at the LHC in 2010, corresponding to an integrated luminosity of about 35 pb^-1. Using the decay lepton transverse momentum and the missing transverse energy, the W decay angular distribution projected onto the transverse plane is obtained and analysed in terms of helicity fractions f0, fL and fR over two ranges of W transverse momentum (ptw): 35 < ptw < 50 GeV and ptw > 50 GeV. Good agreement is found with theoretical predictions. For ptw > 50 GeV, the values of f0 and fL-fR, averaged over charge and lepton flavour, are measured to be : f0 = 0.127 +/- 0.030 +/- 0.108 and fL-fR = 0.252 +/- 0.017 +/- 0.030, where the first uncertainties are statistical, and the second include all systematic effects.Comment: 19 pages plus author list (34 pages total), 9 figures, 11 tables, revised author list, matches European Journal of Physics C versio