76 research outputs found
motifDiverge: a model for assessing the statistical significance of gene regulatory motif divergence between two DNA sequences
Next-generation sequencing technology enables the identification of thousands
of gene regulatory sequences in many cell types and organisms. We consider the
problem of testing if two such sequences differ in their number of binding site
motifs for a given transcription factor (TF) protein. Binding site motifs
impart regulatory function by providing TFs the opportunity to bind to genomic
elements and thereby affect the expression of nearby genes. Evolutionary
changes to such functional DNA are hypothesized to be major contributors to
phenotypic diversity within and between species; but despite the importance of
TF motifs for gene expression, no method exists to test for motif loss or gain.
Assuming that motif counts are Binomially distributed, and allowing for
dependencies between motif instances in evolutionarily related sequences, we
derive the probability mass function of the difference in motif counts between
two nucleotide sequences. We provide a method to numerically estimate this
distribution from genomic data and show through simulations that our estimator
is accurate. Finally, we introduce the R package {\tt motifDiverge} that
implements our methodology and illustrate its application to gene regulatory
enhancers identified by a mouse developmental time course experiment. While
this study was motivated by analysis of regulatory motifs, our results can be
applied to any problem involving two correlated Bernoulli trials
From Scientific Discovery to Cures: Bright Stars within a Galaxy
We propose that data mining and network analysis utilizing public databases can identify and quantify relationships between scientific discoveries and major advances in medicine (cures). Further development of such approaches could help to increase public understanding and governmental support for life science research and could enhance decision making in the quest for cures
Does Positive Selection Drive Transcription Factor Binding Site Turnover? A Test with Drosophila Cis-Regulatory Modules
Transcription factor binding site(s) (TFBS) gain and loss (i.e., turnover) is a well-documented feature of cis-regulatory module (CRM) evolution, yet little attention has been paid to the evolutionary force(s) driving this turnover process. The predominant view, motivated by its widespread occurrence, emphasizes the importance of compensatory mutation and genetic drift. Positive selection, in contrast, although it has been invoked in specific instances of adaptive gene expression evolution, has not been considered as a general alternative to neutral compensatory evolution. In this study we evaluate the two hypotheses by analyzing patterns of single nucleotide polymorphism in the TFBS of well-characterized CRM in two closely related Drosophila species, Drosophila melanogaster and Drosophila simulans. An important feature of the analysis is classification of TFBS mutations according to the direction of their predicted effect on binding affinity, which allows gains and losses to be evaluated independently along the two phylogenetic lineages. The observed patterns of polymorphism and divergence are not compatible with neutral evolution for either class of mutations. Instead, multiple lines of evidence are consistent with contributions of positive selection to TFBS gain and loss as well as purifying selection in its maintenance. In discussion, we propose a model to reconcile the finding of selection driving TFBS turnover with constrained CRM function over long evolutionary time
Adaptive Gene Expression Divergence Inferred from Population Genomics
Detailed studies of individual genes have shown that gene expression divergence often results from adaptive evolution of regulatory sequence. Genome-wide analyses, however, have yet to unite patterns of gene expression with polymorphism and divergence to infer population genetic mechanisms underlying expression evolution. Here, we combined genomic expression data—analyzed in a phylogenetic context—with whole genome light-shotgun sequence data from six Drosophila simulans lines and reference sequences from D. melanogaster and D. yakuba. These data allowed us to use molecular population genetics to test for neutral versus adaptive gene expression divergence on a genomic scale. We identified recent and recurrent adaptive evolution along the D. simulans lineage by contrasting sequence polymorphism within D. simulans to divergence from D. melanogaster and D. yakuba. Genes that evolved higher levels of expression in D. simulans have experienced adaptive evolution of the associated 3′ flanking and amino acid sequence. Concomitantly, these genes are also decelerating in their rates of protein evolution, which is in agreement with the finding that highly expressed genes evolve slowly. Interestingly, adaptive evolution in 5′ cis-regulatory regions did not correspond strongly with expression evolution. Our results provide a genomic view of the intimate link between selection acting on a phenotype and associated genic evolution
Rampant Adaptive Evolution in Regions of Proteins with Unknown Function in Drosophila simulans
Adaptive protein evolution is pervasive in Drosophila. Genomic studies, thus far, have analyzed each protein as a single entity. However, the targets of adaptive events may be localized to particular parts of proteins, such as protein domains or regions involved in protein folding. We compared the population genetic mechanisms driving sequence polymorphism and divergence in defined protein domains and non-domain regions. Interestingly, we find that non-domain regions of proteins are more frequent targets of directional selection. Protein domains are also evolving under directional selection, but appear to be under stronger purifying selection than non-domain regions. Non-domain regions of proteins clearly play a major role in adaptive protein evolution on a genomic scale and merit future investigations of their functional properties
Population Genomics: Whole-Genome Analysis of Polymorphism and Divergence in Drosophila simulans
The population genetic perspective is that the processes shaping genomic variation can be revealed only through simultaneous investigation of sequence polymorphism and divergence within and between closely related species. Here we present a population genetic analysis of Drosophila simulans based on whole-genome shotgun sequencing of multiple inbred lines and comparison of the resulting data to genome assemblies of the closely related species, D. melanogaster and D. yakuba. We discovered previously unknown, large-scale fluctuations of polymorphism and divergence along chromosome arms, and significantly less polymorphism and faster divergence on the X chromosome. We generated a comprehensive list of functional elements in the D. simulans genome influenced by adaptive evolution. Finally, we characterized genomic patterns of base composition for coding and noncoding sequence. These results suggest several new hypotheses regarding the genetic and biological mechanisms controlling polymorphism and divergence across the Drosophila genome, and provide a rich resource for the investigation of adaptive evolution and functional variation in D. simulans
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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
The 2006 NESCent Phyloinformatics Hackathon: A Field Report
In December, 2006, a group of 26 software developers from some of the most widely used life science programming toolkits and phylogenetic software projects converged on Durham, North Carolina, for a Phyloinformatics Hackathon, an intense five-day collaborative software coding event sponsored by the National Evolutionary Synthesis Center (NESCent). The goal was to help researchers to integrate multiple phylogenetic software tools into automated workflows. Participants addressed deficiencies in interoperability between programs by implementing “glue code” and improving support for phylogenetic data exchange standards (particularly NEXUS) across the toolkits. The work was guided by use-cases compiled in advance by both developers and users, and the code was documented as it was developed. The resulting software is freely available for both users and developers through incorporation into the distributions of several widely-used open-source toolkits. We explain the motivation for the hackathon, how it was organized, and discuss some of the outcomes and lessons learned. We conclude that hackathons are an effective mode of solving problems in software interoperability and usability, and are underutilized in scientific software development
Genes Expressed in Specific Areas of the Human Fetal Cerebral Cortex Display Distinct Patterns of Evolution
The developmental mechanisms through which the cerebral cortex increased in size and complexity during primate evolution are essentially unknown. To uncover genetic networks active in the developing cerebral cortex, we combined three-dimensional reconstruction of human fetal brains at midgestation and whole genome expression profiling. This novel approach enabled transcriptional characterization of neurons from accurately defined cortical regions containing presumptive Broca and Wernicke language areas, as well as surrounding associative areas. We identified hundreds of genes displaying differential expression between the two regions, but no significant difference in gene expression between left and right hemispheres. Validation by qRTPCR and in situ hybridization confirmed the robustness of our approach and revealed novel patterns of area- and layer-specific expression throughout the developing cortex. Genes differentially expressed between cortical areas were significantly associated with fast-evolving non-coding sequences harboring human-specific substitutions that could lead to divergence in their repertoires of transcription factor binding sites. Strikingly, while some of these sequences were accelerated in the human lineage only, many others were accelerated in chimpanzee and/or mouse lineages, indicating that genes important for cortical development may be particularly prone to changes in transcriptional regulation across mammals. Genes differentially expressed between cortical regions were also enriched for transcriptional targets of FoxP2, a key gene for the acquisition of language abilities in humans. Our findings point to a subset of genes with a unique combination of cortical areal expression and evolutionary patterns, suggesting that they play important roles in the transcriptional network underlying human-specific neural traits
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