 Inferring Evolutionary Histories of Pathway Regulation from Transcriptional Profiling DataJoshua G Schraiber, Yulia Mostovoy, Tiffany Y Hsu and Rachel B Brem PLOS Computational Biology, 2013, vol. 9, issue 10, 1-13 Abstract: One of the outstanding challenges in comparative genomics is to interpret the evolutionary importance of regulatory variation between species. Rigorous molecular evolution-based methods to infer evidence for natural selection from expression data are at a premium in the field, and to date, phylogenetic approaches have not been well-suited to address the question in the small sets of taxa profiled in standard surveys of gene expression. We have developed a strategy to infer evolutionary histories from expression profiles by analyzing suites of genes of common function. In a manner conceptually similar to molecular evolution models in which the evolutionary rates of DNA sequence at multiple loci follow a gamma distribution, we modeled expression of the genes of an a priori-defined pathway with rates drawn from an inverse gamma distribution. We then developed a fitting strategy to infer the parameters of this distribution from expression measurements, and to identify gene groups whose expression patterns were consistent with evolutionary constraint or rapid evolution in particular species. Simulations confirmed the power and accuracy of our inference method. As an experimental testbed for our approach, we generated and analyzed transcriptional profiles of four Saccharomyces yeasts. The results revealed pathways with signatures of constrained and accelerated regulatory evolution in individual yeasts and across the phylogeny, highlighting the prevalence of pathway-level expression change during the divergence of yeast species. We anticipate that our pathway-based phylogenetic approach will be of broad utility in the search to understand the evolutionary relevance of regulatory change.Author Summary: Comparative transcriptomic studies routinely identify thousands of genes differentially expressed between species. The central question in the field is whether and how such regulatory changes have been the product of natural selection. Can the signal of evolutionarily relevant expression divergence be detected amid the noise of changes resulting from genetic drift? Our work develops a theory of gene expression variation among a suite of genes that function together. We derive a formalism that relates empirical observations of expression of pathway genes in divergent species to the underlying strength of natural selection on expression output. We show that fitting this type of model to simulated data accurately recapitulates the parameters used to generate the simulation. We then make experimental measurements of gene expression in a panel of single-celled eukaryotic yeast species. To these data we apply our inference method, and identify pathways with striking evidence for accelerated or constrained regulatory evolution, in particular species and across the phylogeny. Our method provides a key advance over previous approaches in that it maximizes the power of rigorous molecular-evolution analysis of regulatory variation even when data are relatively sparse. As such, the theory and tools we have developed will likely find broad application in the field of comparative genomics. Date: 2013 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1003255 DOI: 10.1371/journal.pcbi.1003255 Access Statistics for this article More articles in PLOS Computational Biology from Public Library of Science |
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