Functional Evolution of a cis-Regulatory Module

Ludwig, Michael; Pálsson, Arnar; Алексеева, Е. А.; Bergman, Casey M.; Nathan, Janaki; Kreitman, Martin

doi:10.1371/journal.pbio.0030093

Cited by 196 publications

(212 citation statements)

References 37 publications

(37 reference statements)

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“…In addition, they uncovered several binding sites that have been gained and lost among these four species: a lineage-specific addition of the bicoid-3 binding site in D. melanogaster that is absent in the other species, a lineage-specific loss of the hunchback-1 site in D. yakuba, and the presence of an extra Kruppel site in D. pseudoobscura relative to D. melanogaster. These differences are nicely summarized in Figure 2B of Ludwig et al (2005).…”

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confidence: 76%

“…Ludwig et al (1998Ludwig et al ( , 2000Ludwig et al ( , 2005 studied the evolution of the even-skipped stripe 2 enhancer in four Drosophila species (Drosophila melanogaster, D. yakuba, D. erecta, and D. pseuodoobscura). While expression is strongly conserved, they found many substitutions in the binding sites for bicoid, hunchback, Kruppel, and giant, as well as large differences in the overall size of the enhancer region.…”

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confidence: 99%

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Waiting for Two Mutations: With Applications to Regulatory Sequence Evolution and the Limits of Darwinian Evolution

Durrett¹,

Schmidt

2008

Genetics

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Results of Nowak and collaborators concerning the onset of cancer due to the inactivation of tumor suppressor genes give the distribution of the time until some individual in a population has experienced two prespecified mutations and the time until this mutant phenotype becomes fixed in the population. In this article we apply these results to obtain insights into regulatory sequence evolution in Drosophila and humans. In particular, we examine the waiting time for a pair of mutations, the first of which inactivates an existing transcription factor binding site and the second of which creates a new one. Consistent with recent experimental observations for Drosophila, we find that a few million years is sufficient, but for humans with a much smaller effective population size, this type of change would take .100 million years. In addition, we use these results to expose flaws in some of Michael Behe's arguments concerning mathematical limits to Darwinian evolution.

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confidence: 76%

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confidence: 99%

Waiting for Two Mutations: With Applications to Regulatory Sequence Evolution and the Limits of Darwinian Evolution

Durrett¹,

Schmidt

2008

Genetics

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“…3). We note that we are likely to be missing a number of targets of positive selection: gene expression varies across tissues and developmental stages 26 , and as a result, the absence of support for selection in primate expression data is weak evidence against it.…”

Section: Lettersmentioning

confidence: 89%

Expression profiling in primates reveals a rapid evolution of human transcription factors

Gilad

Oshlack

Smyth

et al. 2006

Nature

285

253

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Although it has been hypothesized for thirty years that many human adaptations are likely to be due to changes in gene regulation 1 , almost nothing is known about the modes of natural selection acting on regulation in primates. Here we identify a set of genes for which expression is evolving under natural selection. We use a new multi-species complementary DNA array to compare steady-state messenger RNA levels in liver tissues within and between humans, chimpanzees, orangutans and rhesus macaques. Using estimates from a linear mixed model, we identify a set of genes for which expression levels have remained constant across the entire phylogeny (,70 million years), and are therefore likely to be under stabilizing selection. Among the top candidates are five genes with expression levels that have previously been shown to be altered in liver carcinoma. We also find a number of genes with similar expression levels among non-human primates but significantly elevated or reduced expression in the human lineage, features that point to the action of directional selection. Among the gene set with a human-specific increase in expression, there is an excess of transcription factors; the same is not true for genes with increased expression in chimpanzee.A number of recent studies have used DNA microarrays to compare patterns of gene expression between closely related species 2-9 . Within primates, the focus has been primarily on human-chimpanzee comparisons, estimating gene expression profiles for a number of tissues, including liver, brain and heart 2,6,7,10 . The aim has been to characterize general trends in the evolution of gene expression rather than to identify specific genes of interest. To date, conclusions about the selection pressures acting on gene expression have been conflicting 2,3,6,[11][12][13] .These studies have all relied on data collected from arrays using gene probes that were designed on the basis of human sequences only. However, sequence mismatches affect hybridization intensity and can therefore bias estimates of gene expression differences between species 14 . This limitation of single-species arrays is especially problematic when the goal is to study how expression changes over evolutionary time. To make comparisons between more distantly related primate species, we generated a multi-species cDNA array that allows comparison of gene expression between species without the confounding effects of sequence divergence 14 . This cDNA array contains probes for 1,056 orthologous genes from four species (see Supplementary Methods) 14 .We used this array to compare gene expression profiles in the livers of humans, chimpanzees (Pan troglodytes), orangutans (Pongo pygmaeus) and rhesus macaques (Macaca mulatta), the phylogeny of which represents approximately 70 million years (Myr) of evolution. By assigning expression changes in the liver to particular lineages, we were able to identify the first set of genes for which regulation seems to be under lineage-specific selection pressures. In order to measure gene...

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“…We found that comparative genomics resulted in many functionally meaningful sites for transcription factors Mef2, Twist and Snail outside ChIPbound regions, probably representing targets from diverse conditions not surveyed experimentally. Similarly, ChIP resulted in many additional sites outside those recovered by comparative genomics: some of these may have been replaced by functionally equivalent non-orthologous sequence, rendering them apparently non-conserved in sequence alignments [122][123][124] ; others may have species-or lineagespecific roles, thus lacking sufficient signal for their comparative detection; finally, some bound sites may be biochemically active yet selectively neutral 125 . It is worth noting, however, that ChIP-bound motifs that were not conserved showed decreased enrichment in muscle/ mesoderm development where the factors are known to act, suggesting that potential lineage-specific roles may lie outside the regulators' conserved functions.…”

Section: Discussionmentioning

confidence: 99%

Discovery of functional elements in 12 Drosophila genomes using evolutionary signatures

Stark

Lin

Kheradpour³

et al. 2007

Nature

571

566

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Sequencing of multiple related species followed by comparative genomics analysis constitutes a powerful approach for the systematic understanding of any genome. Here, we use the genomes of 12 Drosophila species for the de novo discovery of functional elements in the fly. Each type of functional element shows characteristic patterns of change, or 'evolutionary signatures', dictated by its precise selective constraints. Such signatures enable recognition of new protein-coding genes and exons, spurious and incorrect gene annotations, and numerous unusual gene structures, including abundant stop-codon readthrough. Similarly, we predict non-protein-coding RNA genes and structures, and new microRNA (miRNA) genes. We provide evidence of miRNA processing and functionality from both hairpin arms and both DNA strands. We identify several classes of pre-and post-transcriptional regulatory motifs, and predict individual motif instances with high confidence. We also study how discovery power scales with the divergence and number of species compared, and we provide general guidelines for comparative studies.The sequencing of the human genome and the genomes of dozens of other metazoan species has intensified the need for systematic methods to extract biological information directly from DNA sequence. Comparative genomics has emerged as a powerful methodology for this endeavour 1,2 . Comparison of few (two-four) closely related genomes has proven successful for the discovery of protein-coding genes 3-5 , RNA genes 6,7 , miRNA genes 8-11 and catalogues of regulatory elements 3,4,12-14 . The resolution and discovery power of these studies should increase with the number of genomes [15][16][17][18][19][20] , in principle enabling the systematic discovery of all conserved functional elements.The fruitfly Drosophila melanogaster is an ideal system for developing and evaluating comparative genomics methodologies. Over the past century, Drosophila has been a pioneering model in which many of the basic principles governing animal development and population biology were established 21 . In the past decade, the genome sequence of D. melanogaster provided one of the first systematic views *These authors contributed equally to this work. {Lists of participants and affiliations appear at the end of the paper.

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Functional Evolution of a cis-Regulatory Module

Cited by 196 publications

References 37 publications

Waiting for Two Mutations: With Applications to Regulatory Sequence Evolution and the Limits of Darwinian Evolution

Waiting for Two Mutations: With Applications to Regulatory Sequence Evolution and the Limits of Darwinian Evolution

Expression profiling in primates reveals a rapid evolution of human transcription factors

Discovery of functional elements in 12 Drosophila genomes using evolutionary signatures

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