2,004 research outputs found

    ZRT1 harbors an excess of nonsynonymous polymorphism and shows evidence of balancing selection in Saccharomyces cerevisiae

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    Estimates of the fraction of nucleotide substitutions driven by positive selection vary widely across different species. Accounting for different estimates of positive selection has been difficult, in part because selection on polymorphism within a species is known to obscure a signal of positive selection between species. While methods have been developed to control for the confounding effects of negative selection against deleterious polymorphism, the impact of balancing selection on estimates of positive selection has not been assessed. In Saccharomyces cerevisiae, there is no signal of positive selection within protein coding sequences as the ratio of nonsynonymous to synonymous polymorphism is higher than that of divergence. To investigate the impact of balancing selection on estimates of positive selection we examined five genes with high rates of nonsynonymous polymorphism in S. cerevisiae relative to divergence from S. paradoxus. One of the genes, a high affinity zinc transporter ZRT1, shows an elevated rate of synonymous polymorphism indicative of balancing selection. The high rate of synonymous polymorphism coincides with nonsynonymous divergence between three haplotype groups, which we find to be functionally indistinguishable. We conclude that balancing selection is not likely to be a common cause of genes harboring a large excess of nonsynonymous polymorphism in yeast

    Multiple changes underlie allelic divergence of CUP2 between Saccharomyces species

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    Under the model of micromutationism, phenotypic divergence between species is caused by accumulation of many small-effect changes. While mapping the causal changes to single nucleotide resolution could be difficult for diverged species, genetic dissection via chimeric constructs allows us to evaluate whether a large-effect gene is composed of many small-effect nucleotide changes. In a previously described non-complementation screen, we found an allele difference of CUP2, a copper-binding transcription factor, underlies divergence in copper resistance between Saccharomyces cerevisiae and S. uvarum. Here, we tested whether the allele effect of CUP2 was caused by multiple nucleotide changes. By analyzing chimeric constructs containing four separate regions in the CUP2 gene, including its distal promoter, proximal promoter, DNA binding domain and transcriptional activation domain, we found that all four regions of the S. cerevisiae allele conferred copper resistance, with the proximal promoter showing the largest effect, and that both additive and epistatic effects are likely involved. These findings support a model of multiple changes underlying evolution and suggest an important role of both protein coding and cis-regulatory changes in evolution

    Mitochondria-encoded genes contribute to evolution of heat and cold tolerance in yeast

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    Genetic analysis of phenotypic differences between species is typically limited to interfertile species. Here, we conducted a genome-wide noncomplementation screen to identify genes that contribute to a major difference in thermal growth profile between two reproductively isolated yeast species, Saccharomyces cerevisiae and Saccharomyces uvarum. The screen identified only a single nuclear-encoded gene with a moderate effect on heat tolerance, but, in contrast, revealed a large effect of mitochondrial DNA (mitotype) on both heat and cold tolerance. Recombinant mitotypes indicate that multiple genes contribute to thermal divergence, and we show that protein divergence in COX1 affects both heat and cold tolerance. Our results point to the yeast mitochondrial genome as an evolutionary hotspot for thermal divergence.This work was supported by the NIH (grant GM080669) to J.C.F. Additional support to C.T.H. was provided by the USDA National Institute of Food and Agriculture (Hatch project 1003258), the National Science Foundation (DEB-1253634), and the DOE Great Lakes Bioenergy Research Center (DOE BER Office of Science DE-SC0018409 and DE-FC02-07ER64494 to T. J. Donohue). C.T.H. is a Pew Scholar in the Biomedical Sciences and a Vilas Faculty Early Career Investigator, supported by the Pew Charitable Trusts and the Vilas Trust Estate, respectively. D.P. is a Marie Sklodowska-Curie fellow of the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 747775).Peer reviewe

    Patterns of gene conversion in duplicated yeast histones suggest strong selection on a coadapted macromolecular complex

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    We find evidence for interlocus gene conversion in five duplicated histone genes from six yeast species. The sequences of these duplicated genes, surviving from the ancient genome duplication, show phylogenetic patterns inconsistent with the well-resolved orthology relationships inferred from a likelihood model of gene loss after the genome duplication. Instead, these paralogous genes are more closely related to each other than any is to its nearest ortholog. In addition to simulations supporting gene conversion, we also present evidence for elevated rates of radical amino acid substitutions along the branches implicated in the conversion events. As these patterns are similar to those seen in ribosomal proteins that have undergone gene conversion, we speculate that in cases where duplicated genes code for proteins that are a part of tightly interacting complexes, selection may favor the fixation of gene conversion events in order to maintain high protein identities between duplicated copies

    On Theoretical Models of Gene Expression Evolution with Random Genetic Drift and Natural Selection

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    The relative contributions of natural selection and random genetic drift are a major source of debate in the study of gene expression evolution, which is hypothesized to serve as a bridge from molecular to phenotypic evolution. It has been suggested that the conflict between views is caused by the lack of a definite model of the neutral hypothesis, which can describe the long-run behavior of evolutionary change in mRNA abundance. Therefore previous studies have used inadequate analogies with the neutral prediction of other phenomena, such as amino acid or nucleotide sequence evolution, as the null hypothesis of their statistical inference.In this study, we introduced two novel theoretical models, one based on neutral drift and the other assuming natural selection, by focusing on a common property of the distribution of mRNA abundance among a variety of eukaryotic cells, which reflects the result of long-term evolution. Our results demonstrated that (1) our models can reproduce two independently found phenomena simultaneously: the time development of gene expression divergence and Zipf's law of the transcriptome; (2) cytological constraints can be explicitly formulated to describe long-term evolution; (3) the model assuming that natural selection optimized relative mRNA abundance was more consistent with previously published observations than the model of optimized absolute mRNA abundances.The models introduced in this study give a formulation of evolutionary change in the mRNA abundance of each gene as a stochastic process, on the basis of previously published observations. This model provides a foundation for interpreting observed data in studies of gene expression evolution, including identifying an adequate time scale for discriminating the effect of natural selection from that of random genetic drift of selectively neutral variations

    Identification of functional transcription factor binding sites using closely related Saccharomyces species

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    Comparative genomics provides a rapid means of identifying functional DNA elements by their sequence conservation between species. Transcription factor binding sites (TFBSs) may constitute a significant fraction of these conserved sequences, but the annotation of specific TFBSs is complicated by the fact that these short, degenerate sequences may frequently be conserved by chance rather than functional constraint. To identify intergenic sequences that function as TFBSs, we calculated the probability of binding site conservation between Saccharomyces cerevisiae and its two closest relatives under a neutral model of evolution. We found that this probability is <5% for 134 of 163 transcription factor binding motifs, implying that we can reliably annotate binding sites for the majority of these transcription factors by conservation alone. Although our annotation relies on a number of assumptions, mutations in five of five conserved Ume6 binding sites and three of four conserved Ndt80 binding sites show Ume6- and Ndt80-dependent effects on gene expression. We also found that three of five unconserved Ndt80 binding sites show Ndt80-dependent effects on gene expression. Together these data imply that although sequence conservation can be reliably used to predict functional TFBSs, unconserved sequences might also make a significant contribution to a species' biology

    Mitochondrial DNA and temperature tolerance in lager yeasts

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    A growing body of research suggests that the mitochondrial genome (mtDNA) is important for temperature adaptation. In the yeast genus Saccharomyces, species have diverged in temperature tolerance, driving their use in high- or low-temperature fermentations. Here, we experimentally test the role of mtDNA in temperature tolerance in synthetic and industrial hybrids (Saccharomyces cerevisiae × Saccharomyces eubayanus or Saccharomyces pastorianus), which cold-brew lager beer. We find that the relative temperature tolerances of hybrids correspond to the parent donating mtDNA, allowing us to modulate lager strain temperature preferences. The strong influence of mitotype on the temperature tolerance of otherwise identical hybrid strains provides support for the mitochondrial climactic adaptation hypothesis in yeasts and demonstrates how mitotype has influenced the world’s most commonly fermented beverage.This work was supported by the USDA National Institute of Food and Agriculture (Hatch project no. 1003258), the NSF (grant no. DEB-1253634), and in part by the DOE Great Lakes Bioenergy Research Center (DOE BER Office of Science; nos. DE-SC0018409 and DE-FC02-07ER64494). E.P.B. was supported by a Louis and Elsa Thomsen Wisconsin Distinguished Graduate Fellowship. C.T.H. is a Pew Scholar in the Biomedical Sciences and a Vilas Faculty Early Career Investigator, supported by the Pew Charitable Trusts and the Vilas Trust Estate. D.P. is a Marie Sklodowska-Curie fellow of the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 747775). J.C.F. was supported by the NIH (no. GM080669)Peer Reviewe

    Phylogeny based discovery of regulatory elements

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    BACKGROUND: Algorithms that locate evolutionarily conserved sequences have become powerful tools for finding functional DNA elements, including transcription factor binding sites; however, most methods do not take advantage of an explicit model for the constrained evolution of functional DNA sequences. RESULTS: We developed a probabilistic framework that combines an HKY85 model, which assigns probabilities to different base substitutions between species, and weight matrix models of transcription factor binding sites, which describe the probabilities of observing particular nucleotides at specific positions in the binding site. The method incorporates the phylogenies of the species under consideration and takes into account the position specific variation of transcription factor binding sites. Using our framework we assessed the suitability of alignments of genomic sequences from commonly used species as substrates for comparative genomic approaches to regulatory motif finding. We then applied this technique to Saccharomyces cerevisiae and related species by examining all possible six base pair DNA sequences (hexamers) and identifying sequences that are conserved in a significant number of promoters. By combining similar conserved hexamers we reconstructed known cis-regulatory motifs and made predictions of previously unidentified motifs. We tested one prediction experimentally, finding it to be a regulatory element involved in the transcriptional response to glucose. CONCLUSION: The experimental validation of a regulatory element prediction missed by other large-scale motif finding studies demonstrates that our approach is a useful addition to the current suite of tools for finding regulatory motifs

    Frequent Gain and Loss of Functional Transcription Factor Binding Sites

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    Cis-regulatory sequences are not always conserved across species. Divergence within cis-regulatory sequences may result from the evolution of species-specific patterns of gene expression or the flexible nature of the cis-regulatory code. The identification of functional divergence in cis-regulatory sequences is therefore important for both understanding the role of gene regulation in evolution and annotating regulatory elements. We have developed an evolutionary model to detect the loss of constraint on individual transcription factor binding sites (TFBSs). We find that a significant fraction of functionally constrained binding sites have been lost in a lineage-specific manner among three closely related yeast species. Binding site loss has previously been explained by turnover, where the concurrent gain and loss of a binding site maintains gene regulation. We estimate that nearly half of all loss events cannot be explained by binding site turnover. Recreating the mutations that led to binding site loss confirms that these sequence changes affect gene expression in some cases. We also estimate that there is a high rate of binding site gain, as more than half of experimentally identified S. cerevisiae binding sites are not conserved across species. The frequent gain and loss of TFBSs implies that cis-regulatory sequences are labile and, in the absence of turnover, may contribute to species-specific patterns of gene expression
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