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  • 1
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    Selection on noise constrains variation in a eukaryotic promoter (2015)
    Nature Publishing Group (NPG)
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    Publication Date: 2015-03-18
    Description: Genetic variation segregating within a species reflects the combined activities of mutation, selection, and genetic drift. In the absence of selection, polymorphisms are expected to be a random subset of new mutations; thus, comparing the effects of polymorphisms and new mutations provides a test for selection. When evidence of selection exists, such comparisons can identify properties of mutations that are most likely to persist in natural populations. Here we investigate how mutation and selection have shaped variation in a cis-regulatory sequence controlling gene expression by empirically determining the effects of polymorphisms segregating in the TDH3 promoter among 85 strains of Saccharomyces cerevisiae and comparing their effects to a distribution of mutational effects defined by 236 point mutations in the same promoter. Surprisingly, we find that selection on expression noise (that is, variability in expression among genetically identical cells) appears to have had a greater impact on sequence variation in the TDH3 promoter than selection on mean expression level. This is not necessarily because variation in expression noise impacts fitness more than variation in mean expression level, but rather because of differences in the distributions of mutational effects for these two phenotypes. This study shows how systematically examining the effects of new mutations can enrich our understanding of evolutionary mechanisms. It also provides rare empirical evidence of selection acting on expression noise.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4455047/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4455047/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Metzger, Brian P H -- Yuan, David C -- Gruber, Jonathan D -- Duveau, Fabien -- Wittkopp, Patricia J -- 1 F32 GM083513-0/GM/NIGMS NIH HHS/ -- 1R01GM108826/GM/NIGMS NIH HHS/ -- R01 GM108826/GM/NIGMS NIH HHS/ -- T32 GM007544/GM/NIGMS NIH HHS/ -- T32HG000040/HG/NHGRI NIH HHS/ -- England -- Nature. 2015 May 21;521(7552):344-7. doi: 10.1038/nature14244. Epub 2015 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA. ; 1] Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, Michigan 48109, USA [2] Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25778704" target="_blank"〉PubMed〈/a〉
    Keywords: Evolution, Molecular ; Gene Expression Regulation, Fungal/genetics ; Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)/genetics ; Mutation/genetics ; Phenotype ; Polymorphism, Genetic/*genetics ; Promoter Regions, Genetic/*genetics ; Saccharomyces cerevisiae/*genetics ; Saccharomyces cerevisiae Proteins/genetics ; Selection, Genetic/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Intraspecific polymorphism to interspecific divergence: genetics of pigmentation in Drosophila (2009)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2009-11-11
    Description: Genetic changes contributing to phenotypic differences within or between species have been identified for a handful of traits, but the relationship between alleles underlying intraspecific polymorphism and interspecific divergence is largely unknown. We found that noncoding changes in the tan gene, as well as changes linked to the ebony gene, contribute to pigmentation divergence between closely related Drosophila species. Moreover, we found that alleles linked to tan and ebony fixed in one Drosophila species also contribute to variation within another species, and that multiple genotypes underlie similar phenotypes even within the same population. These alleles appear to predate speciation, which suggests that standing genetic variation present in the common ancestor gave rise to both intraspecific polymorphism and interspecific divergence.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wittkopp, Patricia J -- Stewart, Emma E -- Arnold, Lisa L -- Neidert, Adam H -- Haerum, Belinda K -- Thompson, Elizabeth M -- Akhras, Saleh -- Smith-Winberry, Gabriel -- Shefner, Laura -- New York, N.Y. -- Science. 2009 Oct 23;326(5952):540-4. doi: 10.1126/science.1176980.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, MI 48109, USA. wittkopp@umich.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19900891" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Animals, Genetically Modified ; Base Sequence ; Chromosomal Proteins, Non-Histone/*genetics/metabolism ; Crosses, Genetic ; DNA-Binding Proteins/*genetics/metabolism ; Drosophila/classification/*genetics/growth & development/metabolism ; Drosophila Proteins/*genetics/metabolism ; Female ; Gene Expression ; Gene Expression Regulation ; Genes, Insect ; Genetic Speciation ; Genotype ; Introns ; Male ; Molecular Sequence Data ; Phenotype ; Pigmentation/*genetics ; *Polymorphism, Genetic ; Quantitative Trait Loci ; Species Specificity
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 3
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    Drosophila pigmentation evolution: Divergent genotypes underlying convergent phenotypes (2003)
    National Academy of Sciences
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    Publication Date: 2003-02-06
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 4
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    Evaluating the role of natural selection in the evolution of gene regulation (2007)
    Springer Nature
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    Publication Date: 2007-05-23
    Print ISSN: 0018-067X
    Electronic ISSN: 1365-2540
    Topics: Biology
    Published by Springer Nature
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  • 5
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    Molecular Mechanisms and Evolutionary Processes Contributing to Accelerated Divergence of Gene Expression on the Drosophila X Chromosome (2015)
    Oxford University Press
    Details
    Publication Date: 2015-09-22
    Description: In species with a heterogametic sex, population genetics theory predicts that DNA sequences on the X chromosome can evolve faster than comparable sequences on autosomes. Both neutral and nonneutral evolutionary processes can generate this pattern. Complex traits like gene expression are not predicted to have accelerated evolution by these theories, yet a "faster-X" pattern of gene expression divergence has recently been reported for both Drosophila and mammals. Here, we test the hypothesis that accelerated adaptive evolution of cis -regulatory sequences on the X chromosome is responsible for this pattern by comparing the relative contributions of cis - and trans -regulatory changes to patterns of faster-X expression divergence observed between strains and species of Drosophila with a range of divergence times. We find support for this hypothesis, especially among male-biased genes, when comparing different species. However, we also find evidence that trans -regulatory differences contribute to a faster-X pattern of expression divergence both within and between species. This contribution is surprising because trans -acting regulators of X-linked genes are generally assumed to be randomly distributed throughout the genome. We found, however, that X-linked transcription factors appear to preferentially regulate expression of X-linked genes, providing a potential mechanistic explanation for this result. The contribution of trans -regulatory variation to faster-X expression divergence was larger within than between species, suggesting that it is more likely to result from neutral processes than positive selection. These data show how accelerated evolution of both coding and noncoding sequences on the X chromosome can lead to accelerated expression divergence on the X chromosome relative to autosomes.
    Print ISSN: 0737-4038
    Electronic ISSN: 1537-1719
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    Genomic sources of regulatory variation in cis and in trans (2005)
    Springer
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    Publication Date: 2005-06-17
    Print ISSN: 1420-682X
    Electronic ISSN: 1420-9071
    Topics: Biology , Medicine
    Published by Springer
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  • 7
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    Mapping Small Effect Mutations in Saccharomyces cerevisiae: Impacts of Experimental Design and Mutational Properties (2014)
    Genetics Society of America (GSA)
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    Publication Date: 2014-07-18
    Description: Genetic variants identified by mapping are biased toward large phenotypic effects because of methodologic challenges for detecting genetic variants with small phenotypic effects. Recently, bulk segregant analysis combined with next-generation sequencing (BSA-seq) was shown to be a powerful and cost-effective way to map small effect variants in natural populations. Here, we examine the power of BSA-seq for efficiently mapping small effect mutations isolated from a mutagenesis screen. Specifically, we determined the impact of segregant population size, intensity of phenotypic selection to collect segregants, number of mitotic generations between meiosis and sequencing, and average sequencing depth on power for mapping mutations with a range of effects on the phenotypic mean and standard deviation as well as relative fitness. We then used BSA-seq to map the mutations responsible for three ethyl methanesulfonate–induced mutant phenotypes in Saccharomyces cerevisiae . These mutants display small quantitative variation in the mean expression of a fluorescent reporter gene (–3%, +7%, and +10%). Using a genetic background with increased meiosis rate, a reliable mating type marker, and fluorescence-activated cell sorting to efficiently score large segregating populations and isolate cells with extreme phenotypes, we successfully mapped and functionally confirmed a single point mutation responsible for the mutant phenotype in all three cases. Our simulations and experimental data show that the effects of a causative site not only on the mean phenotype, but also on its standard deviation and relative fitness should be considered when mapping genetic variants in microorganisms such as yeast that require population growth steps for BSA-seq.
    Electronic ISSN: 2160-1836
    Topics: Biology
    Published by Genetics Society of America (GSA)
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  • 8
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    Contrasting Frequencies and Effects of cis- and trans-Regulatory Mutations Affecting Gene Expression (2016)
    Oxford University Press
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    Publication Date: 2016-04-22
    Description: Heritable differences in gene expression are caused by mutations in DNA sequences encoding cis -regulatory elements and trans -regulatory factors. These two classes of regulatory change differ in their relative contributions to expression differences in natural populations because of the combined effects of mutation and natural selection. Here, we investigate how new mutations create the regulatory variation upon which natural selection acts by quantifying the frequencies and effects of hundreds of new cis - and trans -acting mutations altering activity of the TDH3 promoter in the yeast Saccharomyces cerevisiae in the absence of natural selection. We find that cis -regulatory mutations have larger effects on expression than trans -regulatory mutations and that while trans -regulatory mutations are more common overall, cis - and trans -regulatory changes in expression are equally abundant when only the largest changes in expression are considered. In addition, we find that cis -regulatory mutations are skewed toward decreased expression while trans -regulatory mutations are skewed toward increased expression. We also measure the effects of cis - and trans -regulatory mutations on the variability in gene expression among genetically identical cells, a property of gene expression known as expression noise, finding that trans -regulatory mutations are much more likely to decrease expression noise than cis -regulatory mutations. Because new mutations are the raw material upon which natural selection acts, these differences in the frequencies and effects of cis - and trans -regulatory mutations should be considered in models of regulatory evolution.
    Print ISSN: 0737-4038
    Electronic ISSN: 1537-1719
    Topics: Biology
    Published by Oxford University Press
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  • 9
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    Sensitivity of Allelic Divergence to Genomic Position: Lessons from the Drosophila tan Gene (2016)
    Genetics Society of America (GSA)
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    Publication Date: 2016-09-09
    Description: To identify genetic variants underlying changes in phenotypes within and between species, researchers often utilize transgenic animals to compare the function of alleles in different genetic backgrounds. In Drosophila , targeted integration mediated by the C31 integrase allows activity of alternative alleles to be compared at the same genomic location. By using the same insertion site for each transgene, position effects are generally assumed to be controlled for because both alleles are surrounded by the same genomic context. Here, we test this assumption by comparing the activity of tan alleles from two Drosophila species, D. americana and D. novamexicana , at five different genomic locations in D. melanogaster . We found that the relative effects of these alleles varied among insertion sites, with no difference in activity observed between them at two sites. One of these sites simply silenced both transgenes, but the other allowed expression of both alleles that was sufficient to rescue a mutant phenotype yet failed to reveal the functional differences between the two alleles. These results suggest that more than one insertion site should be used when comparing the activity of transgenes because failing to do so could cause functional differences between alleles to go undetected.
    Electronic ISSN: 2160-1836
    Topics: Biology
    Published by Genetics Society of America (GSA)
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  • 10
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    Potential Direct Regulators of the Drosophila yellow Gene Identified by Yeast One-Hybrid and RNAi Screens (2016)
    Genetics Society of America (GSA)
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    Publication Date: 2016-10-14
    Description: The regulation of gene expression controls development, and changes in this regulation often contribute to phenotypic evolution. Drosophila pigmentation is a model system for studying evolutionary changes in gene regulation, with differences in expression of pigmentation genes such as yellow that correlate with divergent pigment patterns among species shown to be caused by changes in cis - and trans -regulation. Currently, much more is known about the cis -regulatory component of divergent yellow expression than the trans -regulatory component, in part because very few trans -acting regulators of yellow expression have been identified. This study aims to improve our understanding of the trans -acting control of yellow expression by combining yeast-one-hybrid and RNAi screens for transcription factors binding to yellow cis -regulatory sequences and affecting abdominal pigmentation in adults, respectively. Of the 670 transcription factors included in the yeast-one-hybrid screen, 45 showed evidence of binding to one or more sequence fragments tested from the 5' intergenic and intronic yellow sequences from D. melanogaster , D. pseudoobscura , and D. willistoni , suggesting that they might be direct regulators of yellow expression. Of the 670 transcription factors included in the yeast-one-hybrid screen, plus another TF previously shown to be genetically upstream of yellow , 125 were also tested using RNAi, and 32 showed altered abdominal pigmentation. Nine transcription factors were identified in both screens, including four nuclear receptors related to ecdysone signaling ( Hr78 , Hr38 , Hr46 , and Eip78C ). This finding suggests that yellow expression might be directly controlled by nuclear receptors influenced by ecdysone during early pupal development when adult pigmentation is forming.
    Electronic ISSN: 2160-1836
    Topics: Biology
    Published by Genetics Society of America (GSA)
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