Marginal Fitness Contributions of Nonessential Genes in Yeast
06 Jan 1998-Proceedings of the National Academy of Sciences of the United States of America (National Academy of Sciences)-Vol. 95, Iss: 1, pp 253-257
TL;DR: Analysis of the complete genome sequence of Saccharomyces cerevisiae confirms and extends earlier evidence that a majority of yeast genes are not essential, at least under laboratory conditions, and tests the second "marginal benefit" hypothesis by measuring the fitnesses of a random collection of disruption mutants in direct competition with their wild-type progenitor.
Abstract: Analysis of the complete genome sequence of Saccharomyces cerevisiae confirms and extends earlier evidence that a majority of yeast genes are not essential, at least under laboratory conditions. Many fail to yield a discernible mutant phenotype even when disrupted. Genes not subject to natural selection would accumulate inactivating mutations, so these “cryptic” genes must have functions that are overlooked by the standard methods of yeast genetics. Two explanations seem possible: (i) They have important functions only in environments not yet duplicated in the laboratory and would have conditional phenotypes if tested appropriately. (ii) They make small, but significant, contributions to fitness even under routine growth conditions, but the effects are not large enough to be detected by conventional methods. We have tested the second “marginal benefit” hypothesis by measuring the fitnesses of a random collection of disruption mutants in direct competition with their wild-type progenitor. A substantial majority of mutant strains that lack obvious defects nevertheless are at a significant selective disadvantage just growing on rich medium under normal conditions. This result has important implications for efforts to understand the functions of novel genes revealed by sequencing projects.
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TL;DR: The distribution of fitness effects (DFE) of new mutations is a fundamental entity in genetics that has implications ranging from the genetic basis of complex disease to the stability of the molecular clock.
Abstract: The distribution of fitness effects (DFE) of new mutations is a fundamental entity in genetics that has implications ranging from the genetic basis of complex disease to the stability of the molecular clock. It has been studied by two different approaches: mutation accumulation and mutagenesis experiments, and the analysis of DNA sequence data. The proportion of mutations that are advantageous, effectively neutral and deleterious varies between species, and the DFE differs between coding and non-coding DNA. Despite these differences between species and genomic regions, some general principles have emerged: advantageous mutations are rare, and those that are strongly selected are exponentially distributed; and the DFE of deleterious mutations is complex and multi-modal.
1,365 citations
TL;DR: The use of complete-genome sequencing in the characterization of spontaneously arising mutations in the yeast Saccharomyces cerevisiae yields numerous unexpected findings, in particular a very high rate of point mutation and skewed distribution of base-substitution types in the mitochondrion and segmental duplication and deletion in the nuclear genome.
Abstract: The mutation process ultimately defines the genetic features of all populations and, hence, has a bearing on a wide range of issues involving evolutionary genetics, inheritance, and genetic disorders, including the predisposition to cancer. Nevertheless, formidable technical barriers have constrained our understanding of the rate at which mutations arise and the molecular spectrum of their effects. Here, we report on the use of complete-genome sequencing in the characterization of spontaneously arising mutations in the yeast Saccharomyces cerevisiae. Our results confirm some findings previously obtained by indirect methods but also yield numerous unexpected findings, in particular a very high rate of point mutation and skewed distribution of base-substitution types in the mitochondrion, a very high rate of segmental duplication and deletion in the nuclear genome, and substantial deviations in the mutational profile among various model organisms.
702 citations
Cites background from "Marginal Fitness Contributions of N..."
...(4) found that complete gene knockouts in this species have average selection coefficients of 0....
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Wageningen University and Research Centre1, Ludwig Maximilian University of Munich2, Yale University3, University of Texas at Austin4, Santa Fe Institute5, National Center for Genome Resources6, University of California, San Diego7, Washington University in St. Louis8, Spanish National Research Council9, North Carolina State University10, Florida State University11, Harvard University12, Michigan State University13, University of Washington14, University of New Mexico15, University of British Columbia16
TL;DR: This work focuses on the first kind of robustness—genetic robustness)—and survey three growing avenues of research: measuring genetic robustness in nature and in the laboratory; understanding the evolution of genetic robusts; and exploring the implications of genetic resilientness for future evolution.
Abstract: Robustness is the invariance of phenotypes in the face of perturbation. The robustness of phenotypes appears at various levels of biological organization, including gene expression, protein folding, metabolic flux, physiological homeostasis, development, and even organismal fitness. The mechanisms underlying robustness are diverse, ranging from thermodynamic stability at the RNA and protein level to behavior at the organismal level. Phenotypes can be robust either against heritable perturbations (e.g., mutations) or nonheritable perturbations (e.g., the weather). Here we primarily focus on the first kind of robustness-genetic robustness-and survey three growing avenues of research: (1) measuring genetic robustness in nature and in the laboratory; (2) understanding the evolution of genetic robustness; and (3) exploring the implications of genetic robustness for future evolution.
681 citations
Cites background from "Marginal Fitness Contributions of N..."
...%) hardly affects fitness because the function of the knocked-out gene is compensated by other genes under the growth conditions applied (Thatcher et al. 1998)....
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TL;DR: It is shown that neural activity in the ventral striatum and the anterior insula displays a marked correspondence to the signals for sequential learning predicted by temporal difference models, revealing a flexible aversive learning process ideally suited to the changing and uncertain nature of real-world environments.
Abstract: The ability to use environmental stimuli to predict impending harm is critical for survival. Such predictions should be available as early as they are reliable. In pavlovian conditioning, chains of successively earlier predictors are studied in terms of higher-order relationships, and have inspired computational theories such as temporal difference learning. However, there is at present no adequate neurobiological account of how this learning occurs. Here, in a functional magnetic resonance imaging (fMRI) study of higher-order aversive conditioning, we describe a key computational strategy that humans use to learn predictions about pain. We show that neural activity in the ventral striatum and the anterior insula displays a marked correspondence to the signals for sequential learning predicted by temporal difference models. This result reveals a flexible aversive learning process ideally suited to the changing and uncertain nature of real-world environments. Taken with existing data on reward learning, our results suggest a critical role for the ventral striatum in integrating complex appetitive and aversive predictions to coordinate behaviour.
592 citations
TL;DR: Comparative genomics with flux balance analysis is integrated to examine the contribution of different genetic mechanisms to network growth in bacteria, the selective forces driving network evolution and the integration of new nodes into the network.
Abstract: Numerous studies have considered the emergence of metabolic pathways, but the modes of recent evolution of metabolic networks are poorly understood. Here, we integrate comparative genomics with flux balance analysis to examine (i) the contribution of different genetic mechanisms to network growth in bacteria, (ii) the selective forces driving network evolution and (iii) the integration of new nodes into the network. Most changes to the metabolic network of Escherichia coli in the past 100 million years are due to horizontal gene transfer, with little contribution from gene duplicates. Networks grow by acquiring genes involved in the transport and catalysis of external nutrients, driven by adaptations to changing environments. Accordingly, horizontally transferred genes are integrated at the periphery of the network, whereas central parts remain evolutionarily stable. Genes encoding physiologically coupled reactions are often transferred together, frequently in operons. Thus, bacterial metabolic networks evolve by direct uptake of peripheral reactions in response to changed environments.
495 citations
References
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Book•
01 Jan 1983
TL;DR: The neutral theory as discussed by the authors states that the great majority of evolutionary changes at the molecular level are caused not by Darwinian selection but by random drift of selectively neutral mutants, which has caused controversy ever since.
Abstract: Motoo Kimura, as founder of the neutral theory, is uniquely placed to write this book. He first proposed the theory in 1968 to explain the unexpectedly high rate of evolutionary change and very large amount of intraspecific variability at the molecular level that had been uncovered by new techniques in molecular biology. The theory - which asserts that the great majority of evolutionary changes at the molecular level are caused not by Darwinian selection but by random drift of selectively neutral mutants - has caused controversy ever since. This book is the first comprehensive treatment of this subject and the author synthesises a wealth of material - ranging from a historical perspective, through recent molecular discoveries, to sophisticated mathematical arguments - all presented in a most lucid manner.
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TL;DR: It is stated that these sequences differed in the cytochromes c of various species to an extent that seemed unnecessary from the standpoint of their function.
Abstract: IN 1966, I became interested in the amino acid sequences of cytochrome c molecules ([Jukes 1966][1]). I noted that these sequences differed in the cytochromes c of various species to an extent that seemed unnecessary from the standpoint of their function. I stated, “The changes produced in
3,011 citations
"Marginal Fitness Contributions of N..." refers background in this paper
...The marginal benefit model is consistent with theoretical treatments of ‘‘nearly neutral’’ mutations (8, 9, 15)....
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...What about that 20%? The theory of nearly neutral replacement (8, 15) indicates that a selection coefficient approximately the inverse of the effective population size is sufficient FIG....
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...The neutral theory of molecular evolution (8) predicts that genes not subject to natural selection will accumulate inactivating mutations, including stop codons, and the rapid accumulation of synonymous relative to nonsynonymous substitutions substantiates that expectation (9, 10)....
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TL;DR: The nucleotide sequence of a contiguous 2,181,032 base pairs in the central gene cluster of chromosome III is completed, and comparison with the public sequence databases reveals similarities to previously known genes for about one gene in three.
Abstract: As part of our effort to sequence the 100-megabase (Mb) genome of the nematode Caenorhabditis elegans, we have completed the nucleotide sequence of a contiguous 2,181,032 base pairs in the central gene cluster of chromosome III. Analysis of the finished sequence has indicated an average density of about one gene per five kilobases; comparison with the public sequence databases reveals similarities to previously known genes for about one gene in three. In addition, the genomic sequence contains several intriguing features, including putative gene duplications and a variety of other repeats with potential evolutionary implications.
1,612 citations
TL;DR: The degree to which adaptation to a uniform environment among independently evolving asexual populations is associated with increasing divergence of those populations is assessed, consistent with theoretical expectations that do not invoke divergence due to multiple fitness peaks in a Wrightian evolutionary landscape.
Abstract: We assess the degree to which adaptation to a uniform environment among independently evolving asexual populations is associated with increasing divergence of those populations. In addition, we are concerned with the pattern of adaptation itself, particularly whether the rate of increase in mean fitness tends to decline with the number of generations of selection in a constant environment. The correspondence between the rate of increase in mean fitness and the within-population genetic variance of fitness, as expected from Fisher's fundamental theorem, is also addressed. Twelve Escherichia coli populations were founded from a single clonal ancestor and allowed to evolve for 2,000 generations. Mean fitness increased by about 37%. However, the rate of increase in mean fitness was slower in later generations. There was no statistically significant within-population genetic variance of fitness, but there was significant between-population variance. Although the estimated genetic variation in fitness within po...
1,523 citations
University of Manchester1, Leiden University2, University of Milan3, Curie Institute4, University of Paris5, University of Aberdeen6, Katholieke Universiteit Leuven7, Pasteur Institute8, Ludwig Maximilian University of Munich9, Sapienza University of Rome10, Norwich Research Park11, Université catholique de Louvain12, Université libre de Bruxelles13, University of Amsterdam14, École Normale Supérieure15, Centre national de la recherche scientifique16, Kobe University17, Trinity College, Dublin18, VU University Amsterdam19, Rutgers University20, University of Konstanz21
TL;DR: The entire DNA sequence of chromosome III of the yeast Saccharomyces cerevisiae has been determined, which is the first complete sequence analysis of an entire chromosome from any organism.
Abstract: The entire DNA sequence of chromosome III of the yeast Saccharomyces cerevisiae has been determined. This is the first complete sequence analysis of an entire chromosome from any organism. The 315-kilobase sequence reveals 182 open reading frames for proteins longer than 100 amino acids, of which 37 correspond to known genes and 29 more show some similarity to sequences in databases. Of 55 new open reading frames analysed by gene disruption, three are essential genes; of 42 non-essential genes that were tested, 14 show some discernible effect on phenotype and the remaining 28 have no overt function.
811 citations