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ABSTRACT: Epistasis refers to the phenomenon in which phenotypic consequences caused by mutation of one gene depend on one or more mutations at another gene. Epistasis is critical for understanding many genetic and evolutionary processes, including pathway organization, evolution of sexual reproduction, mutational load, ploidy, genomic complexity, speciation, and the origin of life. Nevertheless, current understandings for the genome-wide distribution of epistasis are mostly inferred from interactions among one mutant type per gene, whereas how epistatic interaction partners change dynamically for different mutant alleles of the same gene is largely unknown. Here we address this issue by combining predictions from flux balance analysis and data from a recently published high-throughput experiment. Our results show that different alleles can epistatically interact with very different gene sets. Furthermore, between two random mutant alleles of the same gene, the chance for the allele with more severe mutational consequence to develop a higher percentage of negative epistasis than the other allele is 50~70% in eukaryotic organisms, but only 20~30% in bacteria and archaea. We developed a population genetics model that predicts that the observed distribution for the sign of epistasis can speed up the process of purging deleterious mutations in eukaryotic organisms. Our results indicate that epistasis among genes can be dynamically rewired at the genome level, and call on future efforts to revisit theories that can integrate epistatic dynamics among genes in biological systems.
Proceedings of the National Academy of Sciences 06/2012; 109(26):10420-5. · 9.68 Impact Factor
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ABSTRACT: In this paper we present a new method for detecting block duplications in a genome. It is more stringent than previous ones
in that it requires a more rigorous definition of paralogous genes and that it requires the paralogous proteins on the two
blocks to be contiguous. In addition, it provides three criterion choices: (1) the same composition (i.e., having the same
paralogues in the two windows), (2) the same composition and gene order, and (3) the same composition, gene order, and gene
orientation. The method is completely automated, requiring no visual inspection as in previous methods. We applied it to analyze
the complete genomes of S. cerevisiae and C. elegans. In yeast we detected fewer duplicated blocks than previously reported. In C. elegans, however, we detected more block duplications than previously reported, indicating that although our method has a more stringent
definition of block duplication than previous ones, it may be more sensitive in detection because it considers every possible
window rather than only fixed nonoverlapping windows. Our results show that block duplication is a common phenomenon in both
organisms. The patterns of block duplication in the two species are, however, markedly different. The yeast shows much more
extensive block duplication than the nematode, with some chromosomes having more than 40% of the duplications derived from
block duplications. Moreover, in the yeast the majority of block duplications occurred between chromosomes, while in the nematode
most block duplications occurred within chromosomes.
Gene duplication Block duplication Protein families Database cleaning Whole-genome duplication
Journal of Molecular Evolution 04/2012; 56(1):28-37. · 2.27 Impact Factor
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ABSTRACT: It has been increasingly clear that changes in gene regulation play important roles in physiological and phenotypic evolution. Rewiring gene-regulatory networks, i.e., alteration of the gene-regulation system for different biological functions, has been demonstrated in various species. Posttranscriptional regulons have prominent roles in coordinating gene expression in a variety of eukaryotes. In this study, using Puf4p in fungi as an example, we demonstrate that posttranscriptional regulatory networks can also be rewired during evolution. Although Puf4p is highly conserved in fungi, targets of the posttranscriptional regulon are functionally diverse among known fungal species. In the Saccharomycotina subdivision, target genes of Puf4p mostly conduct function in the nucleolus; however, in the Pezizomycotina subdivision, they are enriched in the mitochondria. Furthermore, we demonstrate different regulation efficiencies of mitochondrial function by PUF proteins in different fungal clades. Our results indicate that rewiring of posttranscription regulatory networks may be an important way of generating genetic novelties in gene regulation during evolution.
Molecular Biology and Evolution 03/2012; 29(9):2169-76. · 5.55 Impact Factor
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ABSTRACT: Multidrug resistance protein Pdr5p is a yeast ATP-binding cassette (ABC) transporter in the plasma membrane. It confers multidrug resistance by active efflux of intracellular drugs. However, the highly polymorphic Pdr5p from clinical strain YJM789 loses its ability to expel azole and cyclohexmide. To investigate the role of amino acid changes in this functional change, PDR5 chimeras were constructed by segmental replacement of homologous BY4741 PDR5 fragments. Functions of PDR5 chimeras were evaluated by fluconazole and cycloheximide resistance assays. Their expression, ATPase activity, and efflux efficiency for other substrates were also analyzed. Using multiple lines of evidence, we show that an alanine-to-methionine mutation at position 1352 located in the predicted short intracellular loop 4 significantly contributes to the observed transport deficiency. The degree of impairment is likely correlated to the size of the mutant residue.
PLoS ONE 01/2012; 7(1):e29520. · 4.09 Impact Factor
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ABSTRACT: Dietary transitions in human history have been suggested to play important roles in the evolution of mankind. Genetic variations caused by adaptation to diet during human evolution could have important health consequences in current society. The advance of sequencing technologies and the rapid accumulation of genome information provide an unprecedented opportunity to comprehensively characterize genetic variations in human populations and unravel the genetic basis of human evolution. Series of selection detection methods, based on various theoretical models and exploiting different aspects of selection signatures, have been developed. Their applications at the species and population levels have respectively led to the identification of human specific selection events that distinguish human from nonhuman primates and local adaptation events that contribute to human diversity. Scrutiny of candidate genes has revealed paradigms of adaptations to specific nutritional components and genome-wide selection scans have verified the prevalence of diet-related selection events and provided many more candidates awaiting further investigation. Understanding the role of diet in human evolution is fundamental for the development of evidence-based, genome-informed nutritional practices in the era of personal genomics.
Advances in nutrition (Bethesda, Md.). 11/2011; 2(6):486-96.
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ABSTRACT: Epistasis has long been recognized as fundamentally important in understanding the structure, function, and evolutionary dynamics of biological systems. Yet, little is known about how it is distributed underlying specific traits. Based on a global map of epistatic interactions in baker's yeast, Saccharomyces cerevisiae, we show that epistasis is prevalent (∼13% increase from random expectation) and displays modular architecture among genes that underlie the same growth traits. More interestingly, our results indicate that hub genes responsible for the same growth traits tend to link epistatically with each other more frequently than random expectation. Our results provide a genome-wide perspective on the genetic architecture of growth traits in a eukaryotic organism.
Genome Biology and Evolution 08/2011; 3:909-14. · 4.62 Impact Factor
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ABSTRACT: Inositol-requiring enzyme 1α (IRE1α), an endoplasmic reticulum-resident sensor for mammalian unfolded protein response, is a bifunctional enzyme containing kinase and RNase domains critical for trans-autophosphorylation and Xbp1 mRNA splicing, respectively, in response to endoplasmic reticulum stress. However, the amino acid residues important for its function and activation remain largely unexplored. Here, through analysis of IRE1α mutants associated with human somatic cancers, we have identified a highly conserved proline residue at position 830 (Pro(830)) that is critical for its structural integrity and hence, the activation of both kinase and RNase domains. Structural analysis revealed that Pro(830) may form a highly conserved structural linker with adjacent tryptophan and tyrosine residues at positions 833 and 945 (Trp(833) and Tyr(945)), thereby bridging the kinase and RNase domains. Indeed, mutation of Pro(830) to leucine (P830L) completely abolished the kinase and RNase activities, significantly decreased protein stability, and prevented oligomerization of IRE1α upon ER stress; similar observations were made for mutations of Trp(833) to alanine (W833A) and to a lesser extent for Y945A. Our finding may facilitate the identification of small molecules to compromise IRE1α function specifically.
Journal of Biological Chemistry 07/2011; 286(35):30859-66. · 4.77 Impact Factor
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ABSTRACT: TATA box, the core promoter element, exists in a broad range of eukaryotes, and the expression of TATA-containing genes usually responds to various environmental stresses. Hence, the evolution of TATA-box in duplicate genes may provide some clues for the interrelationship among environmental stress, expression differentiation, and duplicate gene preservation. In the present study, we observed that the TATA box is significantly overrepresented in duplicate genes compared with singletons in human, worm, Arabidopsis, and yeast genomes. We then conducted an extensive functional genomic analysis to investigate the evolution of TATA box along over 700 yeast gene family phylogenies. After reconstructing the ancestral TATA-box states (presence or absence), we found that significantly higher numbers of TATA box gain events than loss events had occurred after yeast gene duplications-the overall gain-loss ratio is about 3-4 to 1. Interestingly, these TATA-gain duplicate genes on average have experienced greater expression divergence from the ancestral expression states than their most closely related TATA-less duplicate partners, but only under environmental stress conditions (asymmetric evolution); indeed, under normal physiological conditions, they have similar expression divergence (symmetric evolution). Moreover, we showed that TATA-gain duplicates are enriched in stress-associated functional categories but that is not the case for TATA-ancestral duplicates (those inherited from their ancestors prior to duplication). Together, we conclude that after the gene duplication, gain of the TATA box in duplicate promoters may have played an important role in yeast duplicate preservation by accelerating expression divergence that may facilitate the adaptive evolution of the organism in response to environmental changes.
Molecular Biology and Evolution 04/2011; 28(10):2893-904. · 5.55 Impact Factor
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ABSTRACT: Epistasis has long been recognized as fundamentally important in understanding the structure, function, and evolutionary dynamics of biological systems. Gene duplication is a major mechanism of evolution for genetic novelties. Here, we demonstrate that genes evolved significantly more epistatic interactions after duplication. The connectivity of duplicate gene pairs in epistatic networks is positively correlated with the extent of their sequence divergence. Furthermore, duplicate gene pairs tend to epistatically interact with genes that occupy more functional spaces than do single-copy genes. These results show that gene duplication plays an important role in the evolution of epistasis.
Genome Biology and Evolution 03/2011; 3:295-301. · 4.62 Impact Factor
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ABSTRACT: DNA replication errors that escape polymerase proofreading and mismatch repair (MMR) can lead to base substitution and frameshift mutations. Such mutations can disrupt gene function, reduce fitness, and promote diseases such as cancer and are also the raw material of molecular evolution. To analyze with limited bias genomic features associated with DNA polymerase errors, we performed a genome-wide analysis of mutations that accumulate in MMR-deficient diploid lines of Saccharomyces cerevisiae. These lines were derived from a common ancestor and were grown for 160 generations, with bottlenecks reducing the population to one cell every 20 generations. We sequenced to between 8- and 20-fold coverage one wild-type and three mutator lines using Illumina Solexa 36-bp reads. Using an experimentally aware Bayesian genotype caller developed to pool experimental data across sequencing runs for all strains, we detected 28 heterozygous single-nucleotide polymorphisms (SNPs) and 48 single-nt insertion/deletions (indels) from the data set. This method was evaluated on simulated data sets and found to have a very low false-positive rate (∼6 × 10(-5)) and a false-negative rate of 0.08 within the unique mapping regions of the genome that contained at least sevenfold coverage. The heterozygous mutations identified by the Bayesian genotype caller were confirmed by Sanger sequencing. All of the mutations were unique to a given line, except for a single-nt deletion mutation which occurred independently in two lines. All 48 indels, composed of 46 deletions and two insertions, occurred in homopolymer (HP) tracts [i.e., 47 poly(A) or (T) tracts, 1 poly(G) or (C) tract] between 5 and 13 bp long. Our findings are of interest because HP tracts are present at high levels in the yeast genome (>77,400 for 5- to 20-nt HP tracts), and frameshift mutations in these regions are likely to disrupt gene function. In addition, they demonstrate that the mutation pattern seen previously in mismatch repair defective strains using a limited number of reporters holds true for the entire genome.
Genetics 10/2010; 186(2):493-503. · 4.01 Impact Factor
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K T Nishant,
Wu Wei,
Eugenio Mancera,
Juan Lucas Argueso,
Andreas Schlattl,
Nicolas Delhomme,
Xin Ma,
Carlos D Bustamante,
Jan O Korbel, Zhenglong Gu,
Lars M Steinmetz,
Eric Alani
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ABSTRACT: Accurate estimates of mutation rates provide critical information to analyze genome evolution and organism fitness. We used whole-genome DNA sequencing, pulse-field gel electrophoresis, and comparative genome hybridization to determine mutation rates in diploid vegetative and meiotic mutation accumulation lines of Saccharomyces cerevisiae. The vegetative lines underwent only mitotic divisions while the meiotic lines underwent a meiotic cycle every ∼20 vegetative divisions. Similar base substitution rates were estimated for both lines. Given our experimental design, these measures indicated that the meiotic mutation rate is within the range of being equal to zero to being 55-fold higher than the vegetative rate. Mutations detected in vegetative lines were all heterozygous while those in meiotic lines were homozygous. A quantitative analysis of intra-tetrad mating events in the meiotic lines showed that inter-spore mating is primarily responsible for rapidly fixing mutations to homozygosity as well as for removing mutations. We did not observe 1-2 nt insertion/deletion (in-del) mutations in any of the sequenced lines and only one structural variant in a non-telomeric location was found. However, a large number of structural variations in subtelomeric sequences were seen in both vegetative and meiotic lines that did not affect viability. Our results indicate that the diploid yeast nuclear genome is remarkably stable during the vegetative and meiotic cell cycles and support the hypothesis that peripheral regions of chromosomes are more dynamic than gene-rich central sections where structural rearrangements could be deleterious. This work also provides an improved estimate for the mutational load carried by diploid organisms.
PLoS Genetics 09/2010; 6(9). · 8.69 Impact Factor
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ABSTRACT: Genome-wide studies of post-transcriptional mRNA regulation in model organisms indicate a "post-transcriptional RNA regulon" model, in which a set of functionally related genes is regulated by mRNA-binding RNAs or proteins. One well-studied post-transcriptional regulon by Puf3p functions in mitochondrial biogenesis in budding yeast. The evolution of the Puf3p regulon remains unclear because previous studies have shown functional divergence of Puf3p regulon targets among yeast, fruit fly, and humans. By analyzing evolutionary patterns of Puf3p and its targeted genes in forty-two sequenced fungi, we demonstrated that, although the Puf3p regulon is conserved among all of the studied fungi, the dedicated regulation of mitochondrial biogenesis by Puf3p emerged only in the Saccharomycotina clade. Moreover, the evolution of the Puf3p regulon was coupled with evolution of codon usage bias in down-regulating expression of genes that function in mitochondria in yeast species after genome duplication. Our results provide a scenario for how evolution like a tinker exploits pre-existing materials of a conserved post-transcriptional regulon to regulate gene expression for novel functional roles.
PLoS Genetics 07/2010; 6(7):e1001030. · 8.69 Impact Factor
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ABSTRACT: Fungal pathogens can be lethal, especially among immunocompromised populations, such as patients with AIDS and recipients of tissue transplantation or chemotherapy. Prolonged usage of antifungal reagents can lead to drug resistance and treatment failure. Understanding mechanisms that underlie drug resistance by pathogenic microorganisms is thus vital for dealing with this emerging issue. In this study, we show that dramatic sequence changes in PDR5, an ABC (ATP-binding cassette) efflux transporter protein gene in an opportunistic fungal pathogen, caused the organism to become hypersensitive to azole, a widely used antifungal drug. Surprisingly, the same mutations conferred growth advantages to the organism on polyenes, which are also commonly used antimycotics. Our results indicate that Pdr5p might be important for ergosterol homeostasis. The observed remarkable sequence divergence in the PDR5 gene in yeast strain YJM789 may represent an interesting case of adaptive loss of gene function with significant clinical implications.
PLoS ONE 01/2010; 5(6):e11309. · 4.09 Impact Factor
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Molecular Phylogenetics and Evolution 08/2009; · 3.61 Impact Factor
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ABSTRACT: A report of the workshop 'Evolutionary and Environmental Genomics of Yeasts', Heidelberg, Germany, 1-5 October 2008.
Genome biology 04/2009; 10(3):304. · 6.63 Impact Factor
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ABSTRACT: The filamentous fungus Ashbya gossypii grows into a multicellular mycelium that is distinct from the unicellular morphology of its closely related yeast species. It has been proposed that genes important for cell cycle regulation play central roles for such phenotypic differences. Because A. gossypii shares an almost identical set of cell cycle genes with the typical yeast Saccharomyces cerevisiae, the differences might occur at the level of orthologous gene regulation. Codon usage patterns were compared to identify orthologous genes with different gene regulation between A. gossypii and nine closely related yeast species.
Here we identified 3,151 orthologous genes between A. gossypii and nine yeast species. Two groups of genes with significant differences in codon usage (gene translation efficiency) were identified between A. gossypii and yeasts. 333 genes (Group I) and 552 genes (Group II) have significantly higher translation efficiency in A. gossypii and yeasts, respectively. Functional enrichment and pathway analysis show that Group I genes are significantly enriched with cell cycle functions whereas Group II genes are biased toward metabolic functions.
Because translation efficiency of a gene is closely related to its functional importance, the observed functional distributions of orthologous genes with different translation efficiency might account for phenotypic differentiation between A. gossypii and yeast species. The results shed light on the mechanisms for pseudohyphal growth in pathogenic yeast species.
BMC Evolutionary Biology 01/2009; 8:343. · 3.52 Impact Factor
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Molecular Phylogenetics and Evolution 12/2008; 50(2):397-400. · 3.61 Impact Factor
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ABSTRACT: Saccharomyces cerevisiae and its close relatives are characterized by their propensity to ferment even in the presence of oxygen. It was hypothesized that whole-genome duplication (WGD) led to the development of this efficient fermentative lifestyle (WGD-fermentation hypothesis, Piskur 2001. In this study, we found that a significantly higher proportion of WGD genes than non-WGD genes are dynamically regulated during metabolic oscillation in response to oxygen change. The same data set also shows that the WGD genes, as compared with the smaller scale duplicate genes, are enriched with pairs where both copies have cyclic expression during the metabolic oscillation (either with the same or different phases). These results provide new evidences for the WGD-fermentation hypothesis and new insights into the relationship between the genome duplication and the evolution of new lifestyles in eukaryotic organisms.
Molecular Biology and Evolution 10/2008; 25(12):2513-6. · 5.55 Impact Factor
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ABSTRACT: Mitochondria are essential for cellular energy production in most eukaryotic organisms. However, when glucose is abundant, yeast species that underwent whole-genome duplication (WGD) mostly conduct fermentation even under aerobic conditions, and most can survive without a functional mitochondrial genome. In this study, we show that the rate of evolution for the nuclear-encoded mitochondrial genes was greater in post-WGD species than pre-WGD species. Furthermore, codon usage bias was relaxed for these genes in post-WGD yeast species. The codon usage pattern and the distribution of a particular transcription regulatory element suggest that the change to an efficient aerobic fermentation lifestyle in this lineage might have emerged after WGD between the divergence of Kluyveromyces polysporus and Saccharomyces castellii from their common ancestor. This new energy production strategy could have led to the relaxation of mitochondrial function in the relevant yeast species.
Genome Research 10/2008; 18(9):1466-71. · 13.61 Impact Factor
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Wu Wei,
John H McCusker,
Richard W Hyman,
Ted Jones,
Ye Ning,
Zhiwei Cao, Zhenglong Gu,
Dan Bruno,
Molly Miranda,
Michelle Nguyen, [......],
Raquel Tamse,
Xiaojing Wang,
Peilin Jia,
Philippe Luedi,
Peter J Oefner,
Lior David,
Fred S Dietrich,
Yixue Li,
Ronald W Davis,
Lars M Steinmetz
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ABSTRACT: We sequenced the genome of Saccharomyces cerevisiae strain YJM789, which was derived from a yeast isolated from the lung of an AIDS patient with pneumonia. The strain is used for studies of fungal infections and quantitative genetics because of its extensive phenotypic differences to the laboratory reference strain, including growth at high temperature and deadly virulence in mouse models. Here we show that the approximately 12-Mb genome of YJM789 contains approximately 60,000 SNPs and approximately 6,000 indels with respect to the reference S288c genome, leading to protein polymorphisms with a few known cases of phenotypic changes. Several ORFs are found to be unique to YJM789, some of which might have been acquired through horizontal transfer. Localized regions of high polymorphism density are scattered over the genome, in some cases spanning multiple ORFs and in others concentrated within single genes. The sequence of YJM789 contains clues to pathogenicity and spurs the development of more powerful approaches to dissecting the genetic basis of complex hereditary traits.
Proceedings of the National Academy of Sciences 08/2007; 104(31):12825-30. · 9.68 Impact Factor
