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Publication Record


Comparative genomics of biotechnologically important yeasts.
Riley R, Haridas S, Wolfe KH, Lopes MR, Hittinger CT, Göker M, Salamov AA, Wisecaver JH, Long TM, Calvey CH, Aerts AL, Barry KW, Choi C, Clum A, Coughlan AY, Deshpande S, Douglass AP, Hanson SJ, Klenk HP, LaButti KM, Lapidus A, Lindquist EA, Lipzen AM, Meier-Kolthoff JP, Ohm RA, Otillar RP, Pangilinan JL, Peng Y, Rokas A, Rosa CA, Scheuner C, Sibirny AA, Slot JC, Stielow JB, Sun H, Kurtzman CP, Blackwell M, Grigoriev IV, Jeffries TW
(2016) Proc Natl Acad Sci U S A 113: 9882-7
MeSH Terms: Ascomycota, Biotechnology, Evolution, Molecular, Fungal Proteins, Genetic Code, Genome, Fungal, Genomics, Metabolic Networks and Pathways, Phylogeny, Species Specificity, Yeasts
Show Abstract · Added April 6, 2017
Ascomycete yeasts are metabolically diverse, with great potential for biotechnology. Here, we report the comparative genome analysis of 29 taxonomically and biotechnologically important yeasts, including 16 newly sequenced. We identify a genetic code change, CUG-Ala, in Pachysolen tannophilus in the clade sister to the known CUG-Ser clade. Our well-resolved yeast phylogeny shows that some traits, such as methylotrophy, are restricted to single clades, whereas others, such as l-rhamnose utilization, have patchy phylogenetic distributions. Gene clusters, with variable organization and distribution, encode many pathways of interest. Genomics can predict some biochemical traits precisely, but the genomic basis of others, such as xylose utilization, remains unresolved. Our data also provide insight into early evolution of ascomycetes. We document the loss of H3K9me2/3 heterochromatin, the origin of ascomycete mating-type switching, and panascomycete synteny at the MAT locus. These data and analyses will facilitate the engineering of efficient biosynthetic and degradative pathways and gateways for genomic manipulation.
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11 MeSH Terms
Endogenous Estrogens, Estrogen Metabolites, and Breast Cancer Risk in Postmenopausal Chinese Women.
Moore SC, Matthews CE, Ou Shu X, Yu K, Gail MH, Xu X, Ji BT, Chow WH, Cai Q, Li H, Yang G, Ruggieri D, Boyd-Morin J, Rothman N, Hoover RN, Gao YT, Zheng W, Ziegler RG
(2016) J Natl Cancer Inst 108:
MeSH Terms: Aged, Asian Americans, Breast Neoplasms, Case-Control Studies, China, Estradiol, Estrogens, Estrone, Female, Humans, Incidence, Metabolic Networks and Pathways, Middle Aged, Odds Ratio, Postmenopause, United States
Show Abstract · Added May 4, 2017
BACKGROUND - The role of estrogen metabolism in determining breast cancer risk and differences in breast cancer rates between high-incidence and low-incidence nations is poorly understood.
METHODS - We measured urinary concentrations of estradiol and estrone (parent estrogens) and 13 estrogen metabolites formed by irreversible hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring in a nested case-control study of 399 postmenopausal invasive breast cancer case participants and 399 matched control participants from the population-based Shanghai Women's Health Study cohort. Odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer by quartiles of metabolic pathway groups, pathway ratios, and individual estrogens/estrogen metabolites were estimated by multivariable conditional logistic regression. Urinary estrogen/estrogen metabolite measures were compared with those of postmenopausal non-hormone-using Asian Americans, a population with three-fold higher breast cancer incidence rates. All statistical tests were two-sided.
RESULTS - Urinary concentrations of parent estrogens were strongly associated with breast cancer risk (ORQ4vsQ1 = 1.94, 95% CI = 1.21 to 3.12, Ptrend = .01). Of the pathway ratios, the 2-pathway:total estrogens/estrogen metabolites and 2-pathway:parent estrogens were inversely associated with risk (ORQ4vsQ1 = 0.57, 95% CI = 0.35 to 0.91, Ptrend = .03, and ORQ4vsQ1 = 0.61, 95% CI = 0.37 to 0.99, Ptrend = .04, respectively). After adjusting for parent estrogens, these associations remained clearly inverse but lost statistical significance (ORQ4vsQ1 = 0.65, 95% CI = 0.39 to 1.06, Ptrend = .12 and ORQ4vsQ1 = 0.76, 95% CI = 0.44 to 1.32, Ptrend = .28). The urinary concentration of all estrogens/estrogen metabolites combined in Asian American women was triple that in Shanghai women.
CONCLUSIONS - Lower urinary parent estrogen concentrations and more extensive 2-hydroxylation were each associated with reduced postmenopausal breast cancer risk in a low-risk nation. Markedly higher total estrogen/estrogen metabolite concentrations in postmenopausal United States women (Asian Americans) than in Shanghai women may partly explain higher breast cancer rates in the United States.
Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the United States.
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16 MeSH Terms
Heme Synthesis and Acquisition in Bacterial Pathogens.
Choby JE, Skaar EP
(2016) J Mol Biol 428: 3408-28
MeSH Terms: Bacteria, Heme, Host-Pathogen Interactions, Metabolic Networks and Pathways
Show Abstract · Added April 19, 2016
Bacterial pathogens require the iron-containing cofactor heme to cause disease. Heme is essential to the function of hemoproteins, which are involved in energy generation by the electron transport chain, detoxification of host immune effectors, and other processes. During infection, bacterial pathogens must synthesize heme or acquire heme from the host; however, host heme is sequestered in high-affinity hemoproteins. Pathogens have evolved elaborate strategies to acquire heme from host sources, particularly hemoglobin, and both heme acquisition and synthesis are important for pathogenesis. Paradoxically, excess heme is toxic to bacteria and pathogens must rely on heme detoxification strategies. Heme is a key nutrient in the struggle for survival between host and pathogen, and its study has offered significant insight into the molecular mechanisms of bacterial pathogenesis.
Copyright © 2016 Elsevier Ltd. All rights reserved.
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4 MeSH Terms
Reproducibility of Differential Proteomic Technologies in CPTAC Fractionated Xenografts.
Tabb DL, Wang X, Carr SA, Clauser KR, Mertins P, Chambers MC, Holman JD, Wang J, Zhang B, Zimmerman LJ, Chen X, Gunawardena HP, Davies SR, Ellis MJ, Li S, Townsend RR, Boja ES, Ketchum KA, Kinsinger CR, Mesri M, Rodriguez H, Liu T, Kim S, McDermott JE, Payne SH, Petyuk VA, Rodland KD, Smith RD, Yang F, Chan DW, Zhang B, Zhang H, Zhang Z, Zhou JY, Liebler DC
(2016) J Proteome Res 15: 691-706
MeSH Terms: Breast Neoplasms, Chromatography, Liquid, Data Interpretation, Statistical, Female, Gene Expression Profiling, Heterografts, Humans, Metabolic Networks and Pathways, Observer Variation, Proteome, Proteomics, Quality Control, Reproducibility of Results, Tandem Mass Spectrometry
Show Abstract · Added February 15, 2016
The NCI Clinical Proteomic Tumor Analysis Consortium (CPTAC) employed a pair of reference xenograft proteomes for initial platform validation and ongoing quality control of its data collection for The Cancer Genome Atlas (TCGA) tumors. These two xenografts, representing basal and luminal-B human breast cancer, were fractionated and analyzed on six mass spectrometers in a total of 46 replicates divided between iTRAQ and label-free technologies, spanning a total of 1095 LC-MS/MS experiments. These data represent a unique opportunity to evaluate the stability of proteomic differentiation by mass spectrometry over many months of time for individual instruments or across instruments running dissimilar workflows. We evaluated iTRAQ reporter ions, label-free spectral counts, and label-free extracted ion chromatograms as strategies for data interpretation (source code is available from http://homepages.uc.edu/~wang2x7/Research.htm ). From these assessments, we found that differential genes from a single replicate were confirmed by other replicates on the same instrument from 61 to 93% of the time. When comparing across different instruments and quantitative technologies, using multiple replicates, differential genes were reproduced by other data sets from 67 to 99% of the time. Projecting gene differences to biological pathways and networks increased the degree of similarity. These overlaps send an encouraging message about the maturity of technologies for proteomic differentiation.
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14 MeSH Terms
Examining the evolution of the regulatory circuit controlling secondary metabolism and development in the fungal genus Aspergillus.
Lind AL, Wisecaver JH, Smith TD, Feng X, Calvo AM, Rokas A
(2015) PLoS Genet 11: e1005096
MeSH Terms: Aspergillus, Biological Evolution, Evolution, Molecular, Genome, Fungal, Metabolic Networks and Pathways
Show Abstract · Added February 22, 2016
Filamentous fungi produce diverse secondary metabolites (SMs) essential to their ecology and adaptation. Although each SM is typically produced by only a handful of species, global SM production is governed by widely conserved transcriptional regulators in conjunction with other cellular processes, such as development. We examined the interplay between the taxonomic narrowness of SM distribution and the broad conservation of global regulation of SM and development in Aspergillus, a diverse fungal genus whose members produce well-known SMs such as penicillin and gliotoxin. Evolutionary analysis of the 2,124 genes comprising the 262 SM pathways in four Aspergillus species showed that most SM pathways were species-specific, that the number of SM gene orthologs was significantly lower than that of orthologs in primary metabolism, and that the few conserved SM orthologs typically belonged to non-homologous SM pathways. RNA sequencing of two master transcriptional regulators of SM and development, veA and mtfA, showed that the effects of deletion of each gene, especially veA, on SM pathway regulation were similar in A. fumigatus and A. nidulans, even though the underlying genes and pathways regulated in each species differed. In contrast, examination of the role of these two regulators in development, where 94% of the underlying genes are conserved in both species showed that whereas the role of veA is conserved, mtfA regulates development in the homothallic A. nidulans but not in the heterothallic A. fumigatus. Thus, the regulation of these highly conserved developmental genes is divergent, whereas-despite minimal conservation of target genes and pathways-the global regulation of SM production is largely conserved. We suggest that the evolution of the transcriptional regulation of secondary metabolism in Aspergillus represents a novel type of regulatory circuit rewiring and hypothesize that it has been largely driven by the dramatic turnover of the target genes involved in the process.
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5 MeSH Terms
A roadmap for interpreting (13)C metabolite labeling patterns from cells.
Buescher JM, Antoniewicz MR, Boros LG, Burgess SC, Brunengraber H, Clish CB, DeBerardinis RJ, Feron O, Frezza C, Ghesquiere B, Gottlieb E, Hiller K, Jones RG, Kamphorst JJ, Kibbey RG, Kimmelman AC, Locasale JW, Lunt SY, Maddocks OD, Malloy C, Metallo CM, Meuillet EJ, Munger J, Nöh K, Rabinowitz JD, Ralser M, Sauer U, Stephanopoulos G, St-Pierre J, Tennant DA, Wittmann C, Vander Heiden MG, Vazquez A, Vousden K, Young JD, Zamboni N, Fendt SM
(2015) Curr Opin Biotechnol 34: 189-201
MeSH Terms: Animals, Carbon Isotopes, Cell Survival, Humans, Isotope Labeling, Metabolic Networks and Pathways
Show Abstract · Added March 31, 2016
Measuring intracellular metabolism has increasingly led to important insights in biomedical research. (13)C tracer analysis, although less information-rich than quantitative (13)C flux analysis that requires computational data integration, has been established as a time-efficient method to unravel relative pathway activities, qualitative changes in pathway contributions, and nutrient contributions. Here, we review selected key issues in interpreting (13)C metabolite labeling patterns, with the goal of drawing accurate conclusions from steady state and dynamic stable isotopic tracer experiments.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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6 MeSH Terms
Shared Selective Pressures on Fungal and Human Metabolic Pathways Lead to Divergent yet Analogous Genetic Responses.
Eidem HR, McGary KL, Rokas A
(2015) Mol Biol Evol 32: 1449-55
MeSH Terms: Evolution, Molecular, Fungi, Gene Expression Regulation, Fungal, Genes, Fungal, Genetic Linkage, Humans, Metabolic Networks and Pathways, Selection, Genetic
Show Abstract · Added February 19, 2015
Reduced metabolic efficiency, toxic intermediate accumulation, and deficits of molecular building blocks, which all stem from disruptions of flux through metabolic pathways, reduce organismal fitness. Although these represent shared selection pressures across organisms, the genetic signatures of the responses to them may differ. In fungi, a frequently observed signature is the physical linkage of genes from the same metabolic pathway. In contrast, human metabolic genes are rarely tightly linked; rather, they tend to show tissue-specific coexpression. We hypothesized that the physical linkage of fungal metabolic genes and the tissue-specific coexpression of human metabolic genes are divergent yet analogous responses to the range of selective pressures imposed by disruptions of flux. To test this, we examined the degree to which the human homologs of physically linked metabolic genes in fungi (fungal linked homologs or FLOs) are coexpressed across six human tissues. We found that FLOs are significantly more correlated in their expression profiles across human tissues than other metabolic genes. We obtained similar results in analyses of the same six tissues from chimps, gorillas, orangutans, and macaques. We suggest that when selective pressures remain stable across large evolutionary distances, evidence of selection in a given evolutionary lineage can become a highly reliable predictor of the signature of selection in another, even though the specific adaptive response in each lineage is markedly different.
© The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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8 MeSH Terms
The evolution of fungal metabolic pathways.
Wisecaver JH, Slot JC, Rokas A
(2014) PLoS Genet 10: e1004816
MeSH Terms: Ascomycota, Evolution, Molecular, Gene Duplication, Gene Regulatory Networks, Gene Transfer, Horizontal, Genes, Fungal, Genome, Fungal, Metabolic Networks and Pathways, Multigene Family, Phylogeny
Show Abstract · Added February 19, 2015
Fungi contain a remarkable range of metabolic pathways, sometimes encoded by gene clusters, enabling them to digest most organic matter and synthesize an array of potent small molecules. Although metabolism is fundamental to the fungal lifestyle, we still know little about how major evolutionary processes, such as gene duplication (GD) and horizontal gene transfer (HGT), have interacted with clustered and non-clustered fungal metabolic pathways to give rise to this metabolic versatility. We examined the synteny and evolutionary history of 247,202 fungal genes encoding enzymes that catalyze 875 distinct metabolic reactions from 130 pathways in 208 diverse genomes. We found that gene clustering varied greatly with respect to metabolic category and lineage; for example, clustered genes in Saccharomycotina yeasts were overrepresented in nucleotide metabolism, whereas clustered genes in Pezizomycotina were more common in lipid and amino acid metabolism. The effects of both GD and HGT were more pronounced in clustered genes than in their non-clustered counterparts and were differentially distributed across fungal lineages; specifically, GD, which was an order of magnitude more abundant than HGT, was most frequently observed in Agaricomycetes, whereas HGT was much more prevalent in Pezizomycotina. The effect of HGT in some Pezizomycotina was particularly strong; for example, we identified 111 HGT events associated with the 15 Aspergillus genomes, which sharply contrasts with the 60 HGT events detected for the 48 genomes from the entire Saccharomycotina subphylum. Finally, the impact of GD within a metabolic category was typically consistent across all fungal lineages, whereas the impact of HGT was variable. These results indicate that GD is the dominant process underlying fungal metabolic diversity, whereas HGT is episodic and acts in a category- or lineage-specific manner. Both processes have a greater impact on clustered genes, suggesting that metabolic gene clusters represent hotspots for the generation of fungal metabolic diversity.
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10 MeSH Terms
(13)C metabolic flux analysis of recombinant expression hosts.
Young JD
(2014) Curr Opin Biotechnol 30: 238-45
MeSH Terms: Carbon Isotopes, Glucose, Industrial Microbiology, Metabolic Flux Analysis, Metabolic Networks and Pathways, Recombinant Proteins, Software
Show Abstract · Added January 23, 2015
Identifying host cell metabolic phenotypes that promote high recombinant protein titer is a major goal of the biotech industry. (13)C metabolic flux analysis (MFA) provides a rigorous approach to quantify these metabolic phenotypes by applying isotope tracers to map the flow of carbon through intracellular metabolic pathways. Recent advances in tracer theory and measurements are enabling more information to be extracted from (13)C labeling experiments. Sustained development of publicly available software tools and standardization of experimental workflows is simultaneously encouraging increased adoption of (13)C MFA within the biotech research community. A number of recent (13)C MFA studies have identified increased citric acid cycle and pentose phosphate pathway fluxes as consistent markers of high recombinant protein expression, both in mammalian and microbial hosts. Further work is needed to determine whether redirecting flux into these pathways can effectively enhance protein titers while maintaining acceptable glycan profiles.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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7 MeSH Terms
Meta-analysis of genome-wide association studies of adult height in East Asians identifies 17 novel loci.
He M, Xu M, Zhang B, Liang J, Chen P, Lee JY, Johnson TA, Li H, Yang X, Dai J, Liang L, Gui L, Qi Q, Huang J, Li Y, Adair LS, Aung T, Cai Q, Cheng CY, Cho MC, Cho YS, Chu M, Cui B, Gao YT, Go MJ, Gu D, Gu W, Guo H, Hao Y, Hong J, Hu Z, Hu Y, Huang J, Hwang JY, Ikram MK, Jin G, Kang DH, Khor CC, Kim BJ, Kim HT, Kubo M, Lee J, Lee J, Lee NR, Li R, Li J, Liu J, Longe J, Lu W, Lu X, Miao X, Okada Y, Ong RT, Qiu G, Seielstad M, Sim X, Song H, Takeuchi F, Tanaka T, Taylor PR, Wang L, Wang W, Wang Y, Wu C, Wu Y, Xiang YB, Yamamoto K, Yang H, Liao M, Yokota M, Young T, Zhang X, Kato N, Wang QK, Zheng W, Hu FB, Lin D, Shen H, Teo YY, Mo Z, Wong TY, Lin X, Mohlke KL, Ning G, Tsunoda T, Han BG, Shu XO, Tai ES, Wu T, Qi L
(2015) Hum Mol Genet 24: 1791-800
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Asian Continental Ancestry Group, Body Height, European Continental Ancestry Group, Far East, Female, Gene Frequency, Genetic Loci, Genome-Wide Association Study, Humans, Male, Metabolic Networks and Pathways, Middle Aged, Polymorphism, Single Nucleotide, Protein Tyrosine Phosphatases, Young Adult
Show Abstract · Added February 16, 2015
Human height is associated with risk of multiple diseases and is profoundly determined by an individual's genetic makeup and shows a high degree of ethnic heterogeneity. Large-scale genome-wide association (GWA) analyses of adult height in Europeans have identified nearly 180 genetic loci. A recent study showed high replicability of results from Europeans-based GWA studies in Asians; however, population-specific loci may exist due to distinct linkage disequilibrium patterns. We carried out a GWA meta-analysis in 93 926 individuals from East Asia. We identified 98 loci, including 17 novel and 81 previously reported loci, associated with height at P < 5 × 10(-8), together explaining 8.89% of phenotypic variance. Among the newly identified variants, 10 are commonly distributed (minor allele frequency, MAF > 5%) in Europeans, with comparable frequencies with in Asians, and 7 single-nucleotide polymorphisms are with low frequency (MAF < 5%) in Europeans. In addition, our data suggest that novel biological pathway such as the protein tyrosine phosphatase family is involved in regulation of height. The findings from this study considerably expand our knowledge of the genetic architecture of human height in Asians.
© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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19 MeSH Terms