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Calvo, Sarah

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Calvo

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Sarah

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Calvo, Sarah
Author's Publications: search.filters.isAuthorOfPublication.dee2e2c8-e070-44c8-a4e0-3ce51acda528

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Now showing 1 - 10 of 10
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    CLIC, a tool for expanding biological pathways based on co-expression across thousands of datasets
    (Public Library of Science, 2017) Li, Yang; Jourdain, Alexis A.; Calvo, Sarah; Liu, Jun; Mootha, Vamsi
    In recent years, there has been a huge rise in the number of publicly available transcriptional profiling datasets. These massive compendia comprise billions of measurements and provide a special opportunity to predict the function of unstudied genes based on co-expression to well-studied pathways. Such analyses can be very challenging, however, since biological pathways are modular and may exhibit co-expression only in specific contexts. To overcome these challenges we introduce CLIC, CLustering by Inferred Co-expression. CLIC accepts as input a pathway consisting of two or more genes. It then uses a Bayesian partition model to simultaneously partition the input gene set into coherent co-expressed modules (CEMs), while assigning the posterior probability for each dataset in support of each CEM. CLIC then expands each CEM by scanning the transcriptome for additional co-expressed genes, quantified by an integrated log-likelihood ratio (LLR) score weighted for each dataset. As a byproduct, CLIC automatically learns the conditions (datasets) within which a CEM is operative. We implemented CLIC using a compendium of 1774 mouse microarray datasets (28628 microarrays) or 1887 human microarray datasets (45158 microarrays). CLIC analysis reveals that of 910 canonical biological pathways, 30% consist of strongly co-expressed gene modules for which new members are predicted. For example, CLIC predicts a functional connection between protein C7orf55 (FMC1) and the mitochondrial ATP synthase complex that we have experimentally validated. CLIC is freely available at www.gene-clic.org. We anticipate that CLIC will be valuable both for revealing new components of biological pathways as well as the conditions in which they are active.
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    Next generation sequencing with copy number variant detection expands the phenotypic spectrum of HSD17B4-deficiency
    (BioMed Central, 2014) Lieber, Daniel S; Hershman, Steven G; Slate, Nancy G; Calvo, Sarah; Sims, Katherine Bustin; Schmahmann, Jeremy; Mootha, Vamsi
    Background: D-bifunctional protein deficiency, caused by recessive mutations in HSD17B4, is a severe, infantile-onset disorder of peroxisomal fatty acid oxidation. Few affected patients survive past two years of age. Compound heterozygous mutations in HSD17B4 have also been reported in two sisters diagnosed with Perrault syndrome (MIM # 233400), who presented in adolescence with ovarian dysgenesis, hearing loss, and ataxia. Case presentation: An adult male presented with cerebellar ataxia, peripheral neuropathy, hearing loss, and azoospermia. The clinical presentation, in combination with biochemical findings in serum, urine, and muscle biopsy, suggested a mitochondrial disorder. Commercial genetic testing of 18 ataxia and mitochondrial disease genes was negative. Targeted exome sequencing followed by analysis of single nucleotide variants and small insertions/deletions failed to reveal a genetic basis of disease. Application of a computational algorithm to infer copy number variants (CNVs) from exome data revealed a heterozygous 12 kb deletion of exons 10–13 of HSD17B4 that was compounded with a rare missense variant (p.A196V) at a highly conserved residue. Retrospective review of patient records revealed mildly elevated ratios of pristanic:phytanic acid and arachidonic:docosahexaenoic acid, consistent with dysfunctional peroxisomal fatty acid oxidation. Conclusion: Our case expands the phenotypic spectrum of HSD17B4-deficiency, representing the first male case reported with infertility. Furthermore, it points to crosstalk between mitochondria and peroxisomes in HSD17B4-deficiency and Perrault syndrome.
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    Expansion of Biological Pathways Based on Evolutionary Inference
    (Elsevier BV, 2014) Li, Yang; Calvo, Sarah; Gutman, Roee; Liu, Jun; Mootha, Vamsi
    The availability of diverse genomes makes it possible to predict gene function based on shared evolutionary history. This approach can be challenging, however, for pathways whose components do not exhibit a shared history but rather consist of distinct “evolutionary modules.” We introduce a computational algorithm, clustering by inferred models of evolution (CLIME), which inputs a eukaryotic species tree, homology matrix, and pathway (gene set) of interest. CLIME partitions the gene set into disjoint evolutionary modules, simultaneously learning the number of modules and a tree-based evolutionary history that defines each module. CLIME then expands each module by scanning the genome for new components that likely arose under the inferred evolutionary model. Application of CLIME to ∼1,000 annotated human pathways and to the proteomes of yeast, red algae, and malaria reveals unanticipated evolutionary modularity and coevolving components. CLIME is freely available and should become increasingly powerful with the growing wealth of eukaryotic genomes.
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    MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins
    (Oxford University Press, 2016) Calvo, Sarah; Clauser, Karl R.; Mootha, Vamsi
    Mitochondria are complex organelles that house essential pathways involved in energy metabolism, ion homeostasis, signalling and apoptosis. To understand mitochondrial pathways in health and disease, it is crucial to have an accurate inventory of the organelle's protein components. In 2008, we made substantial progress toward this goal by performing in-depth mass spectrometry of mitochondria from 14 organs, epitope tagging/microscopy and Bayesian integration to assemble MitoCarta (www.broadinstitute.org/pubs/MitoCarta): an inventory of genes encoding mitochondrial-localized proteins and their expression across 14 mouse tissues. Using the same strategy we have now reconstructed this inventory separately for human and for mouse based on (i) improved gene transcript models, (ii) updated literature curation, including results from proteomic analyses of mitochondrial sub-compartments, (iii) improved homology mapping and (iv) updated versions of all seven original data sets. The updated human MitoCarta2.0 consists of 1158 human genes, including 918 genes in the original inventory as well as 240 additional genes. The updated mouse MitoCarta2.0 consists of 1158 genes, including 967 genes in the original inventory plus 191 additional genes. The improved MitoCarta 2.0 inventory provides a molecular framework for system-level analysis of mammalian mitochondria.
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    Atypical Case Of Wolfram Syndrome Revealed Through Targeted Exome Sequencing In A Patient With Suspected Mitochondrial Disease
    (BioMed Central, 2012) Lieber, Daniel Solomon; Vafai, Scott B.; Horton, Laura C; Slate, Nancy G; Liu, Shangtao; Borowsky, Mark L; Calvo, Sarah; Schmahmann, Jeremy; Mootha, Vamsi
    Background: Mitochondrial diseases comprise a diverse set of clinical disorders that affect multiple organ systems with varying severity and age of onset. Due to their clinical and genetic heterogeneity, these diseases are difficult to diagnose. We have developed a targeted exome sequencing approach to improve our ability to properly diagnose mitochondrial diseases and apply it here to an individual patient. Our method targets mitochondrial DNA (mtDNA) and the exons of 1,600 nuclear genes involved in mitochondrial biology or Mendelian disorders with multi-system phenotypes, thereby allowing for simultaneous evaluation of multiple disease loci. Case Presentation: Targeted exome sequencing was performed on a patient initially suspected to have a mitochondrial disorder. The patient presented with diabetes mellitus, diffuse brain atrophy, autonomic neuropathy, optic nerve atrophy, and a severe amnestic syndrome. Further work-up revealed multiple heteroplasmic mtDNA deletions as well as profound thiamine deficiency without a clear nutritional cause. Targeted exome sequencing revealed a homozygous c.1672C > T (p.R558C) missense mutation in exon 8 of WFS1 that has previously been reported in a patient with Wolfram syndrome. Conclusion: This case demonstrates how clinical application of next-generation sequencing technology can enhance the diagnosis of patients suspected to have rare genetic disorders. Furthermore, the finding of unexplained thiamine deficiency in a patient with Wolfram syndrome suggests a potential link between WFS1 biology and thiamine metabolism that has implications for the clinical management of Wolfram syndrome patients.
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    Genomic Analysis of the Basal Lineage Fungus Rhizopus oryzae Reveals a Whole-Genome Duplication
    (Public Library of Science, 2009) Ma, Li-Jun; Ibrahim, Ashraf S.; Skory, Christopher; Grabherr, Manfred G.; Burger, Gertraud; Butler, Margi; Elias, Marek; Idnurm, Alexander; Lang, B. Franz; Sone, Teruo; Abe, Ayumi; Corrochano, Luis M.; Fu, Jianmin; Hansberg, Wilhelm; Kim, Jung-Mi; Kodira, Chinnappa D.; Koehrsen, Michael J.; Miranda-Saavedra, Diego; O'Leary, Sinead; Ortiz-Castellanos, Lucila; Poulter, Russell; Rodriguez-Romero, Julio; Ruiz-Herrera, José; Shen, Yao-Qing; Zeng, Qiandong; Birren, Bruce W.; Cuomo, Christina A.; Wickes, Brian L.; Calvo, Sarah; Engels, Reinhard; Galagan, James E.; Liu, Bo
    Rhizopus oryzae is the primary cause of mucormycosis, an emerging, life-threatening infection characterized by rapid angioinvasive growth with an overall mortality rate that exceeds 50%. As a representative of the paraphyletic basal group of the fungal kingdom called “zygomycetes,” R. oryzae is also used as a model to study fungal evolution. Here we report the genome sequence of R. oryzae strain 99–880, isolated from a fatal case of mucormycosis. The highly repetitive 45.3 Mb genome assembly contains abundant transposable elements (TEs), comprising approximately 20% of the genome. We predicted 13,895 protein-coding genes not overlapping TEs, many of which are paralogous gene pairs. The order and genomic arrangement of the duplicated gene pairs and their common phylogenetic origin provide evidence for an ancestral whole-genome duplication (WGD) event. The WGD resulted in the duplication of nearly all subunits of the protein complexes associated with respiratory electron transport chains, the V-ATPase, and the ubiquitin–proteasome systems. The WGD, together with recent gene duplications, resulted in the expansion of multiple gene families related to cell growth and signal transduction, as well as secreted aspartic protease and subtilase protein families, which are known fungal virulence factors. The duplication of the ergosterol biosynthetic pathway, especially the major azole target, lanosterol 14α-demethylase (ERG11), could contribute to the variable responses of R. oryzae to different azole drugs, including voriconazole and posaconazole. Expanded families of cell-wall synthesis enzymes, essential for fungal cell integrity but absent in mammalian hosts, reveal potential targets for novel and R. oryzae-specific diagnostic and therapeutic treatments.
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    Biallelic C1QBP Mutations Cause Severe Neonatal-, Childhood-, or Later-Onset Cardiomyopathy Associated with Combined Respiratory-Chain Deficiencies
    (Elsevier, 2017) Feichtinger, René G.; Oláhová, Monika; Kishita, Yoshihito; Garone, Caterina; Kremer, Laura S.; Yagi, Mikako; Uchiumi, Takeshi; Jourdain, Alexis A.; Thompson, Kyle; D’Souza, Aaron R.; Kopajtich, Robert; Alston, Charlotte L.; Koch, Johannes; Sperl, Wolfgang; Mastantuono, Elisa; Strom, Tim M.; Wortmann, Saskia B.; Meitinger, Thomas; Pierre, Germaine; Chinnery, Patrick F.; Chrzanowska-Lightowlers, Zofia M.; Lightowlers, Robert N.; DiMauro, Salvatore; Calvo, Sarah; Mootha, Vamsi; Moggio, Maurizio; Sciacco, Monica; Comi, Giacomo P.; Ronchi, Dario; Murayama, Kei; Ohtake, Akira; Rebelo-Guiomar, Pedro; Kohda, Masakazu; Kang, Dongchon; Mayr, Johannes A.; Taylor, Robert W.; Okazaki, Yasushi; Minczuk, Michal; Prokisch, Holger
    Complement component 1 Q subcomponent-binding protein (C1QBP; also known as p32) is a multi-compartmental protein whose precise function remains unknown. It is an evolutionary conserved multifunctional protein localized primarily in the mitochondrial matrix and has roles in inflammation and infection processes, mitochondrial ribosome biogenesis, and regulation of apoptosis and nuclear transcription. It has an N-terminal mitochondrial targeting peptide that is proteolytically processed after import into the mitochondrial matrix, where it forms a homotrimeric complex organized in a doughnut-shaped structure. Although C1QBP has been reported to exert pleiotropic effects on many cellular processes, we report here four individuals from unrelated families where biallelic mutations in C1QBP cause a defect in mitochondrial energy metabolism. Infants presented with cardiomyopathy accompanied by multisystemic involvement (liver, kidney, and brain), and children and adults presented with myopathy and progressive external ophthalmoplegia. Multiple mitochondrial respiratory-chain defects, associated with the accumulation of multiple deletions of mitochondrial DNA in the later-onset myopathic cases, were identified in all affected individuals. Steady-state C1QBP levels were decreased in all individuals’ samples, leading to combined respiratory-chain enzyme deficiency of complexes I, III, and IV. C1qbp−/− mouse embryonic fibroblasts (MEFs) resembled the human disease phenotype by showing multiple defects in oxidative phosphorylation (OXPHOS). Complementation with wild-type, but not mutagenized, C1qbp restored OXPHOS protein levels and mitochondrial enzyme activities in C1qbp−/− MEFs. C1QBP deficiency represents an important mitochondrial disorder associated with a clinical spectrum ranging from infantile lactic acidosis to childhood (cardio)myopathy and late-onset progressive external ophthalmoplegia.
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    Defective mitochondrial rRNA methyltransferase MRM2 causes MELAS-like clinical syndrome
    (Oxford University Press, 2017) Garone, Caterina; D’Souza, Aaron R; Dallabona, Cristina; Lodi, Tiziana; Rebelo-Guiomar, Pedro; Rorbach, Joanna; Donati, Maria Alice; Procopio, Elena; Montomoli, Martino; Guerrini, Renzo; Zeviani, Massimo; Calvo, Sarah; Mootha, Vamsi; DiMauro, Salvatore; Ferrero, Ileana; Minczuk, Michal
    Abstract Defects in nuclear-encoded proteins of the mitochondrial translation machinery cause early-onset and tissue-specific deficiency of one or more OXPHOS complexes. Here, we report a 7-year-old Italian boy with childhood-onset rapidly progressive encephalomyopathy and stroke-like episodes. Multiple OXPHOS defects and decreased mtDNA copy number (40%) were detected in muscle homogenate. Clinical features combined with low level of plasma citrulline were highly suggestive of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, however, the common m.3243 A > G mutation was excluded. Targeted exome sequencing of genes encoding the mitochondrial proteome identified a damaging mutation, c.567 G > A, affecting a highly conserved amino acid residue (p.Gly189Arg) of the MRM2 protein. MRM2 has never before been linked to a human disease and encodes an enzyme responsible for 2’-O-methyl modification at position U1369 in the human mitochondrial 16S rRNA. We generated a knockout yeast model for the orthologous gene that showed a defect in respiration and the reduction of the 2’-O-methyl modification at the equivalent position (U2791) in the yeast mitochondrial 21S rRNA. Complementation with the mrm2 allele carrying the equivalent yeast mutation failed to rescue the respiratory phenotype, which was instead completely rescued by expressing the wild-type allele. Our findings establish that defective MRM2 causes a MELAS-like phenotype, and suggests the genetic screening of the MRM2 gene in patients with a m.3243 A > G negative MELAS-like presentation.
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    The Complete Genome and Proteome of Mycoplasma mobile
    (Cold Spring Harbor Laboratory, 2004-08) Jaffe, JD; Stange-Thomann, N; Smith, Craig; DeCaprio, D; Fisher, Sean; Butler, J; Calvo, Sarah; Elkins, T; FitzGerald, MG; Hafez, N; Kodira, CD; Major, Justin; Wang, Sally; Wilkinson, J; Nicol, R; Nusbaum, C; Birren, B; Berg, HC; Church, George
    Although often considered “minimal” organisms, mycoplasmas show a wide range of diversity with respect to host environment, phenotypic traits, and pathogenicity. Here we report the complete genomic sequence and proteogenomic map for the piscine mycoplasma Mycoplasma mobile, noted for its robust gliding motility. For the first time, proteomic data are used in the primary annotation of a new genome, providing validation of expression for many of the predicted proteins. Several novel features were discovered including a long repeating unit of DNA of ∼2435 bp present in five complete copies that are shown to code for nearly identical yet uniquely expressed proteins. M. mobile has among the lowest DNA GC contents (24.9%) and most reduced set of tRNAs of any organism yet reported (28). Numerous instances of tandem duplication as well as lateral gene transfer are evident in the genome. The multiple available complete genome sequences for other motile and immotile mycoplasmas enabled us to use comparative genomic and phylogenetic methods to suggest several candidate genes that might be involved in motility. The results of these analyses leave open the possibility that gliding motility might have arisen independently more than once in the mycoplasma lineage.
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    GeNets: A unified web platform for network-based analyses of genomic data
    Li, Taibo; Kim, April; Rosenbluh, Joseph; Horn, Heiko; Greenfeld, Liraz; An, David; Zimmer, Andrew; Liberzon, Arthur; Bistline, Jon; Natoli, Ted; Li, Yang; Tsherniak, Aviad; Narayan, Rajiv; Subramanian, Aravind; Liefeld, Ted; Wong, Bang; Thompson, Dawn; Calvo, Sarah; Carr, Steve; Boehm, Jesse; Jaffe, Jake; Mesirov, Jill; Hacohen, Nir; Regev, Aviv; Lage, Kasper