Frederick Roth
Pittsburgh
Systematically testing impacts of genetic change & mapping protein interaction dynamics #VariantEffect #Interactome
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Articles by Frederick Roth
Systematic and proactive evaluation of AIRE missense variant effects
Results Here we undertook missense variant effect mapping for AIRE (outlined in Figure 1A). Because insulin is one of the thousands of genes upregulated by AIRE, because dysregulation of insulin is known to lead to either insulin tolerance or autoimmunity,15 and because insulin autoantibodies are implicated in the development of T1D—a symptom of APS-170,71,72—expression from the insulin promoter was chosen as the basis for our assay to evaluate AIRE function.
Image-based, pooled phenotyping reveals multidimensional, disease-specific variant effects
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Results VIS-seq is a platform for pooled, image-based profiling of thousands of transgenically expressed protein-coding variants (Figure 1A). VIS-seq comprises a cassette with a promoter expressing the protein variant and a second promoter expressing an abundant circular RNA,25,26 which contains one or more barcodes that are sequenced in situ to reveal the identity of the variant expressed in each cell (Figure 1B).
By Sriram Pendyala, Katie Partington, Nicholas Bradley, Abbye E McEwen, Gwenneth Straub, Hyeon-Jin Kim, Shawn Fayer, Daniel Holmes, Katherine A. Sitko, Riddhiman K. Garge, Ziyu Wang, Melinda K Wheelock, Allyssa J. Vandi, Rachel Powell, Clayton E Friedman, Evan McDermot, Nishka Kishore, Frederick Roth, Alan Rubin, Kai-Chun Yang, Lea M. Starita, William Noble, Douglas Fowler
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Cell Press
Verified
Experimental assessment of AI-based interactome mapping
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Abstract Genotype-phenotype relationships are mediated through intricate networks of physical and functional interactions among macromolecules. Knowledge of the interactome is vital to understand and model genetics and cellular biology.
By Luke Lambourne, Anupama Yadav, Yang Wang, Dae-Kyum Kim, Florent Laval, Kerstin Spirohn-Fitzgerald, Tiziana M. Cafarelli, Istvan Kovacs, Noor Jailkhani, David De Ridder, Katja Luck, Olivia Debnath, Yun Shen, Zhipeng Yang, Miles W. Mee, Mohamed Nabil Helmy, Yves Jacob, Irma Lemmens, Thomas Rolland, Atina G Cote, Marinella Gebbia, Nishka Kishore, Jennifer Knapp, Joseph C. Mellor, Gonen Memisoglu, Jüri Reimand, Jan Tavernier, Michael Cusick, Quan Zhong, Patrick Aloy, Benoit Charloteaux, Frederick Roth, Pascal Falter-Braun, David Hill, Michael Calderwood, Jean-Claude Twizere, Marc Vidal, Alice Desbuleux, Sadie Schlabach, Vladimir V. Botchkarev Jr., Wenting Bian, Gregory G. McClain
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Nature
Verified
Landscapes of missense variant impact for human superoxide dismutase 1
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Keywords SOD1 superoxide dismutase ALS amyotrophic lateral sclerosis Lou Gehrig disease MAVE multiplexed assay of variant effect variant-effect mapping deep mutational scanning variant classification Introduction Amyotrophic lateral sclerosis (ALS; MIM: 105400) is a heritable mainly autosomal-dominant neurodegenerative disease with a lifetime prevalence of 1 per 300 people.1,2,3 SOD1 encodes the ubiquitously expressed free-radical-scavenging enzyme Cu2+/Zn2+ superoxide dismutase 1 (MIM:...
By Anna Axakova, Megan X Ding, Atina G Cote, Radha Subramaniam, Vignesh Senguttuvan, Haotian Zhang, Jochen Weile, Marinella Gebbia, Ammar Al-Chalabi, Alexander Wahl, Jason Reuter, Jessica Hurt, Adele Mitchell, Stephanie Fradette, Peter Andersen, Warren van Loggerenberg, Frederick Roth, Samuel V. Douville
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The American Journal of Human Genetics
Verified
A missense variant effect map for the human tumor-suppressor protein CHK2
Keywords CHK2 CHEK2 DNA damage repair tumor suppressor deep mutational scanning variant effect mapping yeast Saccharomyces cerevisiae breast cancer Introduction DNA lesions activate cell-cycle checkpoints, which are important for maintaining genome integrity.1,2,3 CHEK2 (MIM: 604373), a tumor suppressor gene encoding the serine/threonine checkpoint kinase 2 (CHK2), is an important checkpoint regulator of DNA repair, cell-cycle regulation, and apoptosis in response to DNA damage.4 Germline...
Understanding genetic variants in context
Introduction As a consequence of stunning technological advances – especially in DNA-sequencing – current databases hold hundreds of millions of human single-nucleotide variants, with nearly 5 million in the tiny portion of the genome that encodes protein sequence (Figure 1).
Benchmarking computational variant effect predictors by their ability to infer human traits - Genome Biology
F.P.R., D.K., and R.L. conceived of the project idea and designed the study. D.R.T., D.K., and R.L. analyzed data from the UK Biobank cohort; M.L. analyzed data from the cohort, supervised by D.M.R.. D.R.T., K.L., and Y.W. curated variant effect predictor scores for the variants examined in this study. D.R.T. and D.K. carried out predictor benchmarking in the UK Biobank, with help from R.L. and K.L.; D.R.T. and M.L. carried out predictor benchmarking in the cohort.
Characterizing glucokinase variant mechanisms using a multiplexed abundance assay - Genome Biology
In order to assay GCK variant abundance, we used the Dihydrofolate Reductase Protein-Fragment Complementation Assay (DHFR-PCA) [31,32,33,34]. In this system, a methotrexate-resistant mutant of mouse DHFR is split into two fragments. One fragment (DHFR[F3]) is fused to the protein of interest, here GCK, while the other fragment (DHFR [F1,2]) is over-expressed freely.
An Atlas of Variant Effects to understand the genome at nucleotide resolution - Genome Biology
Compiling a complete Atlas of Variant Effects for all 20,000 human genes, not to mention potentially hundreds of thousands of noncoding regulatory elements, will require an international collaborative effort involving thousands of researchers, clinicians and technologists. Comparing this initiative to some of the landmark genomic collaborative achievements of the past 30 years highlights some of the key challenges to be addressed.
A comprehensive map of human glucokinase variant activity - Genome Biology
Buffers TE Buffer: 10 mM Tris–HCl, 1 mM EDTA, pH 8.0. SDS sample buffer (4x): 250 mM Tris/HCl, 8% SDS, 40% glycerol, 0.05% bromophenol blue, 0.05% pyronin G, 2% β-mercaptoethanol, pH 6.8. Plasmids The pancreatic isoform of human GCK (Ensembl ENST00000403799.8) was codon optimized for yeast expression and cloned into pDONR221 (Genscript). The initial test set GCK variants were generated by Genscript.
satmut_utils: a simulation and variant calling package for multiplexed assays of variant effect - Genome Biology
satmut_utils “sim” workflow The satmut_utils “sim” workflow takes a Variant Call Format (VCF) and alignment (BAM) file with paired reads as input and generates variants in the reads at specified frequencies. Outputs are a VCF of true positive (truth) variants and counts, along with edited reads (FASTQ). “sim” is comprised of three overall steps: (1) a single samtools “mpileup” call [71, 72] is made to query reads at each position in the target region.
Next-generation large-scale binary protein interaction network for Drosophila melanogaster - Nature Communications
Generation of a large-scale ORF clone resource The entry clone collection was generated from 11,687 BDGP cDNA gold clones40 (see https://www.fruitfly.org/EST/gold_collection.shtml) using attB-tailed PCR. See below for detailed descriptions of primer design and PCR amplification. The PCR products were quality controlled by detection and sizing on agarose gels as follows.
A proteome-scale map of the SARS-CoV-2–human contactome - Nature Biotechnology
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Abstract Understanding the mechanisms of coronavirus disease 2019 (COVID-19) disease severity to efficiently design therapies for emerging virus variants remains an urgent challenge of the ongoing pandemic. Infection and immune reactions are mediated by direct contacts between viral molecules and the host proteome, and the vast majority of these virus–host contacts (the ‘contactome’) have not been identified.
By Benjamin Weller Verified, Jennifer Knapp, Kerstin Spirohn, Luke Lambourne, Mikko Taipale, David Hill, Christine Brun, Michael Calderwood, Frederick Roth, Dayag Sheykhkarimli, Guillaume Dugied, Andreas Zanzoni, Marie J. Tofaute, Florent Laval, Veronika Young, Juline Poirson, Paolo Giuliana, Yves Jacob, Daniel Krappmann
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Nature
Verified
A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase
Song Sun1,2,3,4,5 na1, Jochen Weile1,2,3,4 na1, Marta Verby1,2,4, Yingzhou Wu1,2,3,4, Yang Wang6,7, Atina G. Cote1,2,4, Iosifina Fotiadou1,2,4, Julia Kitaygorodsky1,2,4, Marc Vidal6,7, Jasper Rine8,9, Pavel Ješina10, Viktor Kožich10 & Frederick P. Roth ORCID: orcid.org/0000-0002-6628-649X1,2,3,4 Genome Medicine volume 12, Article number: 13 (2020) Cite this article Abstract Background For the majority of rare clinical missense variants, pathogenicity status cannot currently be classified.
Don’t put too much faith in home-based gene testing
When people learn I’m a genetics researcher, they often ask if I would recommend home-based gene testing kits — the ones that look at your genetic “variants” to predict your disease risk and uncover details of your ancestry. I’ve had myself and my family tested, using one of the better-known services. I felt that it was money well spent, if you include the novelty, entertainment and educational value.
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