John Roth

image of John Roth

Distinguished Professor

Departments

Microbiology and Molecular Genetics

Offices and Labs

314 Briggs Hall
530 752-6679

Degrees

1997 PhD (Honoris Causa) Umeå University, Umeå, Sweden
1965 PhD Biology (Genetics) Johns Hopkins University
1961 BA Biochemical Sciences Harvard College

Research Interests

Origin of Mutations Under Selection

While natural selection is simple to define, it is difficult to follow in natural settings since small-effect mutations often dictate the sequence of events. The high rate at which small-effect mutations arise seems to underlie a controversy that has continued about whether or not the stress of selective growth conditions induces an increase in mutation rate. We propose that growth limitation seems mutagenic because small-effect mutations are more common than generally appreciated and make an unexpectedly large contribution to selective adaptation. We are trying to dissect in detail one system that is often cited as evidence for stress-induced mutagenesis (adaptive mutation). We think we can convince you that it's all about growth under selection and has nothing to do with mutagenesis.

Recombination as an Inside Job

While DNA recombination is generally studied by perfoming genetic crosses in the laboratory, the process of recombination is used internally in bacteria, primarily for DNA repair and replication fork restarting. Sexual recombination is very rare in natural populations. We use chromosome rearrangments in Salmonella to learn about recombination mechanisms. Most recently we've found (to our surprise) that gene duplications arise at an extremely high rate and form by a mechanism that does not require recombination. This is despite the general belief that they form by unequal recombination. Many duplications are not simple tandem repeats but contain direct repeats that flank a central third copy positioned in inverse order (a tandem inversion duplication or TID). We're testing a model in which TIDs form by a series of events initiated by short palindromic sequences in the normal genome. These are then converted by remodeling deletions into the several types of duplications that are commonly studied.

Domesticated transposable elements may dicate species-specific patterns of gene amplification

The chromosomes of enteric bacteria harbor several sets of dispersed repeated sequences that are thought to be derived from ancient transposable elements.  These include REP, BoxC, RSA and ERIC elements.  Despite the inability of these elements to transposose, their sequences and positions appear to be maintained by purifying selection, suggesting that they play a valuable role in cell function.  Two properties are shared by all of these elements --- they are palindromic and are usually found within transcribed regions of the genome.   Recently we've noticed recombination-independent duplications that form between copies of these palindromic elements,  We've also noticed that although these elements are found in many enteric species, particular forms appear to be species specific.  For example the AelRep and LasRep elements consist of an RSA or Eric element with an inserted central palindromic element.   The resulting composite elements are found in virtually all isolates of Salmonella but in no isolate of its closest relative, E. coli.   Convesely the BoxC related BOCE elements are found in E. coli, but ever in Salmonella.   We suggest that palindromic elements dictate endpoints of duplications that are of frequent selective value in the life-styles of various bacteria.  Their palindromic nature allows them to initiate TID duplications as described above.  Duplication formation can be regulated when transcription of the element generates an R-loop, in which the element appears in the excluded sense strand of DNA.  When made single stranded, palindromes can form hairpins or more complex secondary structures that are subject to cutting and initiation of duplicaiton formation.   Similar functionality may be associated ancient elements in metazoan genomes.

A lifestyle that may define a bacterial species

All Salmonellae dedicate 1% of their genome to synthesis of cobalamin (vitamin B12) and another 1% of their genome to use this cofactor for anaerobic growth on two non-fermentable carbon sources -- ethanolamine and propanediol. This constellation of functions must contribute heavily to Salmonella's fitness in a natural setting. Laboratory studies have had difficultly suggesting how these several functions might contribute to success of natural populations. Recently an solution has been suggested by our colleage Andreas Baumler at the UC Davis Medical School. Baumler's lab has shown that these functions contribute together to enhance Salmonella proliferation in an inflammed mouse gut. Salmonella induces gut inflammation and thereby causes the mouse to provide both of the two carbon sources and an repiratory electron acceptor. The inflammed host gut releases ethanolamine and propanediol and oxidizes hydrogen sulfide to tetrathionate which Salmonella can use as electron acceptor. This give Salmonella a source of nutrients that are not availbable to other gut inhabitants. The functions described above (B12 synthesis, ethanolamine and propanediol degradation, tetrathionate oxidation) have been used individually by taxonomists to identify Salmonella. Since essentially all Salmonella isolates show all of the properties, we suggest that these functions may be central to defining the lifestyle that characterizes Salmonellae and selective holds them together as a taxonomic group. Enzymes for catabolizing ethanolamine and propanediol are held within a protein cage or microcompartment that resembles the carboxysome of photosynthetic bacteria. We are trying to determine how this compartment works and how it benefits Salmonella in the wild. We think that understanding this compartment in Salmonella, may help us understand why similar compartments contain enzymes of CO2 fixation in bacteria that perform 30% of the global carbon fixation.

Awards

1974-5 Guggenheim Fellow, Cold Spring Harbor Laboratory
1986 University of Utah Distinguished Research Award
1987 First Governor's Medal for Science and Technology for the State of Utah
1988 Member, National Academy of Sciences
1990 Rosenblatt Prize, University of Utah
1990-2002 Distinguished Professor, University of Utah
1996 Recipient of the James E. Talmage Presidential Endowed Chair in Biology, U. of Utah
1997 Fellow, American Academy of Microbiology
1998 Sackler Fellow at Tel Aviv University, Tel Aviv, Israel
2000-1 Leverhulme Fellow, Oxford University, Oxford, England
2009 Thomas Hunt Morgan Medal, Genetics Society of America
2009 Fellow, American Association for the Advancement of Science
2015 ASM Lifetime Achievement Award (Abbvie)

Department and Center Affiliations

Department of Microbiology

ProfessionalSocieties

American Society for Microbiology
Genetics Society of America
Society for General Microbiology

CBS Grad Group Affiliations

Integrated Genetics and Genomics

Graduate Groups not Housed in CBS

Microbiology

Labs

Briggs 316, 318 website
  • Associates: Eric Kofoid, Sophie Maisnier-Patin, Andrew Reams Undergraduates: Ivy Roush, Mahtab Danai Support staff: Shery Roth, Natalie Duleba

Teaching Interests

Origins of Life
Genetics of Bacteria
Analytical Genetics

Courses

Biology Bis2A Origins and Essentials of Life (Winter)
Genetics GGG201A Analytical Genetics (Fall)

Publications

3/18/2015 3:08:56 PM
  • Maisnier-Patin, S. and John R. Roth (2015)  The origin of mutants under selection:  How natural                  selection mimics mutagenesis (adaptive mutation)  In: Microbial Evolution  
    Editor: Howard Ochman.   Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

  • Reams, A. B. and J. R. Roth (2015)  Mechanisms of Gene Duplication and Amplification   In:  Recombination Mechanisms   Editors: Stephen Kowalczykowski, Neil Hunter and Wolf Heyer   Cold Spring Harbor Laboratory Press,  Cold Spring Harbor, NY

  • Sano, E., S. Maisnier-Patin, J. P. Aboubechara, S. Quinones-Soto, John R. Roth (2014)  Plasmid copy number underlies adaptive mutability in bacteria,  Genetics 198(3):919-33.  PMID: 25173846     PMCID: PMC4224180

  • Reams, A.B., Kofoid, E. Duleba, N. and J. R. Roth (2014) Recombination and annealing
    pathways compete for substrates in making rrn duplications in Salmonella enterica  Genetics 196: 1–17.   PMID: 24214339

  • Huseby, D. and J.R. Roth  (2013) Evidence that a metabolic microcompartment contains and recycles private cofactor pools.   J. Bacteriol. 195: 2864-79   PMID: 23585538 PMC3697265

  • Quiñones-Soto, S., A. B. Reams and J. R. Roth (2012) Pathways of genetic adaptation:Multi-step origin of mutants under selection without induced mutagenesis in Salmonella enterica. Genetics 192; 987-999
  • Reams, A. B. E Kofoid, E. Kugelberg and J. R. Roth. (2012) Multiple pathways of duplication formation with and without recombination (RecA) in Salmonella enterica. Genetics 192: 397–415
  • Näsvall, J, L. Sun, J. R. Roth, Dan I. Andersson (2012) Real-time evolution of new genes by innovation, amplification, and divergence. Science 338, 384-6
  • Roth, J. R. and D. I. Andersson (2012) Poxvirus use a ‘‘Gene Accordion’’ to tune out host defenses. Cell 150:671-2
  • Quiñones-Soto, S. and J. R. Roth (2011) Effect of growth under selection on appearance of chromosomal mutations in Salmonella enterica.  Genetics 189: 37-53  PMID: 21705757   PMC3176110 

  • Andersson, D.I., D. Hughes and J.R. Roth  (2011)   The Origin of Mutants under Selection: Interactions of Mutation, Growth, and Selection    In EcoSal: The Cellular and Molecular Biology of Escherichia coli and Salmonella. ASM Press

  • Thiennimitr, P., S. Winter, M. Wiinter, M. Xavier, V. Tolstikov, D. Huseby, T. Sterzenbach, R. Tsolis, J. R. Roth and A. J. Bäumler (2011) Intestinal inflammation allows Salmonella to use ethanolamine to compete with the microbiota Proc. Natl Acad. Sci (US) 108: 17480–17485

  • Winter, S. E., P, Thiennimitr, M.G. Winter, B. P. Butler, D. L. Huseby, R. W. Crawford, J. M. Russell, C L. Bevins, L. G Adams, R. M. Tsolis, J R. Roth and A J. Bäumler (2010)   Inflammation provides a respiratory electron acceptor for Salmonella in the gut. Nature 467: 426-429

  • Kugelberg, E., E. Kofoid, D. I. Andersson, Y. Lu, J. Mellor, F. P. Roth, and J. R. Roth.  (2010). The tandem inversion duplication in Salmonella enterica: Selection drives unstable precursors to final mutation types. Genetics 185:65-80    PMID: 17082307    PMC2870977

  • Reams, A. B., E. Kofoid, M. Savageau, and J. R. Roth. (2010). Duplication frequency in a population of Salmonella enterica rapidly approaches steady state with or without recombination. Genetics 184:1077-94. PMID: 17082307    PMC2865909

  • Reams, D., Kofoid, E., Savageau, M. and J. R. Roth (2010) Duplication frequency in a population of Salmonella enterica rapidly approaches steady state with or without recombination. Genetics 184: 1077–1094

  • Accumulation of mutants in aging bacterial colonies is due to growth under selection, not stress-induced mutagensis. (2008) Wrande, M, Roth, J. R., Hughes, D. Proc Natl Acad Sci (US) 105:11863-11868
  • Ohno's Dilemma: Evolution of new genes under continuous selection. (2007) Bergthorsson, U., Andersson, D. I. and John. R. Roth Proc Natl Acad Sci (US) 104:17004-9
  • Multiple pathways of selected gene amplification during adaptive mutation. (2006) Kugelberg, E., Kofoid. E., Reams, A.B., Andersson, D.I. and J.R. Roth Proc. Natl Acad. Sci 103:17319-24.
  • Conserving a volatile metabolite: a role for carboxysomes in Salmonella enterica. (2006) Penrod, J. T. and J.R. Roth J. Bacteriol. 188: 2865-74
  • Evidence that feedback inhibition of NAD kinase controls responses to oxidative stress. (2006) Grose, J. H., Joss, L., Velick, S. and J.R. Roth Proc Natl Acad. Sci (US) 103:7601-7606