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Joshua Chang Mell

Joshua Chang Mell, PhD

Assistant Professor


Department: Microbiology & Immunology

Education

  • PhD - University of California at Davis (2007)

Dr. Mell is an assistant professor in the Department of Microbiology & Immunology at Drexel University College of Medicine.

Research Overview

Research staff: Jocelyn Hammond, Rachel L. Ehrlich, Ariel Gonzalez

Graduate student: Kevin Raible

Former members: Anthony May, Nora Hajnoczky, Josephine Aiyeku

Research Interests

Using genomics to investigate the mechanism, consequences and evolution of genetic recombination, especially in pathogenic bacteria.

Research

Natural transformation of bacterial DNA

The main goal of my research group is to understand how mechanisms of inheritance affect genetic variation, and conversely, how genetic variation affects mechanisms of inheritance (i.e., “the genetics of genetics”). Our primary model system is the human bacterial pathogen Haemophilus influenzae, an important agent of ear infections (otitis media) in children, as well as lung infections associated with chronic respiratory conditions. H. influenzae, like many other pathogens, is naturally competent, able to actively transport environmental DNA through its cell membranes and incorporate homologous molecules into its chromosomes. This pathway, called “natural transformation,” is a major mechanism of gene transfer across bacteria and has a profound effect on genome evolution, including spreading antibiotic resistances and other virulence determinants. Our current research seeks to answer three major questions using a combination of microbiology, molecular genetics and genomics/bioinformatics approaches:

1. What factors control the variability in transformation frequency across the genome?

Map of transformation of bacterial DNA

We have recently generated high-resolution genome-wide maps of transformation frequency, finding >100-fold variation when feeding the DNA of a diverged clinical isolate to a highly competent laboratory strain. This required extremely deep sequencing (>10,000-fold genomic coverage) and novel analytical tools to distinguish true events from sequencing errors. Unexpectedly, the two known sequence determinants, local sequence identity between donor and recipient and the proximity to known “uptake signal sequences,” explain only a small proportion of the variation (~15%). Other unknown factors must contribute, and current work focuses on the potential role for structural proteins that scaffold the bacterial chromosome in limiting access to the DNA at coldspots of transformation. This work has also uncovered a small number of extreme hotspots (>10% transformation frequency), which may reside at loci undergoing strong diversifying selection.

2. Can experimental natural transformation be exploited to map pathogenesis genes?

Diagram of recombinant enrichment

We have developed a novel method for mapping genes in bacteria, exploiting natural transformation in combination with genome-wide deep sequencing. The approach exploits natural competence to generate complex pools of recombinants between a donor carrying a pathogenesis trait of interest and an avirulent recipient. Selection for recombinants that acquired the trait, followed by genome-wide profiling of donor-specific allele frequencies, we can rapidly identify the relevant genes. We have recently used this method to map an operon involved in intracellular invasion of airway epithelial cells, a trait with implications for chronic infection, bacterial persistence, and trafficking of cells to different body sites. Newer work is using the same approach to map the genes responsible for natural variation in resistance to human complement-mediated killing and in vivo pathogenesis in an animal model of otitis media.

3. How do the genomes of bacterial populations change during the course of chronic infections?

Diagram of tests of correlated evolution

In several ongoing collaborations, we are investigating how the genomes of bacteria isolated from patients with chronic infections change over time. The long-term goal of this research is to apply statistical genomic approaches developed by human geneticists to the identification of bacterial virulence factors that contribute to disease in natural populations. Most (but not all) of our current datasets are clinical isolates of H. influenzae, including mutators from pediatric cystic fibrosis, carriage isolates from healthy children attending the same day care center, serially collected isolates from adult patients with chronic obstructive pulmonary disease and isolates collected from the middle ear of children with otitis media upon insertion of tympanostomy tubes. We are applying a variety of genomic methods to identifying putative virulence genes, including machine learning and phylogenetic correlated evolution methods. Other organisms of interest include Gardnerella vaginalis and Burkholderia cepacia.

In addition to the projects described above, our group is actively involved in several additional collaborations as a member of the Center for Genomic Sciences and the Center for Advanced Microbial Processing. These include deep sequencing of HIV and mitochondrial genomes in HIV/AIDS patients, transcriptome analysis of liver hepatocytes infected with HBV, and microbiome analyses of the human brain and the human nasopharynx. Our primary role in these projects is to support the experimental design and data processing of the massively parallel sequencing datasets.

Publications

View a full list of Joshua Chang Mell's publications.

"Extensive co-transformation of natural variation into chromosomes of naturally competent Haemophilus influenzae"
Mell JC, Lee JY, Firme M, Sinha S, and RJ Redfield
Genes|Genetics|Genomes, 4(4): 717-731, 2014

"Natural competence and the evolution of DNA uptake specificity"
Mell JC and RJ Redfield
J. Bact., 196(8): 1471-1483, 2014

"The availability of purine nucleotides regulates natural competence by controlling translation of the competence activator Sxy"
Sinha S, Mell JC, and RJ Redfield
Mol. Micro., 88(6): 1106-1119, 2013

"17 CRP-S regulated genes are required for DNA uptake and transformation in Haemophilus influenzae"
Sinha S, Mell JC, and RJ Redfield
J. Bact., 194(19): 5245-5254, 2012

"Defining the DNA uptake specificity of naturally competent Haemophilus influenzae cells"
Mell JC, Hall IM, and RJ Redfield
Nucleic Acids Res., 40(17): 8536-8549, 2012

"Natural transformation of Gallibacterium anatis"
Kristensen BM, Sinha S, Boyce JD, Bojesen AM, Mell JC, and RJ Redfield
Applied Environ. Micro., 78(14): 4914-4922, 2012

"Molecular evolution under increasing transposable element burden in Drosophila:  A speed-limit on the evolutionary arms race"
Castillo DM, Mell JC, Box KS, and JP Blumenstiel
BMC Evol. Biol., 11: 258, 2011

"Transformation of natural genetic variation into Haemophilus influenzae genomes"
Mell JC, Shumilina S, Hall IM, and RJ Redfield
PLoS Pathogens 7(7):e1002151, 2011

"Superhelical duplex destabilization and the recombination position effect"
Sershen CL, Mell JC, Madden SM, and CJ Benham
PLoS One, 6(6): e20798, 2011

"Genome-wide mapping and assembly of structural variant breakpoints in the mouse"
Quinlan AR, Clark R, Sokolova S, Leibowitz, ML, Zhang Y, Hurles ME, Mell JC, and IM Hall
Genome Research, 20(5): 623-635, 2010

"Cooperative interactions between homologous chromatids during meiosis in Saccharomyces cerevisiae"
Mell JC, Komachi K, Hughes O, and SM Burgess
Genetics, 179: 1125-1127, 2008

"Sites of recombination are local determinants of homolog pairing in Saccharomyces cerevisiae"
Mell JC, Wienholz BL, Salem A, and SM Burgess
Genetics, 179: 773-784, 2008

"Analysis of close stable homolog juxtaposition during meiosis in mutants of Saccharomyces cerevisiae"
Lui DY, Peoples-Holst TL, Mell JC, Wu HY, Dean EW, and SM Burgess
Genetics, 173: 1207-1222, 2006

"Yeast as a Model Genetic Organism"
Mell JC and SM Burgess
Nature Encyclopedia of Life Sciences, London: Nature Publishing Group, 2003


Contact Information


Research Office

Department of Microbiology & Immunology
245 N. 15th Street
Mail Stop 1013A
Philadelphia, PA 19102
Phone: 215.762.1445
Fax: 215.762.1003