In the Lit: Seasons of change: Mechanisms of genome evolution in human fungal pathogens

Fungi are a diverse kingdom of organisms capable of thriving in various niches across the world including those in close association with multicellular eukaryotes. Fungal pathogens that contribute to human disease reside both within the host as commensal organisms of the microbiota and the environment. Their niche of origin dictates how infection initiates but also places specific selective pressures on the fungal pathogen that contributes to its genome organization and genetic repertoire.

Recent efforts to catalogue genomic variation among major human fungal pathogens have unveiled evolutionary themes that shape the fungal genome. Mechanisms ranging from large scale changes such as aneuploidy and ploidy cycling as well as more targeted mutations like base substitutions and gene copy number variations contribute to the evolution of these species, which are often under multiple competing selective pressures with their host, environment, and other microbes. Here, we provide an overview of the major selective pressures and mechanisms acting to evolve the genome of clinically important fungal pathogens of humans.
https://www.sciencedirect.com/science/article/pii/S1567134819300309?via%3Dihub

In the Lit: Hemizygosity Enables a Mutational Transition Governing Fungal Virulence and Commensalism

Candida albicans is a commensal fungus of human gastrointestinal and reproductive tracts, but also causes life-threatening systemic infections. The balance between colonization and pathogenesis is associated with phenotypic plasticity, with alternative cell states producing different outcomes in a mammalian host. Here, we reveal that gene dosage of a master transcription factor regulates cell differentiation in diploid C. albicans cells, as EFG1 hemizygous cells undergo a phenotypic transition inaccessible to “wild-type” cells with two functional EFG1 alleles.

Notably, clinical isolates are often EFG1 hemizygous and thus licensed to undergo this transition. Phenotypic change corresponds to high-frequency loss of the functional EFG1 allele via de novo mutation or gene conversion events. This phenomenon also occurs during passaging in the gastrointestinal tract with the resulting cell type being hypercompetitive for commensal and systemic infections. A “two-hit” genetic model therefore underlies a key phenotypic transition in C. albicans that enables adaptation to host niches.
https://doi.org/10.1016/j.chom.2019.01.005

Welcome to Audra Crouch

As we approach Spring and end the year’s rotation cycle we are very excited to welcome Audra Crouch to the Anderson lab! Audra will be spearheading the mycobiome work in the lab. Welcome Audra!

Audra Crouch

Studying the mycobiome in native american populations and determining if shifts in mycobiome is a causation behind rheumatoid arthritis
Position:
Graduate Student
Degree:
University of Lynchburg, BS Biomedical Science and Music Performance Minor

In the Lit: Role of Mediator in virulence and antifungal drug resistance in pathogenic fungi

Mediator complex has recently emerged as an important regulator of gene expression in pathogenic fungi. Mediator is a multi-subunit complex of polypeptides involved in transcriptional activation in eukaryotes, with roles including preinitiation complex (PIC) assembly and chromatin remodeling. Within the last decade, Mediator has been shown to play an integral role in regulating virulence gene expression and drug resistance in human fungal pathogens. In some fungi, specific Mediator subunits have been shown to be required for virulence. In Candida species, duplication and expansion of Mediator subunit encoding genes has occurred on at least three occasions (CgMED15 in C. glabrata and MED2/TLO in C. albicans and C. dubliniensis) suggesting important roles for Mediator in the evolution of these pathogens. This review summarises recent developments in our understanding of Mediator in fungal pathogens and the potential for the development of therapeutic drugs to target Mediator functions.
Curr Genet. 2019 Jan 14. https://doi.org/10.1007/s00294-019-00932-8

A Brisk Start to the New Year

Joining us for the third rotation of the academic year are Peter Brechting and Jacqueline Wong from the Department of Microbiology! Jacqueline is continuing to progress on the mycobiome project and Peter is investigating the gamma-clade members of the TLO expanded gene family.

Peter Brechting

Investigating the functional effects of the TLO genes on mitochondrial gene expression in C. albicans
Position:
Graduate Rotation Student
Degree:
Miami University, B.S. Microbiology, Minor in Economics

Jacqueline Wong

Studying the mycobiome in Native American populations and determining if shifts in mycobiome is a causation behind rheumatoid arthritis
Position:
Graduate Rotation Student
Degree:
University of California, Los Angeles B.S. in Microbiology, Immunology, and Molecular Genetics, Minor in Biomedical Research

In the Lit: The association of mannose binding lectin genotype and immune response to Chlamydia pneumoniae: The Strong Heart Study

Cardiovascular disease (CVD) is an important contributor to morbidity and mortality in American Indian communities. The Strong Heart Study (SHS) was initiated in response to the need for population based estimates of cardiovascular disease in American Indians. This study demonstrates that MBL2 genotype associates with immune reactivity to C. pneumoniae in the SHS cohort. Thus, MBL2 may contribute to the progression of cardiovascular disease (CVD) among American Indians indirectly through pathogen interactions in addition to its previously defined roles.

In The Lit: The Galleria mellonella Waxworm Infection Model for Disseminated Candidiasis

Summary: Galleria mellonella serves as an invertebrate model for disseminated candidiasis. Here, we detail the infection protocol and provide supporting data for the model’s effectiveness.

Dunn, M. J., Woodruff, A. L., Anderson, M. Z. The Galleria mellonella Waxworm Infection Model for Disseminated Candidiasis. J. Vis. Exp. (141), e58914, doi:10.3791/58914 (2018).

Rotations Changing with the Leaves

We are excited to welcome Audra Crouch for the second rotation cycle this year! Audra comes from the Department of Microbiology and is rotating with the ongoing microbiome work in the lab.

Audra Crouch

Studying the mycobiome in native american populations and determining if shifts in mycobiome is a causation behind rheumatoid arthritis
Position:
Graduate Rotation Student
Degree:
University of Lynchburg, BS Biomedical Science and Music Performance Minor

Autumn at Ohio State

With the new academic year fully in motion we welcome Pranav Rana as a rotation student in the lab from the Department of Microbiology!

Pranav Rana

Investigating the role of TLO gene family expansion in C. albicans using CRISPR-mediated gene editing
Position:
Graduate Rotation Student
Degree:
University of Idaho, B.S. Microbiology

In The Lit: The Genome of the Human Pathogen Candida albicans Is Shaped by Mutation and Cryptic Sexual Recombination

Abstract: The opportunistic fungal pathogen Candida albicans lacks a conventional sexual program and is thought to evolve, at least primarily, through the clonal acquisition of genetic changes. Here, we performed an analysis of heterozygous diploid genomes from 21 clinical isolates to determine the natural evolutionary processes acting on the C. albicans genome. Mutation and recombination shaped the genomic landscape among the C. albicans isolates. Strain-specific single nucleotide polymorphisms (SNPs) and insertions/deletions (indels) clustered across the genome. Additionally, loss-of-heterozygosity (LOH) events contributed substantially to genotypic variation, with most long-tract LOH events extending to the ends of the chromosomes suggestive of repair via break-induced replication. Consistent with a model of inheritance by descent, most polymorphisms were shared between closely related strains.

However, some isolates contained highly mosaic genomes consistent with strains having experienced interclade recombination during their evolutionary history. A detailed examination of mitochondrial genomes also revealed clear examples of interclade recombination among sequenced strains. These analyses therefore establish that both (para)sexual recombination and mitotic mutational processes drive evolution of this important pathogen. To further facilitate the study of C. albicans genomes, we also introduce an online platform, SNPMap, to examine SNP patterns in sequenced isolates.
https://mbio.asm.org/content/9/5/e01205-18