In the Lit: To Repeat or Not to Repeat: Repetitive Sequences Regulate Genome Stability in Candida albicans

Genome instability often leads to cell death but can also give rise to innovative genotypic and phenotypic variation through mutation and structural rearrangements. Repetitive sequences and chromatin architecture in particular are critical modulators of recombination and mutability. In Candida albicans, four major classes of repeats exist in the genome: telomeres, subtelomeres, the major repeat sequence (MRS), and the ribosomal DNA (rDNA) locus. Characterization of these loci has revealed how their structure contributes to recombination and either promotes or restricts sequence evolution. The mechanisms of recombination that give rise to genome instability are known for some of these regions, whereas others are generally unexplored. More recent work has revealed additional repetitive elements, including expanded gene families and centromeric repeats that facilitate recombination and genetic innovation. Together, the repeats facilitate C. albicans evolution through construction of novel genotypes that underlie C. albicans adaptive potential and promote persistence across its human host.

Genes 2019, 10(11), 866;

In the Lit: A ‘parameiosis’ drives depolyploidization and homologous recombination in Candida albicans

Meiosis is a conserved tenet of sexual reproduction in eukaryotes, yet this program is seemingly absent from many extant species. In the human fungal pathogen Candida albicans, mating of diploid cells generates tetraploid products that return to the diploid state via a non-meiotic process of depolyploidization known as concerted chromosome loss (CCL). Here, we report that recombination rates are more than three orders of magnitude higher during CCL than during normal mitotic growth. Furthermore, two conserved ‘meiosis-specific’ factors play central roles in CCL as SPO11 mediates DNA double-strand break formation while both SPO11 and REC8 regulate chromosome stability and promote inter-homolog recombination. Unexpectedly, SPO11 also promotes DNA repair and recombination during normal mitotic divisions. These results indicate that C. albicans CCL represents a ‘parameiosis’ that blurs the conventional boundaries between mitosis and meiosis. They also reveal parallels with depolyploidization in mammalian cells and provide potential insights into the evolution of meiosis.

Transitioning to Autumn

As we fully enter the new semester we would like to acknowledge two undergraduates who have recently joined the Anderson Lab team. Shruti Gupta is working with Robert Fillinger investigating filamentation using quantitative genetics and Molly Rambeau is working with Audra Crouch studying the mycobiome in Native American populations. Welcome!

Shruti Gupta

Identifying genes that regulate filamentation in Candida albicans using quantitative genetics. Using RNA-seq from human cells to identify the involved pathways.
Undergraduate Student
Data Analytics major (Biomedical Informatics track), Molecular Genetics minor

Molly Rambeau

Studying the mycobiome in native american populations and determining if shifts in mycobiome is a causation behind rheumatoid arthritis.
Undergraduate Student
Pursuing B.S. in Biology (pre-med track)

Award Announcement – 1F31DE029409-01 to Robert Fillinger

Robert Fillinger was recently awarded Ruth L. Kirschstein National Research Service Award (NRSA) Individual Predoctoral Fellowship (Parent F31) for his project entitled: “Quantitative genetic approaches to Candida albicans oropharyngeal pathogenesis

Project Narrative:
Here, quantitative trait loci (QTL) approaches are developed for parasexual species and applied to identification of genetic differences between Candida albicans strains governing differential abilities to filament or damage epithelial surfaces during oropharyngeal candidiasis and filamentation.

In the Lit: Mechanisms of genome evolution in Candida albicans

The fungus Candida albicans exists as a prevalent commensal and an important opportunistic pathogen that can infect multiple niches of its human host. Recent studies have examined the diploid genome of C. albicans by performing both short-term microevolution studies and comparative genomics on collections of clinical isolates. Common mechanisms driving genome dynamics include accumulation of point mutations, loss of heterozygosity (LOH) events, large-scale chromosomal rearrangements, and even ploidy change, with important consequences for both drug resistance and host adaptation. Evidence for recombination between C. albicans lineages also highlights a role for (para)sex in shaping the species population structure. Ongoing work will continue to define the contributions of genome evolution to phenotypic variation and the role of host pressures in driving adaptive processes.

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.

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.

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
Graduate Student
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.