PLoS Genetics: New Articles

Five-week-old juvenile gray mouse lemurs (Microcebus murinus) in a hollow tree in Kirindy Forest, Western Madagascar.

Lemurs are the most distantly related non-human primates. A Research Article by Anne Averdam and colleagues in this issue of PLoS Genetics (see Averdam et al., 10.1371/journal.pgen.1000688) shows that lemurs differ considerably from "higher" primates in receptors of natural killer (NK) cells and their ligands. Instead of KIR or Ly49 genes, lemurs substantially expanded and diversified CD94/NKG2 receptors. Remarkably, this novel system of polymorphic and diverse receptors points to combinatorial diversity as a mechanism to increase the NK cell receptor repertoire of lemurs, a finding that was previously unknown for NK cells.

Image Credit: Manfred Eberle, www.phocus.org (German Primate Center - Leibniz Institute for Primate Research, Germany)

Dissection of the Complex Phenotype in Cuticular Mutants of Arabidopsis Reveals a Role of SERRATE as a Mediator

2009-10-30T07:00:00Z

Author Summary

As the skin of a plant, the epidermis mediates a broad set of protective functions which includes defense against abiotic environmental stresses and pathogens. The majority of its barrier capacity is localized to the outermost cell wall, which is covered by a waxy cuticle. Several distinct cuticular mutants in the model plant Arabidopsis produce a remarkable syndrome that is characterized by ectopic cell adhesion and changes in plant morphology. We used these mutants to study the constitution of the cuticle and the activation of the molecular compensatory mechanisms that are important for adaptation. We examined whole-genome responses in these mutants and used an appropriate statistical procedure to reveal the genes which change their expression. We then applied the same approach to the analysis of hundreds of datasets in repositories. The comparison of gene expression profiles identified the gene SERRATE, which encodes a protein of RNA–processing multi-protein complexes, and further analysis revealed that the syndrome is suppressed in double mutants, as predicted. Our finding suggests that the mechanism which operates to control the integrity of the cuticle involves the regulation of small–RNA signaling.

Progressive GAA·TTC Repeat Expansion in Human Cell Lines

2009-10-30T07:00:00Z

Author Summary

The human genome is comprised of the DNA base sequences used by the cell as a blueprint to direct proper cellular function. Changes in this sequence, known as genomic instability, often interfere with vital cellular functions, resulting in genetic disorders. Repetitive DNA sequences are particularly susceptible to genomic instability. Trinucleotide repeat disorders are caused by three base repeat sequences that increase in size when passed from parent to child and during aging. Trinucleotide repeat expansion results in disease when the size of the repeat sequence increases into the pathogenic size range. Our understanding of the mechanisms responsible for these repeat length changes is incomplete and modeling repeat expansion in human cells has proven difficult. Here, we have developed a unique human cellular model of GAA·TTC trinucleotide repeat expansion, the causative mutation in Friedreich ataxia. Using this model, we characterize GAA·TTC expansion in human cells and identify gene transcription as a key regulator of GAA·TTC repeat expansion. The findings of this study provide novel insight into the mechanisms contributing to trinucleotide repeat expansion in human cells and present new implications for certain therapeutic approaches in Friedreich ataxia.

Acquisition of Aneuploidy Provides Increased Fitness during the Evolution of Antifungal Drug Resistance

2009-10-30T07:00:00Z

Author Summary

C. albicans, the most prevalent human fungal pathogen, acquires resistance to fluconazole by genetic alterations that often include changes in the number of chromosomes or chromosome arms (aneuploidy). Here we demonstrate that chromosomal rearrangements resulting in increased gene dosage are the predominant means of acquired resistance to the antifungal drug fluconazole in replicated experimental populations of C. albicans. A specific aneuploidy, isochromosome 5L, which is composed of two copies of the left arm of Chr5, occurs with high frequency and is detectable soon after fluconazole exposure. The early appearance of aneuploidy in some populations is consistent with a model in which C. albicans becomes more permissive of chromosome rearrangements and segregation defects in the presence of fluconazole. The results presented here indicate that the C. albicans genome is highly plastic and imply that exposure to an antifungal drug induces genome reorganization events, some of which provide a fitness advantage in the presence of drug.

The Key Role of Genomics in Modern Vaccine and Drug Design for Emerging Infectious Diseases

2009-10-26T07:00:00Z

It can be argued that the arrival of the “genomics era” has significantly shifted the paradigm of vaccine and therapeutics development from microbiological to sequence-based approaches. Genome sequences provide a previously unattainable route to investigate the mechanisms that underpin pathogenesis. Genomics, transcriptomics, metabolomics, structural genomics, proteomics, and immunomics are being exploited to perfect the identification of targets, to design new vaccines and drugs, and to predict their effects in patients. Furthermore, human genomics and related studies are providing insights into aspects of host biology that are important in infectious disease. This ever-growing body of genomic data and new genome-based approaches will play a critical role in the future to enable timely development of vaccines and therapeutics to control emerging infectious diseases.

2009-10-23T07:00:00Z

Author Summary

Fusion genes, composed of the complete sequence of two or more other genes, are excellent markers of evolution. In addition, fused genes are usually composed of genes with related functions, which makes them useful in inferring function when the function of one of their components is known. We detected a fusion gene in the eukaryotic organism Tetrahymena thermophila that, although composed of only two genes, seems to perform the function of three genes in this organism. To show that this is the case, we expressed the Tetrahymena fused gene in three different yeast strains, each lacking one of these three genes. The Tetrahymena gene was able to rescue the phenotype of all yeast strains, proving that it can perform the functions of the three genes in yeast. Our results highlight another important biochemical characteristic of fusion genes: they can serve as biological shortcuts, allowing a single fusion of two enzymes to functionally replace three independent enzymes.

Mouse HORMAD1 and HORMAD2, Two Conserved Meiotic Chromosomal Proteins, Are Depleted from Synapsed Chromosome Axes with the Help of TRIP13 AAA-ATPase

2009-10-23T07:00:00Z

Author Summary

Generation of haploid gametes in most organisms requires that homologues become connected via crossovers during meiosis. Efficient formation of crossovers depends on HORMA-domain proteins in diverse taxa. These proteins ensure that programmed meiotic DSBs are preferentially repaired from homologues, rather than from sister chromatids. This inter-homologue bias is crucial for homology search and crossovers formation. HORMA-domain proteins have been also implicated in DSB formation, in suppression of synaptonemal complex formation between non-homologous chromosomes, and in the meiotic prophase checkpoint that monitors DSB repair. Despite the importance of HORMA-domain proteins in various organisms, a role for these proteins in mammalian meiosis hasn't been reported. We examined the behaviour of meiotic mouse HORMA-domain proteins—HORMAD1 and HORMAD2—in wild-type and meiotic mutants. HORMAD1/2 preferentially accumulate on unsynapsed chromosome axes. Our data suggest that HORMAD1/2 depletion from chromosomes is a response to synaptonemal complex formation and it that is a conserved process supported by TRIP13/Pch2 AAA-ATPase. Assuming that HORMA-domain functions are conserved in mammals, we speculate that depletion of HORMADs from axes might contribute to the down-regulation of inter-homologue bias and the prophase checkpoint once homology search is completed and synaptonemal complexes form between aligned homologues.