Convergent Evolution of Chromosomal Sex-Determining Regions in the Animal and Fungal Kingdoms

Sexual identity is governed by sex chromosomes in plants and animals, and by mating type (MAT) loci in fungi. Comparative analysis of the MAT locus from a species cluster of the human fungal pathogen Cryptococcus revealed sequential evolutionary events that fashioned this large, highly unusual region. We hypothesize that MAT evolved via four main steps, beginning with acquisition of genes into two unlinked sex-determining regions, forming independent gene clusters that then fused via chromosomal translocation. A transitional tripolar intermediate state then converted to a bipolar system via gene conversion or recombination between the linked and unlinked sex-determining regions. MAT was subsequently subjected to intra- and interallelic gene conversion and inversions that suppress recombination. These events resemble those that shaped mammalian sex chromosomes, illustrating convergent evolution in sex-determining structures in the animal and fungal kingdoms

Designing Case-control Studies: Decisions About The Controls

The authors quantified, first, the effect of misclassified controls (i.e., individuals who are affected with the disease under study but who are classified as controls) on the ability of a case-control study to detect an association between a disease and a genetic marker, and second, the effect of leaving misclassified controls in the study, as opposed to removing them (thus decreasing sample size). The authors developed an informativeness measure of a study's ability to identify real differences between cases and controls. They then examined this measure's behavior when there are no misclassified controls, when there are misclassified controls, and when there were misclassified controls but they have been removed from the study. The results show that if, for example, 10% of controls are misclassified, the study's informativeness is reduced to approximately 81% of what it would have been in a sample with no misclassified controls, whereas if these misclassified controls are removed from the study, the informativeness is only reduced to about 90%, despite the reduced sample size. If 25% are misclassified, those figures become approximately 56% and 75%, respectively. Thus, leaving the misclassified controls in the control sample is worse than removing them altogether. Finally, the authors illustrate how insufficient power is not necessarily circumvented by having an unlimited number of controls. The formulas provided by the authors enable investigators to make rational decisions about removing misclassified controls or leaving them in

Novel Variants In <i>znf34</i> And Other Brain‐expressed Transcription Factors Are Shared Among Early‐onset Mdd Relatives

There are no known genetic variants with large effects on susceptibility to major depressive disorder (MDD). Although one proposed study approach is to increase sensitivity by increasing sample sizes, another is to focus on families with multiple affected individuals to identify genes with rare or novel variants with strong effects. Choosing the family-based approach, we performed whole-exome analysis on affected individuals (n = 12) across five MDD families, each with at least five affected individuals, early onset, and prepubertal diagnoses. We identified 67 genes where novel deleterious variants were shared among affected relatives. Gene ontology analysis shows that of these 67 genes, 18 encode transcriptional regulators, eight of which are expressed in the human brain, including four KRAB-A box-containing Zn2+ finger repressors. One of these, ZNF34, has been reported as being associated with bipolar disorder and as differentially expressed in bipolar disorder patients compared to healthy controls. We found a novel variant—encoding a non-conservative P17R substitution in the conserved repressor domain of ZNF34 protein—segregating completely with MDD in all available individuals in the family in which it was discovered. Further analysis showed a common ZNF34 coding indel segregating with MDD in a separate family, possibly indicating the presence of an unobserved, linked, rare variant in that particular family. Our results indicate that genes encoding transcription factors expressed in the brain might be an important group of MDD candidate genes and that rare variants in ZNF34 might contribute to susceptibility to MDD and perhaps other affective disorders

Recapitulation of the Sexual Cycle of the Primary Fungal Pathogen Cryptococcus neoformans var. gattii: Implications for an Outbreak on Vancouver Island, Canada

Cryptococcus neoformans is a human fungal pathogen that exists as three distinct varieties or sibling species: the predominantly opportunistic pathogens C. neoformans var. neoformans (serotype D) and C. neoformans var. grubii (serotype A) and the primary pathogen C. neoformans var. gattii (serotypes B and C). While serotypes A and D are cosmopolitan, serotypes B and C are typically restricted to tropical regions. However, serotype B isolates of C. neoformans var. gattii have recently caused an outbreak on Vancouver Island in Canada, highlighting the threat of this fungus and its capacity to infect immunocompetent individuals. Here we report a large-scale analysis of the mating abilities of serotype B and C isolates from diverse sources and identify unusual strains that mate robustly and are suitable for further genetic analysis. Unlike most isolates, which are of both the a and α mating types but are predominantly sterile, the majority of the Vancouver outbreak strains are exclusively of the α mating type and the majority are fertile. In an effort to enhance mating of these isolates, we identified and disrupted the CRG1 gene encoding the GTPase-activating protein involved in attenuating pheromone response. crg1 mutations dramatically increased mating efficiency and enabled mating with otherwise sterile isolates. Our studies provide a genetic and molecular foundation for further studies of this primary pathogen and reveal that the Vancouver Island outbreak may be attributable to a recent recombination event

A Survey Of Putative Anxiety-associated Genes In Panic Disorder Patients With And Without Bladder Symptoms

Background We have previously described a subtype of panic disorder (PD) that we termed ‘bladder syndrome’, characterized by urological and bladder symptoms (and possibly interstitial cystitis) in the patients and/or their family members and confirmed the validity of this subset in family linkage and association analysis. In this study, we determine (a) whether 20 single-nucleotide polymorphisms (SNPs) reported in the literature can be replicated in a new PD dataset and (b) whether dividing the sample into those with and without the ‘bladder syndrome’ can help to resolve the genetic heterogeneity within this new sample. Methods We selected 20 putative associated SNPs from the literature, taken from studies published since 2004. We tested these SNPs for association in a sample of 351 PD patients and 552 controls, and then divided them into subgroups of 92 patients from bladder families and 259 from nonbladder families. Results (a) When analyzed in all PD patients, none of the 20 SNPs appeared to be replicated (except for SLC6A4 from our previous study, but in a sample that overlaps substantially with that in our previous report). (b) However, some intriguing findings emerged when we separated bladder from nonbladder families: SLC6A4, reported by us previously, yielded stronger evidence than before (P=0.0018) when examined only in nonbladder families, and in contrast, is not statistically significant in bladder families. Two other markers yielded nominally significant results in bladder families – rs5751876 in ADORA2A (P=0.046) and rs12579350 in TMEM16B (P=0.035) – but were not significant in nonbladder families. (c) Two markers had noticeably lower P-values when we differentiated the women and analyzed them separately – rs12579350 in TMEM16B (P-value decreased from 0.035, as above, to 0.00055) and a different SNP in ADORA2A, rs4822492 (P-value decreases from 0.07 to 0.028). Significance Our results indicate that most of the 20 reported associations do not hold up when PD is analyzed as one group. However, our findings provide further evidence that PD with bladder symptoms may be genetically different from PD without bladder. We suggest that it is worth pursuing SLC6A4 in nonbladder PD, and ADORA2A and TMEM16B in bladder PD. Also, the possibility of a male–female difference in PD is worth pursuing. We also briefly discuss issues of replication and multiple tests

The Structure of MAT Is Highly Rearranged, with Divergent Gene Alleles Embedded in Syntenic Genomic Regions

<p>The nonrecombining α (blue) and <b>a</b> (yellow) MAT alleles from the divergent but related species are depicted, spanning more than 100–130 kb and including 10 kb of common flank regions on the left and right demarcated by sharp borders with MAT. The original locations of ancient tetrapolar loci proposed to have given rise to MAT are shown in red (ancestral homeodomain locus) and green (ancestral pheromone/receptor locus), with the most ancient genes (encoding homeodomain transcription factors, pheromones and pheromone receptors) bulleted. Genes that show mating type-specific phylogeny are shown in black, and genes with species-specific phylogeny are white. Synteny between the genes with species-specific phylogeny is indicated with grey boxes. Pseudogenes are labeled in blue, and grey bars represent repeated elements in <i>Cn.</i> var. <i>neoformans</i>. Red arrows represent pheromone amplicons.</p

Reconstructing the Ancient MAT Alleles by Inversion-Mediated Rearrangement

<p>Plotting the synonymous mutation rate <i>(K_s)</i> of each protein coding gene in MAT reveals that the different classes of genes in the two least rearranged loci (<i>Cn.</i> var. <i>grubii</i> MATα and C. gattii MAT<b>a</b>; see <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0020384#pbio-0020384-g004" target="_blank">Figure 4</a>) can be clustered by a single inversion. This may represent an ancient linked tetrapolar system—one cluster contains the pheromone and pheromone receptor genes (green bars), and the other a homeodomain-encoding gene (red bar). Transposon remnants are present at the extrapolated inversion breakpoint regions in <i>Cn.</i> var. <i>grubii</i>, as indicated (Tn). <i>K_s</i> cannot be calculated between the <i>SXI1α</i> and <i>SXI2<b>a</b></i> genes, because these are unrelated and not alleles, in contrast to other genes in the locus.</p