Induction and inhibition of Drosophila X chromosome gene expression are both impeded by the dosage compensation complex

Sex chromosomes frequently differ from the autosomes in the frequencies of genes with sexually dimorphic or tissue-specific expression. Multiple hypotheses have been put forth to explain the unique gene content of the X chromosome, including selection against male-beneficial X-linked alleles, expression limits imposed by the haploid dosage of the X in males, and interference by the dosage compensation complex on expression in males. Here, we investigate these hypotheses by examining differential gene expression in Drosophila melanogaster following several treatments that have widespread transcriptomic effects: bacterial infection, viral infection, and abiotic stress. We found that genes that are induced (upregulated) by these biotic and abiotic treatments are frequently under-represented on the X chromosome, but so are those that are repressed (downregulated) following treatment. We further show that whether a gene is bound by the dosage compensation complex in males can largely explain the paucity of both up- and downregulated genes on the X chromosome. Specifically, genes that are bound by the dosage compensation complex, or close to a dosage compensation complex high-affinity site, are unlikely to be up- or downregulated after treatment. This relationship, however, could partially be explained by a correlation between differential expression and breadth of expression across tissues. Nonetheless, our results suggest that dosage compensation complex binding, or the associated chromatin modifications, inhibit both up- and downregulation of X chromosome gene expression within specific contexts, including tissue-specific expression. We propose multiple possible mechanisms of action for the effect, including a role of Males absent on the first, a component of the dosage compensation complex, as a dampener of gene expression variance in both males and females. This effect could explain why the Drosophila X chromosome is depauperate in genes with tissue-specific or induced expression, while the mammalian X has an excess of genes with tissue-specific expression

Genome Diversity and the Origin of the Arabian Horse

The Arabian horse, one of the world\u27s oldest breeds of any domesticated animal, is characterized by natural beauty, graceful movement, athletic endurance, and, as a result of its development in the arid Middle East, the ability to thrive in a hot, dry environment. Here we studied 378 Arabian horses from 12 countries using equine single nucleotide polymorphism (SNP) arrays and whole-genome re-sequencing to examine hypotheses about genomic diversity, population structure, and the relationship of the Arabian to other horse breeds. We identified a high degree of genetic variation and complex ancestry in Arabian horses from the Middle East region. Also, contrary to popular belief, we could detect no significant genomic contribution of the Arabian breed to the Thoroughbred racehorse, including Y chromosome ancestry. However, we found strong evidence for recent interbreeding of Thoroughbreds with Arabians used for flat-racing competitions. Genetic signatures suggestive of selective sweeps across the Arabian breed contain candidate genes for combating oxidative damage during exercise, and within the Straight Egyptian subgroup, for facial morphology. Overall, our data support an origin of the Arabian horse in the Middle East, no evidence for reduced global genetic diversity across the breed, and unique genetic adaptations for both physiology and conformation

Role of plakophilin-2 expression on exercise-related progression of arrhythmogenic right ventricular cardiomyopathy:a translational study

AIMS: Exercise increases arrhythmia risk and cardiomyopathy progression in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients, but the mechanisms remain unknown. We investigated transcriptomic changes caused by endurance training in mice deficient in plakophilin-2 (PKP2cKO), a desmosomal protein important for intercalated disc formation, commonly mutated in ARVC and controls. METHODS AND RESULTS: Exercise alone caused transcriptional downregulation of genes coding intercalated disk proteins. The changes converged with those in sedentary and in exercised PKP2cKO mice. PKP2 loss caused cardiac contractile deficit, decreased muscle mass and increased functional/transcriptomic signatures of apoptosis, despite increased fractional shortening and calcium transient amplitude in single myocytes. Exercise accelerated cardiac dysfunction, an effect dampened by pre-training animals prior to PKP2-KO. Consistent with PKP2-dependent muscle mass deficit, cardiac dimensions in human athletes carrying PKP2 mutations were reduced, compared to matched controls. CONCLUSIONS: We speculate that exercise challenges a cardiomyocyte "desmosomal reserve" which, if impaired genetically (e.g., PKP2 loss), accelerates progression of cardiomyopathy

Orthogonal approaches for surveying genetic variation and its consequences

Supplemental file(s) description: Supplemental Figures and Supplemental Material, Supplemental TablesOur morphological traits, responses to stimuli, and the composition of our microbiomes are all phenotypic adaptations influenced by the genetic variation that defines us. Understanding this multimodal network of relationships requires the analysis of a multitude of orthogonal biological systems. Tailoring our approach to the individual biological outputs and systems allows us to reach a deeper understanding of the evolution, regulation, and interactions among biological processes. When available, we can use genomic data from large populations to establish links between genetic variation and phenotypic adaptation. For instance, positive selection can be inferred from variation computationally and statistically via evidence of selective sweeps. In Chapter 2, I evaluate eight selection scans to detect selective sweeps in domestic dogs, a population with well-documented selection pressures imposed by human preferences for specific morphologies and other traits. Pathogen-driven selective pressures modulate adaptation in the immune response, because hosts must keep up in the host-pathogen arms race. The high energetic cost of mounting an immune response reduces resource availability to other physiological processes. To explore these trade-offs, in Chapter 3 I profile the transcription dynamics of the Drosophila melanogaster innate immune response in a dense time course and I apply a broad range of statistical methods, including temporal clustering, gene set expression analysis, and Granger causality to construct putative gene interactions networks. The interaction of hosts with mutualistic symbionts can drive genetic adaptation in hosts through mutually-beneficial processes. In humans, the gut microbiome provides a wealth of symbiotic interactions. To address whether this mutualistic relationship drives host adaptation, in Chapter 4 I study the influence of host genetics on microbiome composition by performing high-resolution QTL mapping to identify genetic variation in Diversity Outbred mice significantly associated with specific bacterial abundances. This thesis presents three orthogonal approaches for surveying genetic variation and its consequences, using a combination of data collected through three sequencing methods: population genomic data using genotyping, global transcriptome dynamics using RNA-sequencing, and microbiome composition using 16S rRNA gene sequencing

Persian horse genotype data, plink .bim file

Genotype data for Persian horse samples, .bim for plink file se

Persian horse genotype data, plink .fam file

Genotype data for Persian horse samples, .fam file for plink file se

Persian horse genotype data, plink .bed file

Genotype data for Persian horse samples, .bed file for plink file se

Samples Identifier File

List of all samples used, with their sample codes and bree

Data from: Evaluating the performance of selection scans to detect selective sweeps in domestic dogs

Selective breeding of dogs has resulted in repeated artificial selection on breed-specific morphological phenotypes. A number of quantitative trait loci associated with these phenotypes have been identified in genetic mapping studies. We analyzed the population genomic signatures observed around the causal mutations for 12 of these loci in 25 dog breeds, for which we genotyped 25 individuals in each breed. By measuring the population frequencies of the causal mutations in each breed, we identified those breeds in which specific mutations most likely experienced positive selection. These instances were then used as positive controls for assessing the performance of popular statistics to detect selection from population genomic data. We found that artificial selection during dog domestication has left characteristic signatures in the haplotype and nucleotide polymorphism patterns around selected loci that can be detected in the genotype data from a single population sample. However, the sensitivity and accuracy at which such signatures were detected varied widely between loci, the particular statistic used, and the choice of analysis parameters. We observed examples of both hard and soft selective sweeps and detected strong selective events that removed genetic diversity almost entirely over regions >10 Mbp. Our study demonstrates the power and limitations of selection scans in populations with high levels of linkage disequilibrium due to severe founder effects and recent population bottlenecks

Data from: Genetic diversity of Persian Arabian horses and their relationship to other native Iranian horse breeds

The principal aims of this study were to explore genetic diversity and genome-wide selection signatures in Persian Arabian horses and to determine genetic relationship of Persian Arabians with other Iranian horse breeds. We evaluated 71 horses from 8 matrilineal strains tracing to 47 mares from the mid to late 19th century, using the equine 670k SNP BeadChip. Mean observed and expected heterozygosity were (0.43) and (0.45), respectively, average inbreeding measures (FROH and FPED) were low, indicating high genetic diversity in Persian Arabian horses. Analysis of population genetic structure using STRUCTURE and Principal Component Analysis suggested that Persian Arabian horses can be divided into three groups, however the groups do not match traditional matrilineal strains. In total, 15 genomic regions were identified by at least two of the three implemented methods, Tajima’s D, H, and H12, as potentially under selection in Persian Arabian horses. Most of these peaks were found on chromosome 9, overlapping with QTLs previously associated with horse temperament. Biological function analysis of identified candidate genes highlighted enrichment of GO term “response to lipopolysaccharide” and KEGG pathway “chemokine-mediated signaling pathway”, which are associated with immune responses and may have been targets of selection in Persian Arabian horses. Independent analyses of SNP data from 30 horses of four other Iranian breeds suggested distinct population structure between Persian Arabian, and Turkemen and Caspian horse breeds. Overall, the results of this study suggest a rich genetic diversity in the Persian Arabian horses and a clear genetic differentiation with Turkemen and Caspian breeds