Bayesian localization of CNV candidates in WGS data within minutes

Background: Full Bayesian inference for detecting copy number variants (CNV) from whole-genome sequencing (WGS) data is still largely infeasible due to computational demands. A recently introduced approach to perform Forward-Backward Gibbs sampling using dynamic Haar wavelet compression has alleviated issues of convergence and, to some extent, speed. Yet, the problem remains challenging in practice. Results: In this paper, we propose an improved algorithmic framework for this approach. We provide new space-efficient data structures to query sufficient statistics in logarithmic time, based on a linear-Time, in-place transform of the data, which also improves on the compression ratio. We also propose a new approach to efficiently store and update marginal state counts obtained from the Gibbs sampler. Conclusions: Using this approach, we discover several CNV candidates in two rat populations divergently selected for tame and aggressive behavior, consistent with earlier results concerning the domestication syndrome as well as experimental observations. Computationally, we observe a 29.5-fold decrease in memory, an average 5.8-fold speedup, as well as a 191-fold decrease in minor page faults. We also observe that metrics varied greatly in the old implementation, but not the new one. We conjecture that this is due to the better compression scheme. The fully Bayesian segmentation of the entire WGS data set required 3.5 min and 1.24 GB of memory, and can hence be performed on a commodity laptop

Genetic Influences on Brain Gene Expression in Rats Selected for Tameness and Aggression

Inter-individual differences in many behaviors are partly due to genetic differences, but the identification of the genes and variants that influence behavior remains challenging. Here, we studied an F2 intercross of two outbred lines of rats selected for tame and aggressive behavior towards humans for more than 64 generations. By using a mapping approach that is able to identify genetic loci segregating within the lines, we identified four times more loci influencing tameness and aggression than by an approach that assumes fixation of causative alleles, suggesting that many causative loci were not driven to fixation by the selection. We used RNA sequencing in 150 F2 animals to identify hundreds of loci that influence brain gene expression. Several of these loci colocalize with tameness loci and may reflect the same genetic variants. Through analyses of correlations between allele effects on behavior and gene expression, differential expression between the tame and aggressive rat selection lines, and correlations between gene expression and tameness in F2 animals, we identify the genes Gltscr2, Lgi4, Zfp40 and Slc17a7 as candidate contributors to the strikingly different behavior of the tame and aggressive animals

Transcription Factors as Important Regulators of Changes in Behavior through Domestication of Gray Rats: Quantitative Data from RNA Sequencing

Studies on hereditary fixation of the tame-behavior phenotype during animal domestication remain relevant and important because they are of both basic research and applied significance. In model animals, gray rats Rattus norvegicus bred for either an enhancement or reduction in defensive response to humans, for the first time, we used high-throughput RNA sequencing to investigate differential expression of genes in tissue samples from the tegmental region of the midbrain in 2-month-old rats showing either tame or aggressive behavior. A total of 42 differentially expressed genes (DEGs; adjusted p-value   2) were identified, with 20 upregulated and 22 downregulated genes in the tissue samples from tame rats compared with aggressive rats. Among them, three genes encoding transcription factors (TFs) were detected: Ascl3 was upregulated, whereas Fos and Fosb were downregulated in tissue samples from the brains of tame rats brain. Other DEGs were annotated as associated with extracellular matrix components, transporter proteins, the neurotransmitter system, signaling molecules, and immune system proteins. We believe that these DEGs encode proteins that constitute a multifactorial system determining the behavior for which the rats have been artificially selected. We demonstrated that several structural subtypes of E-box motifs—known as binding sites for many developmental TFs of the bHLH class, including the ASCL subfamily of TFs—are enriched in the set of promoters of the DEGs downregulated in the tissue samples of tame rats’. Because ASCL3 may act as a repressor on target genes of other developmental TFs of the bHLH class, we hypothesize that the expression of TF gene Ascl3 in tame rats indicates longer neurogenesis (as compared to aggressive rats), which is a sign of neoteny and domestication. Thus, our domestication model shows a new function of TF ASCL3: it may play the most important role in behavioral changes in animals

On Associations between Fear-Induced Aggression, <i>Bdnf</i> Transcripts, and Serotonin Receptors in the Brains of Norway Rats: An Influence of Antiaggressive Drug TC-2153

The Bdnf (brain-derived neurotrophic factor) gene contains eight regulatory exons (I–VIII) alternatively spliced to the protein-coding exon IX. Only exons I, II, IV, and VI are relatively well studied. The BDNF system and brain serotonergic system are tightly interconnected and associated with aggression. The benzopentathiepine TC-2153 affects both systems and exerts antiaggressive action. Our aim was to evaluate the effects of TC-2153 on the Bdnf exons I–IX’s expressions and serotonin receptors’ mRNA levels in the brain of rats featuring high aggression toward humans (aggressive) or its absence (tame). Aggressive and tame adult male rats were treated once with vehicle or 10 or 20 mg/kg of TC-2153. mRNA was quantified in the cortex, hippocampus, hypothalamus, and midbrain with real-time PCR. Selective breeding for high aggression or its absence affected the serotonin receptors’ and Bdnf exons’ transcripts differentially, depending on the genotype (strain) and brain region. TC-2153 had comprehensive effects on the Bdnf exons’ expressions. The main trend was downregulation in the hypothalamus and midbrain. TC-2153 increased 5-HT1B receptor hypothalamusc mRNA expression. For the first time, an influence of TC-2153 on the expressions of Bdnf regulatory exons and the 5-HT1B receptor was shown, as was an association between Bdnf regulatory exons and fear-induced aggression involving genetic predisposition

Differentially Expressed Genes and Molecular Susceptibility to Human Age-Related Diseases

Mainstream transcriptome profiling of susceptibility versus resistance to age-related diseases (ARDs) is focused on differentially expressed genes (DEGs) specific to gender, age, and pathogeneses. This approach fits in well with predictive, preventive, personalized, participatory medicine and helps understand how, why, when, and what ARDs one can develop depending on their genetic background. Within this mainstream paradigm, we wanted to find out whether the known ARD-linked DEGs available in PubMed can reveal a molecular marker that will serve the purpose in anyone’s any tissue at any time. We sequenced the periaqueductal gray (PAG) transcriptome of tame versus aggressive rats, identified rat-behavior-related DEGs, and compared them with their known homologous animal ARD-linked DEGs. This analysis yielded statistically significant correlations between behavior-related and ARD-susceptibility-related fold changes (log2 values) in the expression of these DEG homologs. We found principal components, PC1 and PC2, corresponding to the half-sum and the half-difference of these log2 values, respectively. With the DEGs linked to ARD susceptibility and ARD resistance in humans used as controls, we verified these principal components. This yielded only one statistically significant common molecular marker for ARDs: an excess of Fcγ receptor IIb suppressing immune cell hyperactivation

Stress Reactivity, Susceptibility to Hypertension, and Differential Expression of Genes in Hypertensive Compared to Normotensive Patients

Although half of hypertensive patients have hypertensive parents, known hypertension-related human loci identified by genome-wide analysis explain only 3% of hypertension heredity. Therefore, mainstream transcriptome profiling of hypertensive subjects addresses differentially expressed genes (DEGs) specific to gender, age, and comorbidities in accordance with predictive preventive personalized participatory medicine treating patients according to their symptoms, individual lifestyle, and genetic background. Within this mainstream paradigm, here, we determined whether, among the known hypertension-related DEGs that we could find, there is any genome-wide hypertension theranostic molecular marker applicable to everyone, everywhere, anytime. Therefore, we sequenced the hippocampal transcriptome of tame and aggressive rats, corresponding to low and high stress reactivity, an increase of which raises hypertensive risk; we identified stress-reactivity-related rat DEGs and compared them with their known homologous hypertension-related animal DEGs. This yielded significant correlations between stress reactivity-related and hypertension-related fold changes (log2 values) of these DEG homologs. We found principal components, PC1 and PC2, corresponding to a half-difference and half-sum of these log2 values. Using the DEGs of hypertensive versus normotensive patients (as the control), we verified the correlations and principal components. This analysis highlighted downregulation of &beta;-protocadherins and hemoglobin as whole-genome hypertension theranostic molecular markers associated with a wide vascular inner diameter and low blood viscosity, respectively

Genetic Architecture of Tameness in a Rat Model of Animal Domestication

A common feature of domestic animals is tameness—i.e., they tolerate and are unafraid of human presence and handling. To gain insight into the genetic basis of tameness and aggression, we studied an intercross between two lines of rats (Rattus norvegicus) selected over >60 generations for increased tameness and increased aggression against humans, respectively. We measured 45 traits, including tameness and aggression, anxiety-related traits, organ weights, and levels of serum components in >700 rats from an intercross population. Using 201 genetic markers, we identified two significant quantitative trait loci (QTL) for tameness. These loci overlap with QTL for adrenal gland weight and for anxiety-related traits and are part of a five-locus epistatic network influencing tameness. An additional QTL influences the occurrence of white coat spots, but shows no significant effect on tameness. The loci described here are important starting points for finding the genes that cause tameness in these rats and potentially in domestic animals in general