Focused multidimensional scaling : interactive visualization for exploration of high-dimensional data

BackgroundVisualization is an important tool for generating meaning from scientific data, but the visualization of structures in high-dimensional data (such as from high-throughput assays) presents unique challenges. Dimension reduction methods are key in solving this challenge, but these methods can be misleading- especially when apparent clustering in the dimension-reducing representation is used as the basis for reasoning about relationships within the data.ResultsWe present two interactive visualization tools, distnet and focusedMDS, that help in assessing the validity of a dimension-reducing plot and in interactively exploring relationships between objects in the data. The distnet tool is used to examine discrepancies between the placement of points in a two dimensional visualization and the points' actual similarities in feature space. The focusedMDS tool is an intuitive, interactive multidimensional scaling tool that is useful for exploring the relationships of one particular data point to the others, that might be useful in a personalized medicine framework.ConclusionsWe introduce here two freely available tools for visually exploring and verifying the validity of dimension-reducing visualizations and biological information gained from these. The use of such tools can confirm that conclusions drawn from dimension-reducing visualizations are not simply artifacts of the visualization method, but are real biological insights.Peer reviewe

Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants

Copy number variants (CNVs) are associated with syndromic and severe neurological and psychiatric disorders (SNPDs), such as intellectual disability, epilepsy, schizophrenia, and bipolar disorder. Although considered high-impact, CNVs are also observed in the general population. This presents a diagnostic challenge in evaluating their clinical significance. To estimate the phenotypic differences between CNV carriers and non-carriers regarding general health and well-being, we compared the impact of SNPD-associated CNVs on health, cognition, and socioeconomic phenotypes to the impact of three genome-wide polygenic risk score (PRS) in two Finnish cohorts (FINRISK, n = 23,053 and NFBC1966, n = 4895). The focus was on CNV carriers and PRS extremes who do not have an SNPD diagnosis. We identified high-risk CNVs (DECIPHER CNVs, risk gene deletions, or large [>1 Mb] CNVs) in 744 study participants (2.66%), 36 (4.8%) of whom had a diagnosed SNPD. In the remaining 708 unaffected carriers, we observed lower educational attainment (EA; OR = 0.77 [95% CI 0.66-0.89]) and lower household income (OR = 0.77 [0.66-0.89]). Income-associated CNVs also lowered household income (OR = 0.50 [0.38-0.66]), and CNVs with medical consequences lowered subjective health (OR = 0.48 [0.32-0.72]). The impact of PRSs was broader. At the lowest extreme of PRS for EA, we observed lower EA (OR = 0.31 [0.26-0.37]), lower-income (OR = 0.66 [0.57-0.77]), lower subjective health (OR = 0.72 [0.61-0.83]), and increased mortality (Cox's HR = 1.55 [1.21-1.98]). PRS for intelligence had a similar impact, whereas PRS for schizophrenia did not affect these traits. We conclude that the majority of working-age individuals carrying high-risk CNVs without SNPD diagnosis have a modest impact on morbidity and mortality, as well as the limited impact on income and educational attainment, compared to individuals at the extreme end of common genetic variation. Our findings highlight that the contribution of traditional high-risk variants such as CNVs should be analyzed in a broader genetic context, rather than evaluated in isolation.Peer reviewe

Mouse strain-specific differences in transposable element expression following psychosocial stress

Anxiety disorders are the most frequently reported mental health disorder in Europe and treatment outcomes for approximately 30% of patients remains poor. Development of new therapies has been hindered by the fact that neural mechanisms of anxiety disorders are poorly understood. Anxiety is known to be heritable but genetic studies have failed to identify significant gene variants, and it appears that it may not be fully explained by common genetic variation. Recent work has suggested that this 'missing heritability' may in part be explained by epigenetic mechanisms, which include the regulation of transposable elements (TEs). Transposable elements are mobile genetic elements that possess the capability to move their location within a genome. TEs have been found to be specifically repressed in the rodent brain following stress, and also have been found to be overexpressed in human brain tissues and animal models of several neuropsychiatric disorders including schizophrenia and post-traumatic stress disorder. Given the evidence of transposable element overexpression in human patients and animal models of psychiatric disorders, we hypothesized that rodents who underwent psychosocial stress would have differential expression of TEs corresponding to their resilience or susceptibility to anxiety-like behaviors. In this study we examined the expression of transposable elements in C57BL/6Crl and DBA/2Crl inbred mouse strains following chronic social defeat stress. We also examined the baseline levels of six inbred strains (DBA/2J, A/J, 129S/SvImJ, C3H/HeJ, C57BL/6J, and FVB/NJ) that were previously characterized for innate anxiety levels. Overall expression of transposable elements was examined with RNA sequencing, while the expression of Long Interspered Element 1 (LINE-1) family TEs was evaluated with quantitative real-time PCR. We found that following psychosocial defeat, C57BL/6 and DBA/2 animals had strain-specific differences in transposable element expression in the ventral hippocampus but not the medial prefrontal cortex. In the ventral hippocampus, C57BL/6Crl animals resilient to anxiety-like behaviors appeared to have distinctly different transposable element expression profiles compared to control and resilient C57BL/6Crl animals. Conversely, DBA/2Crl animals susceptible to anxiety-like behaviors appeared to have distinctly different transposable element expression profiles from DBA/2Crl controls. We also observed innate strain differences between C57BL/6Crl and DBA/2Crl animals in both the medial prefrontal cortex and the ventral hippocampus and some differences between the six inbred strains in LINE-1 family TE expression. Our findings of differential transposable element expression in the hippocampus following psychosocial stress fits in with the current work on TE activity in the adult brain, which indicates that TE activity in the hippocampus may contribute to adult somatic neural diversity and plasticity. We suggest that a mechanistic effect of variable TE expression may exist that contributes to an individual's susceptibility or resilience to anxiety-like behaviors. Further work identifying de novo TE insertions at the genomic level needs to be done to identify the specific role that differential TE expression may be playing in the neural response to psychosocial stress

Sleep alterations following exposure to stress predict fear-associated memory impairments in a rodent model of PTSD

Sleep abnormalities, such as insomnia, nightmares, hyper-arousal, and difficulty initiating or maintaining sleep, are diagnostic criteria of posttraumatic stress disorder (PTSD). The vivid dream state, rapid eye movement (REM) sleep, has been implicated in processing emotional memories. We have hypothesized that REM sleep is maladaptive in those suffering from PTSD. However, the precise neurobiological mechanisms regulating sleep disturbances following trauma exposure are poorly understood. Using single prolonged stress (SPS), a well-validated rodent model of PTSD, we measured sleep alterations in response to stressor exposure and over a subsequent 7-day isolation period during which the PTSD-like phenotype develops. SPS resulted in acute increases in REM sleep and transition to REM sleep, and decreased waking in addition to alterations in sleep architecture. The severity of the PTSD-like phenotype was later assessed by measuring freezing levels on a fear-associated memory test. Interestingly, the change in REM sleep following SPS was significantly correlated with freezing behavior during extinction recall assessed more than a week later. Reductions in theta (4-10 Hz) and sigma (10-15 Hz) band power during transition to REM sleep also correlated with impaired fear-associated memory processing. These data reveal that changes in REM sleep, transition to REM sleep, waking, and theta and sigma power may serve as sleep biomarkers to identify individuals with increased susceptibility to PTSD following trauma exposure

A novel variant in SMG9 causes intellectual disability, confirming a role for nonsense-mediated decay components in neurocognitive development

Abstract Biallelic loss-of-function variants in the SMG9 gene, encoding a regulatory subunit of the mRNA nonsense-mediated decay (NMD) machinery, are reported to cause heart and brain malformation syndrome. Here we report five patients from three unrelated families with intellectual disability (ID) and a novel pathogenic SMG9 c.551 T > C p.(Val184Ala) homozygous missense variant, identified using exome sequencing. Sanger sequencing confirmed recessive segregation in each family. SMG9 c.551T > C p.(Val184Ala) is most likely an autozygous variant identical by descent. Characteristic clinical findings in patients were mild to moderate ID, intention tremor, pyramidal signs, dyspraxia, and ocular manifestations. We used RNA sequencing of patients and age- and sex-matched healthy controls to assess the effect of the variant. RNA sequencing revealed that the SMG9 c.551T > C variant did not affect the splicing or expression level of SMG9 gene products, and allele-specific expression analysis did not provide evidence that the nonsense mRNA-induced NMD was affected. Differential gene expression analysis identified prevalent upregulation of genes in patients, including the genes SMOX, OSBP2, GPX3, and ZNF155. These findings suggest that normal SMG9 function may be involved in transcriptional regulation without affecting nonsense mRNA-induced NMD. In conclusion, we demonstrate that the SMG9 c.551T > C missense variant causes a neurodevelopmental disorder and impacts gene expression. NMD components have roles beyond aberrant mRNA degradation that are crucial for neurocognitive development

Sleep alterations following exposure to stress predict fear-associated memory impairments in a rodent model of PTSD

Sleep abnormalities such as insomnia, nightmares, hyper-arousal, and difficulty initiating or maintaining sleep, are diagnostic criteria of post-traumatic stress disorder (PTSD). The vivid dream state, rapid eye movement (REM) sleep, has been implicated in processing emotional memories. We have hypothesized that REM sleep is maladaptive in those suffering from PTSD. However, the precise neurobiological mechanisms regulating these sleep disturbances following trauma exposure are poorly understood. Using single prolonged stress (SPS), a well-validated rodent model of PTSD, we measured sleep alterations in response to stress exposure and over a subsequent 7-day isolation period during which the PTSD-like phenotype develops in rats. SPS resulted in acutely increased REM sleep, transition to REM sleep, and decreased waking in addition to alterations in sleep architecture. The severity of the PTSD-like phenotype was later assessed by measuring freezing levels on a fear-associated memory test. Interestingly, the change in REM sleep following SPS was significantly correlated with freezing behavior during extinction recall assessed more than a week later. We also report reductions in theta (4–10 Hz) and sigma (10–15 Hz) band power during transition to REM sleep which also correlated with impaired fear-associated memory processing. These data reveal that changes in REM sleep, transition to REM sleep, waking, and theta and sigma power may serve as sleep biomarkers to identify individuals with increased susceptibility to PTSD following trauma exposure