The potential for egg-guarding care in females of the damselfish, Dascyllus reticulatus, in the absence of uniparental male care.

Male damselfish typically demonstrate uniparental egg-guarding care in nature. Potential plasticity in sexual behavior has recently been reported in various teleost fish. To examine behavioral plasticity in parental care, we conducted aquarium experiments to explore the potential for egg-guarding care in the female damselfish, Dascyllus reticulatus. After initial caretaking, males were removed from the mating nests, and cohabiting females frequently exhibited egg predation on the same day. However, we confirmed that females showed significantly decreased egg-predation frequencies on the following day and showed egg-caring behaviors. All experimental females guarded their eggs until they hatched. Females subsequently spawned eggs as females even after performing parental care behaviors, indicating no progression of sex change into males. Molecular analysis of select pituitary gland hormones indicated that egg-caring females and males showed high expression levels of prolactin, suggesting its involvement in the development of parental care behaviors. The cryptic possession of caretaking ability in females may be a tactical response to the need for temporary replacement of the care roles in cases where caretaking males are removed, for example, through predation, in damselfish species living in sexually cohabiting groups.

Massive underrepresentation of Arabs in genomic studies of common disease.

Arabs represent 5% of the world population and have a high prevalence of common disease, yet remain greatly underrepresented in genome-wide association studies, where only 1 in 600 individuals are Arab. We highlight the persistent and unaddressed underrepresentation of Arabs in genomic databases and discuss its impact on public health genomics and missed opportunities for biological discovery.

Clinical utility of polygenic scores for cardiometabolic disease in Arabs.

Arabs account for 5% of the world population and have a high burden of cardiometabolic disease, yet clinical utility of polygenic risk prediction in Arabs remains understudied. Among 5399 Arab patients, we optimize polygenic scores for 10 cardiometabolic traits, achieving a performance that is better than published scores and on par with performance in European-ancestry individuals. Odds ratio per standard deviation (OR per SD) for a type 2 diabetes score was 1.83 (95% CI 1.74-1.92), and each SD of body mass index (BMI) score was associated with 1.18 kg/m2 difference in BMI. Polygenic scores associated with disease independent of conventional risk factors, and also associated with disease severity-OR per SD for coronary artery disease (CAD) was 1.78 (95% CI 1.66-1.90) for three-vessel CAD and 1.41 (95% CI 1.29-1.53) for one-vessel CAD. We propose a pragmatic framework leveraging public data as one way to advance equitable clinical implementation of polygenic scores in non-European populations.

Influence of autozygosity on common disease risk across the phenotypic spectrum.

Autozygosity is associated with rare Mendelian disorders and clinically relevant quantitative traits. We investigated associations between the fraction of the genome in runs of homozygosity (FROH) and common diseases in Genes & Health (n = 23,978 British South Asians), UK Biobank (n = 397,184), and 23andMe. We show that restricting analysis to offspring of first cousins is an effective way of reducing confounding due to social/environmental correlates of FROH. Within this group in G&H+UK Biobank, we found experiment-wide significant associations between FROH and twelve common diseases. We replicated associations with type 2 diabetes (T2D) and post-traumatic stress disorder via within-sibling analysis in 23andMe (median n = 480,282). We estimated that autozygosity due to consanguinity accounts for 5%-18% of T2D cases among British Pakistanis. Our work highlights the possibility of widespread non-additive genetic effects on common diseases and has important implications for global populations with high rates of consanguinity.

S-leaping: an efficient downsampling method for large high-throughput sequencing data.

MOTIVATION: Sequencing coverage is among key determinants considered in the design of omics studies. To help estimate cost-effective sequencing coverage for specific downstream analysis, downsampling, a technique to sample subsets of reads with a specific size, is routinely used. However, as the size of sequencing becomes larger and larger, downsampling becomes computationally challenging. RESULTS: Here, we developed an approximate downsampling method called s-leaping that was designed to efficiently and accurately process large-size data. We compared the performance of s-leaping with state-of-the-art downsampling methods in a range of practical omics-study downsampling settings and found s-leaping to be up to 39% faster than the second-fastest method, with comparable accuracy to the exact downsampling methods. To apply s-leaping on FASTQ data, we developed a light-weight tool called fadso in C. Using whole-genome sequencing data with 208 million reads, we compared fadso's performance with that of a commonly used FASTQ tool with the same downsampling feature and found fadso to be up to 12% faster with 21% lower memory usage, suggesting fadso to have up to 40% higher throughput in a parallel computing setting. AVAILABILITY AND IMPLEMENTATION: The C source code for s-leaping, as well as the fadso package is freely available at https://github.com/hkuwahara/sleaping.

Deep learning identifies and quantifies recombination hotspot determinants.

MOTIVATION: Recombination is one of the essential genetic processes for sexually reproducing organisms, which can happen more frequently in some regions, called recombination hotspots. Although several factors, such as PRDM9 binding motifs, are known to be related to the hotspots, their contributions to the recombination hotspots have not been quantified, and other determinants are yet to be elucidated. Here, we propose a computational method, RHSNet, based on deep learning and signal processing, to identify and quantify the hotspot determinants in a purely data-driven manner, utilizing datasets from various studies, populations, sexes and species. RESULTS: RHSNet can significantly outperform other sequence-based methods on multiple datasets across different species, sexes and studies. In addition to being able to identify hotspot regions and the well-known determinants accurately, more importantly, RHSNet can quantify the determinants that contribute significantly to the recombination hotspot formation in the relation between PRDM9 binding motif, histone modification and GC content. Further cross-sex, cross-population and cross-species studies suggest that the proposed method has the generalization power and potential to identify and quantify the evolutionary determinant motifs. AVAILABILITY AND IMPLEMENTATION: https://github.com/frankchen121212/RHSNet. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Lethal variants in humans: lessons learned from a large molecular autopsy cohort.

BACKGROUND: Molecular autopsy refers to DNA-based identification of the cause of death. Despite recent attempts to broaden its scope, the term remains typically reserved to sudden unexplained death in young adults. In this study, we aim to showcase the utility of molecular autopsy in defining lethal variants in humans. METHODS: We describe our experience with a cohort of 481 cases in whom the cause of premature death was investigated using DNA from the index or relatives (molecular autopsy by proxy). Molecular autopsy tool was typically exome sequencing although some were investigated using targeted approaches in the earlier stages of the study; these include positional mapping, targeted gene sequencing, chromosomal microarray, and gene panels. RESULTS: The study includes 449 cases from consanguineous families and 141 lacked family history (simplex). The age range was embryos to 18 years. A likely causal variant (pathogenic/likely pathogenic) was identified in 63.8% (307/481), a much higher yield compared to the general diagnostic yield (43%) from the same population. The predominance of recessive lethal alleles allowed us to implement molecular autopsy by proxy in 55 couples, and the yield was similarly high (63.6%). We also note the occurrence of biallelic lethal forms of typically non-lethal dominant disorders, sometimes representing a novel bona fide biallelic recessive disease trait. Forty-six disease genes with no OMIM phenotype were identified in the course of this study. The presented data support the candidacy of two other previously reported novel disease genes (FAAH2 and MSN). The focus on lethal phenotypes revealed many examples of interesting phenotypic expansion as well as remarkable variability in clinical presentation. Furthermore, important insights into population genetics and variant interpretation are highlighted based on the results. CONCLUSIONS: Molecular autopsy, broadly defined, proved to be a helpful clinical approach that provides unique insights into lethal variants and the clinical annotation of the human genome.

Identification of Anemia for Predicting Mid-Term Prognosis After Transcatheter Aortic Valve Implantation in Japanese Patients　- Insights From the OCEAN-TAVI Registry.

Background: Patients with anemia have a poor prognosis following transcatheter aortic valve implantation (TAVI). Given the unique distribution of hemoglobin levels in the Japanese cohort, the optimal cut-off hemoglobin value may help stratify Japanese patients' mortality following TAVI. Methods and Results: Data of patients who underwent TAVI were collected from the prospective multicenter Optimized transCathEter vAlvular iNtervention (OCEAN)-TAVI Registry. Receiver operating characteristic analysis was used to calculate a hemoglobin cut-off value to stratify 2-year mortality following TAVI. In all, 2,588 patients (mean [±SD] age 84.4±5.2 years, 795 men) were included in the study. Of these patients, 909 (35.1%) had anemia, which was defined as hemoglobin <10.9 g/dL for men and <10.4 g/dL for women. The presence of anemia, uniquely defined for the Japanese cohort, was independently associated with 2-year mortality following TAVI, with an odds ratio of 1.77 (95% confidence interval 1.39-2.25) adjusted for 14 other clinical variables. Conclusions: The existence of anemia, uniquely defined for the Japanese cohort, was associated with mid-term mortality following TAVI.

Analysis of the effects of related fingerprints on molecular similarity using an eigenvalue entropy approach.

Two-dimensional (2D) chemical fingerprints are widely used as binary features for the quantification of structural similarity of chemical compounds, which is an important step in similarity-based virtual screening (VS). Here, using an eigenvalue-based entropy approach, we identified 2D fingerprints with little to no contribution to shaping the eigenvalue distribution of the feature matrix as related ones and examined the degree to which these related 2D fingerprints influenced molecular similarity scores calculated with the Tanimoto coefficient. Our analysis identified many related fingerprints in publicly available fingerprint schemes and showed that their presence in the feature set could have substantial effects on the similarity scores and bias the outcome of molecular similarity analysis. Our results have implication in the optimal selection of 2D fingerprints for compound similarity analysis and the identification of potential hits for compounds with target biological activity in VS.

Stable maintenance of hidden switches as a strategy to increase the gene expression stability.

In response to severe genetic and environmental perturbations, wild-type organisms can express hidden alternative phenotypes adaptive to such adverse conditions. While our theoretical understanding of the population-level fitness advantage and evolution of phenotypic switching under variable environments has grown, the mechanism by which these organisms maintain phenotypic switching capabilities under static environments remains to be elucidated. Here, using computational simulations, we analyzed the evolution of gene circuits under natural selection and found that different strategies evolved to increase the gene expression stability near the optimum level. In a population comprising bistable individuals, a strategy of maintaining bistability and raising the potential barrier separating the bistable regimes was consistently taken. Our results serve as evidence that hidden bistable switches can be stably maintained during environmental stasis-an essential property enabling the timely release of adaptive alternatives with small genetic changes in the event of substantial perturbations.

Recessive, Deleterious Variants in SMG8 Expand the Role of Nonsense-Mediated Decay in Developmental Disorders in Humans.

We have previously described a heart-, eye-, and brain-malformation syndrome caused by homozygous loss-of-function variants in SMG9, which encodes a critical component of the nonsense-mediated decay (NMD) machinery. Here, we describe four consanguineous families with four different likely deleterious homozygous variants in SMG8, encoding a binding partner of SMG9. The observed phenotype greatly resembles that linked to SMG9 and comprises severe global developmental delay, microcephaly, facial dysmorphism, and variable congenital heart and eye malformations. RNA-seq analysis revealed a general increase in mRNA expression levels with significant overrepresentation of core NMD substrates. We also identified increased phosphorylation of UPF1, a key SMG1-dependent step in NMD, which most likely represents the loss of SMG8--mediated inhibition of SMG1 kinase activity. Our data show that SMG8 and SMG9 deficiency results in overlapping developmental disorders that most likely converge mechanistically on impaired NMD.

B-type Natriuretic Peptide Regulation in Patients with Severe Aortic Stenosis Following Transaortic Valvular Implantation.

Peri-procedural elevated B-type natriuretic peptide (BNP) is also associated with worse outcomes following transcatheter aortic valve implantation (TAVI). However, the mechanism of BNP regulation in patients with severe aortic stenosis (AS) remains unknown. Consecutive patients with severe AS who were referred for TAVI were enrolled in our prospective registry. BNP levels were correlated with other clinical variables. Ninety-six patients (84.7 ± 5.0 years old, 34% males) were investigated in this study. Plasma BNP averaged 353 ± 179 pg/mL. Log10 BNP had no significant correlation with severity of AS including aortic valve area and maximum flow velocity across the aortic valve (P > 0.05 for all), whereas a higher left ventricular end-diastolic dimension (LVDd) index was a significant factor associating with BNP >100 pg/mL with an odds ratio of 1.34 (95% confidence interval 1.06-1.52, P = 0.004) adjusted for several other echocardiographic parameters, with a cutoff of 30.8 mm/m2 (equivalent to LVDd 44 mm). In conclusion, among the patients with severe AS who undergo TAVI, even slight eccentric hypertrophy can cause a considerable increase in BNP level.

Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics.

BACKGROUND: At least 50% of patients with suspected Mendelian disorders remain undiagnosed after whole-exome sequencing (WES), and the extent to which non-coding variants that are not captured by WES contribute to this fraction is unclear. Whole transcriptome sequencing is a promising supplement to WES, although empirical data on the contribution of RNA analysis to the diagnosis of Mendelian diseases on a large scale are scarce. RESULTS: Here, we describe our experience with transcript-deleterious variants (TDVs) based on a cohort of 5647 families with suspected Mendelian diseases. We first interrogate all families for which the respective Mendelian phenotype could be mapped to a single locus to obtain an unbiased estimate of the contribution of TDVs at 18.9%. We examine the entire cohort and find that TDVs account for 15% of all "solved" cases. We compare the results of RT-PCR to in silico prediction. Definitive results from RT-PCR are obtained from blood-derived RNA for the overwhelming majority of variants (84.1%), and only a small minority (2.6%) fail analysis on all available RNA sources (blood-, skin fibroblast-, and urine renal epithelial cells-derived), which has important implications for the clinical application of RNA-seq. We also show that RNA analysis can establish the diagnosis in 13.5% of 155 patients who had received "negative" clinical WES reports. Finally, our data suggest a role for TDVs in modulating penetrance even in otherwise highly penetrant Mendelian disorders. CONCLUSIONS: Our results provide much needed empirical data for the impending implementation of diagnostic RNA-seq in conjunction with genome sequencing.

Paracorporeal Ventricular Assist Device Implantation in a Patient with Transposition of the Great Arteries After Senning Operation.

We experienced a 33-year-old patient with D-looped transposition of the great arteries (D-TGA) and a history of Senning operation who was referred to our institute with cardiogenic shock and subsequently underwent urgent paracorporeal ventricular assist device (VAD) implantation, which was a first in Japan, that was eventually converted to a durable VAD. Central venous pressure was maintained relatively high to obtain VAD filling and recover end-organ dysfunction, given the migration of the inflow cannula due to rich trabeculae carneae of the anatomical right ventricle (systemic ventricle in this case).

Regulation and Clinical Implication of Arginine Vasopressin in Patients with Severe Aortic Stenosis Referred to Trans-Catheter Aortic Valve Implantation.

Background and objectives: Plasma arginine vasopressin (P-AVP) is regulated by the non-osmotic pathway in patients with heart failure (HF) and reduced ejection fraction. However, the regulation of P-AVP in patients with severe aortic stenosis (AS) remains unknown. Materials and Methods: Consecutive patients with severe AS who received trans-catheter aortic valve implantation (TAVI) between Apr 2016 and Apr 2019 were enrolled in this prospective study. Clinical data including P-AVP were obtained just before TAVI, and the correlation between P-AVP and other variables was investigated. Results: In total, 159 patients with severe AS (85.3 ± 4.6 years, male 26%) were enrolled. P-AVP was 1.45 ± 1.13 ng/mL and cardiac index was relatively preserved (2.76 ± 0.54 L/min/m2). There was no significant correlation between cardiac index and P-AVP (p > 0.05), whereas plasma osmolality had a moderate positive correlation with P-AVP (r = 0.35, p < 0.01), predominantly due to blood urea nitrogen (r = 0.27, p < 0.01). Patients with diuretics had significantly higher P-AVP than those without diuretics (1.65 ± 1.43 vs. 1.22 ± 0.57 pg/mL, p < 0.01). Two-year survivals free from HF readmission were statistically comparable irrespective of the level of pre-procedural P-AVP (p = 0.44). Conclusion: In patients with severe high-gradient AS who received TAVI, the P-AVP level was dominantly regulated by plasma osmolality instead of arterial underfilling. The clinical implication of elevated P-AVP in the TAVI candidates is the next concern.

The impact of changes in B-type natriuretic peptide levels on prognosis after transcatheter aortic valve implantation.

Higher B-type natriuretic peptide (BNP) levels at discharge predict higher cardiovascular events in transcatheter aortic valve implantation (TAVI) patients. However, it is not known whether the reduction in BNP levels effectively predicts prognosis. The purpose was to examine the predictive power of percentage changes in BNP levels for all-cause death and hospitalization of heart failure (HF) after TAVI in severe aortic stenosis (AS) patients. We analyzed 70 severe AS patients treated with TAVI who had a record of BNP > 200 pg/mL. Receiver operating characteristics (ROC) curves analysis for all-cause death and hospitalization for HF after TAVI revealed the cut-off percentage change in BNP, and we divided the study population into the "responder group" and the "non-responder group". The cut-off level for the percentage change in BNP evaluated by ROC analysis was a 40% decrease in BNP (AUC = 0.733, p < 0.001). There were 48 patients (68.6%) in the responder group and 22 patients (31.4%) in the non-responder group. Kaplan-Meier estimates showed that the responder group had lower all-cause death and hospitalization for HF than the non-responder group by a log rank test (all-cause mortality; p = 0.006, hospitalization rate for HF; p < 0.001). The predictor of the non-responder group using multivariate logistic regression analysis was AF (OR 4.2, 95% CI 1.15-16.2, p = 0.03). A reduction of BNP was associated with improved prognosis after TAVI.

Clinical Advantages of Using Low Tube Voltage in Third-Generation 192-Slice Dual-Source Computed Tomographic Angiography Before Transcatheter Aortic Valve Implantation.

Low-voltage computed tomographic angiography (CTA) is a highly effective technique to reduce contrast media volume. We sought to examine the suitability of low tube voltage CTA with a reduced contrast media volume protocol using third-generation 192-slice dual-source CT in patients undergoing transcatheter aortic valve implantation (TAVI). CTA was performed to aid TAVI planning for 40 consecutive patients with severe aortic stenosis. For the first 10 patients (120/100 kV group), we used a conventional tube voltage combined CTA protocol (an ECG-gated helical scan; 120 kV, non-gated helical scan; 100 kV). For the subsequent 30 patients (70-kV group), we adopted a low tube voltage CTA protocol. We evaluated vascular attenuation, image noise, contrast-to-noise ratio (CNR), and renal function. The mean contrast media (CM) volume was 77.7 ± 17.7 mL in the 120/100-kV group and 30.9 ± 6.3 mL in the 70-kV group (P < 0.001). In the images of the aortic valve complex, the mean attenuation was not significant difference for both groups. In the images of the aorto-femoral arteries, mean attenuation was > 250 Hounsfield Units and CNR was > 10 in all vascular segments for both groups. There was no significant difference in the change of renal function in the 70-kV group, but renal function in the 120/100-kV group decreased within 1-3 months after CTA. Low tube voltage CTA using third-generation dual-source CT is suitable to assess procedural planning for TAVI. This approach maintains image quality and reduces the required CM volume.

A case of cardiogenic shock due to acute coronary syndrome successfully recovered by percutaneous and paracorporeal left ventricular assist device.

We recently experienced a 70-year-old woman with left main trunk-acute coronary syndrome who was initially supported by Impella 5.0 which converted to paracorporeal left ventricular assist device (LVAD) implantation as a bridge to recovery. Optimized guideline-directed medical therapy with cardiac rehabilitation resulted in successful explantation of LVAD and she discharged on foot.

Promoter analysis and prediction in the human genome using sequence-based deep learning models.

MOTIVATION: Computational identification of promoters is notoriously difficult as human genes often have unique promoter sequences that provide regulation of transcription and interaction with transcription initiation complex. While there are many attempts to develop computational promoter identification methods, we have no reliable tool to analyze long genomic sequences. RESULTS: In this work, we further develop our deep learning approach that was relatively successful to discriminate short promoter and non-promoter sequences. Instead of focusing on the classification accuracy, in this work we predict the exact positions of the transcription start site inside the genomic sequences testing every possible location. We studied human promoters to find effective regions for discrimination and built corresponding deep learning models. These models use adaptively constructed negative set, which iteratively improves the model's discriminative ability. Our method significantly outperforms the previously developed promoter prediction programs by considerably reducing the number of false-positive predictions. We have achieved error-per-1000-bp rate of 0.02 and have 0.31 errors per correct prediction, which is significantly better than the results of other human promoter predictors. AVAILABILITY AND IMPLEMENTATION: The developed method is available as a web server at http://www.cbrc.kaust.edu.sa/PromID/.

Systematic selection of chemical fingerprint features improves the Gibbs energy prediction of biochemical reactions.

MOTIVATION: Accurate and wide-ranging prediction of thermodynamic parameters for biochemical reactions can facilitate deeper insights into the workings and the design of metabolic systems. RESULTS: Here, we introduce a machine learning method with chemical fingerprint-based features for the prediction of the Gibbs free energy of biochemical reactions. From a large pool of 2D fingerprint-based features, this method systematically selects a small number of relevant ones and uses them to construct a regularized linear model. Since a manual selection of 2D structure-based features can be a tedious and time-consuming task, requiring expert knowledge about the structure-activity relationship of chemical compounds, the systematic feature selection step in our method offers a convenient means to identify relevant 2D fingerprint-based features. By comparing our method with state-of-the-art linear regression-based methods for the standard Gibbs free energy prediction, we demonstrated that its prediction accuracy and prediction coverage are most favorable. Our results show direct evidence that a number of 2D fingerprints collectively provide useful information about the Gibbs free energy of biochemical reactions and that our systematic feature selection procedure provides a convenient way to identify them. AVAILABILITY AND IMPLEMENTATION: Our software is freely available for download at http://sfb.kaust.edu.sa/Pages/Software.aspx. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.