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The variation graph toolkit (VG) represents genetic variation as a graph. Each path in the graph is a potential haplotype, though most paths are unlikely recombinations of true haplotypes. We augment the VG model with haplotype information to identify which paths are more likely to be correct. For this purpose, we develop a scalable implementation of the graph extension of the positional Burrows-Wheeler transform. We demonstrate the scalability of the new implementation by indexing the 1000 Genomes Project haplotypes. We also develop an algorithm for simplifying variation graphs for k-mer indexing without losing any k-mers in the haplotypes.

Pangenomes reduce reference bias by representing genetic diversity better than a single reference sequence. Yet when comparing a sample to a pangenome, variants in the pangenome that are not part of the sample can be misleading, for example, causing false read mappings. These irrelevant variants are generally rarer in terms of allele frequency, and have previously been dealt with by filtering rare variants. However, this blunt heuristic both fails to remove some irrelevant variants and removes many relevant variants. We propose a new approach that imputes a personalized pangenome subgraph by sampling local haplotypes according to k-mer counts in the reads. We implement the approach in the vg toolkit ( https://github.com/vgteam/vg ) for the Giraffe short-read aligner and compare its accuracy to state-of-the-art methods using human pangenome graphs from the Human Pangenome Reference Consortium. This reduces small variant genotyping errors by four times relative to the Genome Analysis Toolkit and makes short-read structural variant genotyping of known variants competitive with long-read variant discovery methods., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Attention Deficit Hyperactivity Disorder (ADHD) is a pressing concern in pediatric public health, with its prevalence rising among children and teenagers. This study explored the relationship between group-based physical activity and the well-being, resilience, and distress levels of Israeli youth, with a specific focus on those with ADHD symptoms. Methods: This cross-sectional study surveyed 699 Israeli teenagers, assessing their participation in three types of physical activities: unorganized, structured, and the "Five Fingers" program. Data were collected through an online platform and analyzed using ANOVA, t -tests, and multivariable regression models to identify predictors of resilience. Results : Structured, group-based sport activities are associated with higher resilience ( p < 0.01) and lower distress ( p < 0.01) in adolescents. Adolescents with ADHD symptoms exhibited lower resilience ( p < 0.001) and well-being ( p < 0.001), and higher distress ( p < 0.001). However, those with ADHD symptoms who participated in group-based activities fared better in terms of distress ( p < 0.01) and well-being ( p = 0.018) than those who did not. Participation in any sport activity, older age, male gender, and a higher socio-economic status predicted greater resilience in youth, generally. Conclusions : This study presents the potential of structured physical activities that involve psychosocial and group integration training to improve the mental health of adolescents, especially in the context of ADHD symptoms.

The artery of Bernasconi and Cassinari is a small infraclinoid branch of the internal carotid artery that originates from its cavernous segment and then runs along the tentorium. Because of its gracile appearance, it is often visible only when related to neoplasms and vascular lesions in the tentorial regions. 1 Dural arteriovenous fistulas (dAVFs) are arteriovenous shunts contained within the dural leaflets, supplied largely by the regional meningeal arteries and classified based on the type of venous drainage. Tentorial dAVFs are mostly supplied by branches of the meningohypophyseal trunk, including the artery of Bernasconi and Cassinari. 2 Unlike fistulas of other locations, tentorial fistulas are linked with a higher risk for venous hypertension and hemorrhage and thus demand immediate and appropriate treatment. 3 Digital subtraction angiography is necessary to understand its arterial and venous components. Treatment aims to achieve complete embolization of the fistulous connection and venous portions by either a transarterial or transvenous approach, without causing serious changes in the flow dynamics. 4, 5 ., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Pangenome references address biases of reference genomes by storing a representative set of diverse haplotypes and their alignment, usually as a graph. Alternate alleles determined by variant callers can be used to construct pangenome graphs, but advances in long-read sequencing are leading to widely available, high-quality phased assemblies. Constructing a pangenome graph directly from assemblies, as opposed to variant calls, leverages the graph's ability to represent variation at different scales. Here we present the Minigraph-Cactus pangenome pipeline, which creates pangenomes directly from whole-genome alignments, and demonstrate its ability to scale to 90 human haplotypes from the Human Pangenome Reference Consortium. The method builds graphs containing all forms of genetic variation while allowing use of current mapping and genotyping tools. We measure the effect of the quality and completeness of reference genomes used for analysis within the pangenomes and show that using the CHM13 reference from the Telomere-to-Telomere Consortium improves the accuracy of our methods. We also demonstrate construction of a Drosophila melanogaster pangenome., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Despite great interest in how dynamic fluctuations in psychological states such as mood, social safety, energy, present-focused attention, and burnout impact stress, well-being, and health, most studies examining these constructs use retrospective assessments with relatively long time-lags. Here, we discuss how ecological momentary assessments (EMAs) address methodological issues associated with retrospective reports to help reveal dynamic associations between psychological states at small timescales that are often missed in stress and health research. In addition to helping researchers characterize daily and within-day fluctuations and temporal dynamics between different health-relevant processes, EMAs can elucidate mechanisms through which interventions reduce stress and enhance well-being. EMAs can also be used to identify changes that precede critical health events, which can in turn be used to deliver ecological momentary interventions, or just-in-time interventions, to help prevent such events from occurring. To enable this work, we provide examples of scales and single-item questions used in EMA studies, recommend study designs and statistical approaches that capitalize on EMA data, and discuss limitations of EMA methods. In doing so, we aim to demonstrate how, when used carefully, EMA methods are well poised to greatly advance our understanding of how intrapersonal dynamics affect stress levels, well-being, and human health.

Mental health disorders are an increasing global public health concern that contribute to morbidity, mortality, disability, and healthcare costs across the world. Biomedical and psychological research has come a long way in identifying the importance of mental health and its impact on behavioral risk factors, physiological health, and overall quality of life. Despite this, access to psychological and psychiatric services remains widely unavailable and is a challenge for many healthcare systems, particularly those in developing countries. This review article highlights the strengths and opportunities brought forward by digital mental health in narrowing this divide. Further, it points to the economic and societal benefits of effectively managing mental illness, making a case for investing resources into mental healthcare as a larger priority for large non-governmental organizations and individual nations across the globe.

Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals 1 . These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected per haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample., (© 2023. The Author(s).)

Pangenomics is emerging as a powerful computational paradigm in bioinformatics. This field uses population-level genome reference structures, typically consisting of a sequence graph, to mitigate reference bias and facilitate analyses that were challenging with previous reference-based methods. In this work, we extend these methods into transcriptomics to analyze sequencing data using the pantranscriptome: a population-level transcriptomic reference. Our toolchain, which consists of additions to the VG toolkit and a standalone tool, RPVG, can construct spliced pangenome graphs, map RNA sequencing data to these graphs, and perform haplotype-aware expression quantification of transcripts in a pantranscriptome. We show that this workflow improves accuracy over state-of-the-art RNA sequencing mapping methods, and that it can efficiently quantify haplotype-specific transcript expression without needing to characterize the haplotypes of a sample beforehand., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

(1) Background: Multiple Sclerosis (MS) is a chronic, progressive, immune-mediated disorder that affects the Central Nervous System and is the most common cause of non-traumatic neurological disability in young adults. The study aimed to assess the levels of stress, resilience, well-being, sleep quality, and fatigue in Israeli people with MS (PwMS), and to examine the associations between these factors and the sociodemographic and clinical characteristics. These factors had never before been studied in conjunction in PwMS, nor had they been systematically addressed in Israel, the unique geopolitical situation of which may pose unique challenges. (2) Methods: This was a survey-based, cross-sectional study conducted through an Internet platform. (3) Results: Israeli PwMS who participated in the study were experiencing relatively high levels of stress and low resilience, poor sleep quality, and severe fatigue. The analysis revealed significant associations between resilience and stress, well-being, and anxiety, as well as stress and well-being, resilience, sleep quality, fatigue, and Clinically Isolated Syndrome (CIS). (4) Conclusions: the Israeli PwMS who participated in the study were experiencing higher levels of stress, lower resilience and worse sleep quality than PwMS in other countries, as compared to results previously reported in literature. The findings of this study ought to serve as a call to action for the MS care providers in Israel and warrant further research into the possible causes of the phenomenon and strategies to address it.

(1) Background: Social distancing became a central strategy employed to limit the spread of the SARS-CoV-2 virus. We explore self-reported adherence (SRA) and factors associated with SRA among Israeli adults at the end of the first national lockdown in Israel. (2) Methods: We conducted a cross-sectional consumer panel survey of 820 Israeli adults aged 18 to 70 in May and June 2020. We collected data on the SRA to the social distancing measures, sociodemographic variables, perceptions of pandemic-related danger and of protection provided by the social distancing measures, as well as Sense of Coherence (SoC). (3) Results: 60% of respondents reported complying with 7 measures. Higher SoC was associated with higher SRA (p = 0.04), and was related to income, marital status, age, profession, and education. The SRA was higher among Jews than Arabs (Jews: Mean = 10.5, SD = 4.5; Arabs: Mean = 9.1, SD = 4.1, p < 0.001) and among males (Males: Mean = 10.8, SD = 4.7; Females: Mean = 9, SD = 4.1; p = 0.003). SoC, perception of protection and perception of danger were associated with higher SRA (p = 0.42, p < 0.001 and p = 0.005 respectively). Single people reported higher levels of SRA than people in relationships (Partnered: Mean = 9.7, SD = 4.2, Non-partnered: Mean = 10.9, SD = 4.7, p = 0.033). (4) Conclusions: At the time of exit from the first lockdown, compliance with social distancing measures was high, with Jewish, single and male Israelis more likely to adhere to the guidelines. We identified the populations at risk for non-adherence and associated factors, reporting for the first time the correlation between SoC and SRA. Further research is needed to assess the role of these factors in Jewish and Arab populations.

The human reference genome is the most widely used resource in human genetics and is due for a major update. Its current structure is a linear composite of merged haplotypes from more than 20 people, with a single individual comprising most of the sequence. It contains biases and errors within a framework that does not represent global human genomic variation. A high-quality reference with global representation of common variants, including single-nucleotide variants, structural variants and functional elements, is needed. The Human Pangenome Reference Consortium aims to create a more sophisticated and complete human reference genome with a graph-based, telomere-to-telomere representation of global genomic diversity. Here we leverage innovations in technology, study design and global partnerships with the goal of constructing the highest-possible quality human pangenome reference. Our goal is to improve data representation and streamline analyses to enable routine assembly of complete diploid genomes. With attention to ethical frameworks, the human pangenome reference will contain a more accurate and diverse representation of global genomic variation, improve gene-disease association studies across populations, expand the scope of genomics research to the most repetitive and polymorphic regions of the genome, and serve as the ultimate genetic resource for future biomedical research and precision medicine., (© 2022. Springer Nature Limited.)

We introduce Giraffe, a pangenome short-read mapper that can efficiently map to a collection of haplotypes threaded through a sequence graph. Giraffe maps sequencing reads to thousands of human genomes at a speed comparable to that of standard methods mapping to a single reference genome. The increased mapping accuracy enables downstream improvements in genome-wide genotyping pipelines for both small variants and larger structural variants. We used Giraffe to genotype 167,000 structural variants, discovered in long-read studies, in 5202 diverse human genomes that were sequenced using short reads. We conclude that pangenomics facilitates a more comprehensive characterization of variation and, as a result, has the potential to improve many genomic analyses.

The objective of this study was to estimate the probability of long-term overall survival based on total number of risk factors (RF). We also sought to examine the role of midlife clinical, behavioral, and psychosocial predictors of longevity in a large cohort of Israeli men. This study was based on the Israeli Ischemic Heart Disease (IIHD) cohort that included over 10,000 men who were followed up for mortality over more than four decades. During the 43 years of follow-up, 4634 (46.1%) men survived to 80 years of age or older. We considered cigarette smoking, diabetes mellitus, high systolic blood pressure, hypercholesterolemia, low socioeconomic status, and serious family problems as RF at ages 40-65. Cox proportional hazards regression models, with age as the time scale, were constructed to estimate the hazard ratios (HRs) for failure to survive 80 years of age. Compared with men free of all the above RF, those with one identified RF (HR = 1.58, 95% CI: 1.42-1.75) and counterparts with two identified RF (HR = 2.18, 95% CI: 1.96-2.43) were at a significantly greater risk of death before 80. Additional RF further increased the risk of early mortality (HR = 3.62, 95% CI: 1.50-8.73 for men with 5 RF). The results suggest a role of physiological, behavioral, and psychological risk factors at midlife in predicting longevity.

Importance: The high risk for breast and ovarian cancers conferred by being a carrier of BRCA1 or BRCA2 germline variant can negatively impact physical and psychological well-being. Novel nonpharmacological interventions on well-being in women with BRCA variants have rarely been reported., Objective: To determine the effect of a 12-week inquiry-based stress reduction (IBSR) program on psychological well-being, sleep quality, psychosocial variables, and attitudes toward risk-reducing surgical procedures among women in Israel who carried BRCA variants., Design, Setting, and Participants: This randomized clinical trial had a 12-week intervention period and a 12-week follow-up period. It was conducted between April 1, 2017, and July 31, 2020. Participants were recruited from the Meirav Breast Center at the Sheba Medical Center, Israel, and the intervention was conducted in Tel Aviv, Israel. The cohort included women with BRCA variants. Data were analyzed from August 1 to December 1, 2020., Interventions: Women were randomly assigned to the 12-week IBSR program or standard care. The IBSR technique is based on the skills of mindfulness, inquiry, and cognitive reframing. The intervention included standardized, weekly group meetings conducted throughout 12 weeks. Standard care included semi-annual breast examinations and breast magnetic resonance imaging (alternating), a gynecological examination, a transvaginal ultrasonographic examination, and CA-125 serum determination. Differences between the groups were tested using mixed-effects models in an intent to treat analysis., Main Outcomes and Measures: The primary outcome was psychological well-being, including 6 parameters: autonomy, personal growth, positive relationships, control of the environment, goals in life, and self-acceptance. Secondary outcomes included sleep quality, attitudes toward risk-reducing surgical procedures, and psychosocial variables. Questionnaires were administered at baseline (T1), at completion of the 12-week intervention (T2), and 12 weeks after completion of the intervention (T3)., Results: Overall, 100 women (mean [SD] age, 41.37 [11.06] years) completed the study, with 50 randomized to the intervention group and 50 randomized to the control group. Mean (SD) time from variant discovery was 4.7 (3.3) years. There were no differences between the intervention and control groups in baseline mean (SD) scores of psychological well-being parameters (autonomy: 55.20 [11.12] vs 56.77 [9.90]; environmental control: 56.30 [11.98 vs 58.51 [11.41]; positive relationships: 63.10 [15.91] vs 68.10 [9.86]; goals in life: 60.00 [14.12] vs 64.82 [10.57]; self-acceptance: 55.02 [16.62] vs 60.32 [13.50]) except personal growth (63.70 [14.66] vs 68.85 [8.07]). The IBSR group, compared with the control group, experienced better mean (SD) scores on all psychological well-being parameters at T2 (autonomy: 63.64 [8.35] vs 54.73 [10.41]; environmental control: 63.95 [10.05] vs 57.45 [11.43]; personal growth: 73.00 [8.34] vs 65.76 [10.95]; positive relationships 71.17 [9.99] vs 65.06 [12.58]; goals in life: 67.57 [8.88] vs 61.18 [12.87]; self-acceptance: 66.93 [11.15] vs 58.09 [15.55]) and at T3 (autonomy: 62.68 [9.05] vs 56.12 [10.64]; environmental control: 64.55 [10.28] vs 59.35 [12.98]; personal growth: 72.00 [8.06] vs 67.15 [11.82]; positive relationships: 71.24 [9.78] vs 66.92 [12.37]; goals in life: 68.33 [8.54] vs 62.92 [13.24]; self-acceptance: 66.84 [11.35] vs 58.97 [17.03]). Individuals in the IBSR group also experienced statistically significant improvements in sleep quality (mean [SD]: T1, 7.35 [3.97]; T3, 4.63 [3.21], P < .001), whereas the control group experienced no statistically significant difference. Women in the intervention group had a more favorable consideration of risk-reducing oophorectomy, from 7 women (14%) who refused to consider oophorectomy at T1 to 1 woman (2%) who refused to consider it at T3 (P = .04), and similar change in consideration of mastectomy: from 23 women (46%) who refused to consider mastectomy at T1 to 13 women (29%) who refused to consider it at T3 (P < .001)., Conclusions and Relevance: This randomized clinical trial found that IBSR improved psychological well-being and led to a more favorable view on risk-reducing surgical procedures for at least 6 months among women in Israel who carried BRCA variants. These results suggest that IBSR may be implemented as a self-practice tool to enhance the well-being of individuals who carry BRCA variants and support them in their decision-making processes., Trial Registration: ClinicalTrials.gov Identifier: NCT03162276.

(1) Background: Self-esteem plays an important role in developing emotional resilience and wellbeing in children. Yet, there has been little related research on Cognitive Behavioral Group Therapy on this topic. Our aims were to assess the effect of the Child Self-Esteem CBT (CSE-CBT) protocol on children's self-esteem in grades five and six; to assess the effect of the CSE-CBT protocol on the therapeutic process; and to explore the feasibility of delivering the CSE-CBT protocol in a school setting. (2) Methods: Eighty elementary school children in grades five and six, divided into four intervention and four control groups, attended 12 structured sessions using the CSE-CBT protocol, led by specially trained teachers. The children completed questionnaires to assess their self-esteem at the beginning and at the end of the study, and answered weekly questionnaires that assessed therapeutic process. Hierarchical linear modeling was used to analyze the data. (3) Results: The CSE-CBT protocol had a significant effect on improving children's self-esteem over the course of the study, regardless of the children's working alliance with the teacher leading the group. (4) Conclusions: The findings suggest that the CSE-CBT protocol has the potential to benefit children's self-esteem and indicate that school teachers can be trained to administer the CBT-protocol.

The neural molecular and biochemical response to stress is a distinct physiological process, and multiple lines of evidence indicate that the prefrontal cortex (PFC) is particularly sensitive to, and afflicted by, exposure to stress. Largely through this PFC dysfunction, stress has a characterized role in facilitating cognitive impairment, which is often dissociable from its effects on non-cognitive behaviors. The Rap1 small GTPase pathway has emerged as a commonly disrupted intracellular target in neuropsychiatric conditions, whether it be via alterations in Rap1 expression or through alterations in the expression of direct and specific upstream Rap1 activators and inhibitors. Here we demonstrate that escalating, intermittent stress increases Rap1 in mouse PFC synapses, results in cognitive impairments, and reduces the preponderance of mature dendritic spines in PFC neurons. Using viral-mediated gene transfer, we reveal that the hyper-induction of Rap1 in the PFC is sufficient to drive stress-relevant cognitive and synaptic phenotypes. These findings point to Rap1 as a critical mediator of stress-driven neuronal and behavioral pathology and highlight a previously unrecognized involvement for Rap1 in novelty-driven PFC engagement., (© 2020. The Author(s), under exclusive licence to Springer Nature Limited.)

Motivation: Pangenomics is a growing field within computational genomics. Many pangenomic analyses use bidirected sequence graphs as their core data model. However, implementing and correctly using this data model can be difficult, and the scale of pangenomic datasets can be challenging to work at. These challenges have impeded progress in this field., Results: Here, we present a stack of two C++ libraries, libbdsg and libhandlegraph, which use a simple, field-proven interface, designed to expose elementary features of these graphs while preventing common graph manipulation mistakes. The libraries also provide a Python binding. Using a diverse collection of pangenome graphs, we demonstrate that these tools allow for efficient construction and manipulation of large genome graphs with dense variation. For instance, the speed and memory usage are up to an order of magnitude better than the prior graph implementation in the VG toolkit, which has now transitioned to using libbdsg's implementations., Availability and Implementation: libhandlegraph and libbdsg are available under an MIT License from https://github.com/vgteam/libhandlegraph and https://github.com/vgteam/libbdsg., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

New genome assemblies have been arriving at a rapidly increasing pace, thanks to decreases in sequencing costs and improvements in third-generation sequencing technologies 1-3 . For example, the number of vertebrate genome assemblies currently in the NCBI (National Center for Biotechnology Information) database 4 increased by more than 50% to 1,485 assemblies in the year from July 2018 to July 2019. In addition to this influx of assemblies from different species, new human de novo assemblies 5 are being produced, which enable the analysis of not only small polymorphisms, but also complex, large-scale structural differences between human individuals and haplotypes. This coming era and its unprecedented amount of data offer the opportunity to uncover many insights into genome evolution but also present challenges in how to adapt current analysis methods to meet the increased scale. Cactus 6 , a reference-free multiple genome alignment program, has been shown to be highly accurate, but the existing implementation scales poorly with increasing numbers of genomes, and struggles in regions of highly duplicated sequences. Here we describe progressive extensions to Cactus to create Progressive Cactus, which enables the reference-free alignment of tens to thousands of large vertebrate genomes while maintaining high alignment quality. We describe results from an alignment of more than 600 amniote genomes, which is to our knowledge the largest multiple vertebrate genome alignment created so far.

Low-cost whole-genome assembly has enabled the collection of haplotype-resolved pangenomes for numerous organisms. In turn, this technological change is encouraging the development of methods that can precisely address the sequence and variation described in large collections of related genomes. These approaches often use graphical models of the pangenome to support algorithms for sequence alignment, visualization, functional genomics, and association studies. The additional information provided to these methods by the pangenome allows them to achieve superior performance on a variety of bioinformatic tasks, including read alignment, variant calling, and genotyping. Pangenome graphs stand to become a ubiquitous tool in genomics. Although it is unclear whether they will replace linearreference genomes, their ability to harmoniously relate multiple sequence and coordinate systems will make them useful irrespective of which pangenomic models become most common in the future.

Motivation: Graph representations of genomes are capable of expressing more genetic variation and can therefore better represent a population than standard linear genomes. However, due to the greater complexity of genome graphs relative to linear genomes, some functions that are trivial on linear genomes become much more difficult in genome graphs. Calculating distance is one such function that is simple in a linear genome but complicated in a graph context. In read mapping algorithms such distance calculations are fundamental to determining if seed alignments could belong to the same mapping., Results: We have developed an algorithm for quickly calculating the minimum distance between positions on a sequence graph using a minimum distance index. We have also developed an algorithm that uses the distance index to cluster seeds on a graph. We demonstrate that our implementations of these algorithms are efficient and practical to use for a new generation of mapping algorithms based upon genome graphs., Availability and Implementation: Our algorithms have been implemented as part of the vg toolkit and are available at https://github.com/vgteam/vg., (© The Author(s) 2020. Published by Oxford University Press.)

Structural variants (SVs) remain challenging to represent and study relative to point mutations despite their demonstrated importance. We show that variation graphs, as implemented in the vg toolkit, provide an effective means for leveraging SV catalogs for short-read SV genotyping experiments. We benchmark vg against state-of-the-art SV genotypers using three sequence-resolved SV catalogs generated by recent long-read sequencing studies. In addition, we use assemblies from 12 yeast strains to show that graphs constructed directly from aligned de novo assemblies improve genotyping compared to graphs built from intermediate SV catalogs in the VCF format.

Motivation: The variation graph toolkit (VG) represents genetic variation as a graph. Although each path in the graph is a potential haplotype, most paths are non-biological, unlikely recombinations of true haplotypes., Results: We augment the VG model with haplotype information to identify which paths are more likely to exist in nature. For this purpose, we develop a scalable implementation of the graph extension of the positional Burrows-Wheeler transform. We demonstrate the scalability of the new implementation by building a whole-genome index of the 5008 haplotypes of the 1000 Genomes Project, and an index of all 108 070 Trans-Omics for Precision Medicine Freeze 5 chromosome 17 haplotypes. We also develop an algorithm for simplifying variation graphs for k-mer indexing without losing any k-mers in the haplotypes., Availability and Implementation: Our software is available at https://github.com/vgteam/vg, https://github.com/jltsiren/gbwt and https://github.com/jltsiren/gcsa2., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2019. Published by Oxford University Press.)

Motivation: Compared to traditional haploid reference genomes, graph genomes are an efficient and compact data structure for storing multiple genomic sequences, for storing polymorphisms or for mapping sequencing reads with greater sensitivity. Further, graphs are well-studied computer science objects that can be efficiently analyzed. However, their adoption in genomic research is slow, in part because of the cognitive difficulty in interpreting graphs., Results: We present an intuitive graphical representation for graph genomes that re-uses well-honed techniques developed to display public transport networks, and demonstrate it as a web tool., Availability and Implementation: Code: https://github.com/vgteam/sequenceTubeMap., Demonstration: https://vgteam.github.io/sequenceTubeMap/., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2019. Published by Oxford University Press.)

In March 2019, 45 scientists and software engineers from around the world converged at the University of California, Santa Cruz for the first pangenomics codeathon. The purpose of the meeting was to propose technical specifications and standards for a usable human pangenome as well as to build relevant tools for genome graph infrastructures. During the meeting, the group held several intense and productive discussions covering a diverse set of topics, including advantages of graph genomes over a linear reference representation, design of new methods that can leverage graph-based data structures, and novel visualization and annotation approaches for pangenomes. Additionally, the participants self-organized themselves into teams that worked intensely over a three-day period to build a set of pipelines and tools for specific pangenomic applications. A summary of the questions raised and the tools developed are reported in this manuscript., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Llamas B et al.)

Motivation: Constructing high-quality haplotype-resolved de novo assemblies of diploid genomes is important for revealing the full extent of structural variation and its role in health and disease. Current assembly approaches often collapse the two sequences into one haploid consensus sequence and, therefore, fail to capture the diploid nature of the organism under study. Thus, building an assembler capable of producing accurate and complete diploid assemblies, while being resource-efficient with respect to sequencing costs, is a key challenge to be addressed by the bioinformatics community., Results: We present a novel graph-based approach to diploid assembly, which combines accurate Illumina data and long-read Pacific Biosciences (PacBio) data. We demonstrate the effectiveness of our method on a pseudo-diploid yeast genome and show that we require as little as 50× coverage Illumina data and 10× PacBio data to generate accurate and complete assemblies. Additionally, we show that our approach has the ability to detect and phase structural variants., Availability and Implementation: https://github.com/whatshap/whatshap., Supplementary Information: Supplementary data are available at Bioinformatics online.

Efforts to incorporate human genetic variation into the reference human genome have converged on the idea of a graph representation of genetic variation within a species, a genome sequence graph. A sequence graph represents a set of individual haploid reference genomes as paths in a single graph. When that set of reference genomes is sufficiently diverse, the sequence graph implicitly contains all frequent human genetic variations, including translocations, inversions, deletions, and insertions. In representing a set of genomes as a sequence graph, one encounters certain challenges. One of the most important is the problem of graph linearization, essential both for efficiency of storage and access, and for natural graph visualization and compatibility with other tools. The goal of graph linearization is to order nodes of the graph in such a way that operations such as access, traversal, and visualization are as efficient and effective as possible. A new algorithm for the linearization of sequence graphs, called the flow procedure (FP), is proposed in this article. Comparative experimental evaluation of the FP against other algorithms shows that it outperforms its rivals in the metrics most relevant to sequence graphs.

A superbubble is a type of directed acyclic subgraph with single distinct source and sink vertices. In genome assembly and genetics, the possible paths through a superbubble can be considered to represent the set of possible sequences at a location in a genome. Bidirected and biedged graphs are a generalization of digraphs that are increasingly being used to more fully represent genome assembly and variation problems. In this study, we define snarls and ultrabubbles, generalizations of superbubbles for bidirected and biedged graphs, and give an efficient algorithm for the detection of these more general structures. Key to this algorithm is the cactus graph, which, we show, encodes the nested decomposition of a graph into snarls and ultrabubbles within its structure. We propose and demonstrate empirically that this decomposition on bidirected and biedged graphs solves a fundamental problem by defining genetic sites for any collection of genomic variations, including complex structural variations, without need for any single reference genome coordinate system. Further, the nesting of the decomposition gives a natural way to describe and model variations contained within large variations, a case not currently dealt with by existing formats [e.g., variant cell format (VCF)].

Genetic changes causing brain size expansion in human evolution have remained elusive. Notch signaling is essential for radial glia stem cell proliferation and is a determinant of neuronal number in the mammalian cortex. We find that three paralogs of human-specific NOTCH2NL are highly expressed in radial glia. Functional analysis reveals that different alleles of NOTCH2NL have varying potencies to enhance Notch signaling by interacting directly with NOTCH receptors. Consistent with a role in Notch signaling, NOTCH2NL ectopic expression delays differentiation of neuronal progenitors, while deletion accelerates differentiation into cortical neurons. Furthermore, NOTCH2NL genes provide the breakpoints in 1q21.1 distal deletion/duplication syndrome, where duplications are associated with macrocephaly and autism and deletions with microcephaly and schizophrenia. Thus, the emergence of human-specific NOTCH2NL genes may have contributed to the rapid evolution of the larger human neocortex, accompanied by loss of genomic stability at the 1q21.1 locus and resulting recurrent neurodevelopmental disorders., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Vast amounts of molecular data are being collected on tumor samples, which provide unique opportunities for discovering trends within and between cancer subtypes. Such cross-cancer analyses require computational methods that enable intuitive and interactive browsing of thousands of samples based on their molecular similarity. We created a portal called TumorMap to assist in exploration and statistical interrogation of high-dimensional complex "omics" data in an interactive and easily interpretable way. In the TumorMap, samples are arranged on a hexagonal grid based on their similarity to one another in the original genomic space and are rendered with Google's Map technology. While the important feature of this public portal is the ability for the users to build maps from their own data, we pre-built genomic maps from several previously published projects. We demonstrate the utility of this portal by presenting results obtained from The Cancer Genome Atlas project data. Cancer Res; 77(21); e111-4. ©2017 AACR ., (©2017 American Association for Cancer Research.)

We present a generalization of the positional Burrows-Wheeler transform, or PBWT, to genome graphs, which we call the gPBWT. A genome graph is a collapsed representation of a set of genomes described as a graph. In a genome graph, a haplotype corresponds to a restricted form of walk. The gPBWT is a compressible representation of a set of these graph-encoded haplotypes that allows for efficient subhaplotype match queries. We give efficient algorithms for gPBWT construction and query operations. As a demonstration, we use the gPBWT to quickly count the number of haplotypes consistent with random walks in a genome graph, and with the paths taken by mapped reads; results suggest that haplotype consistency information can be practically incorporated into graph-based read mappers. We estimate that with the gPBWT of the order of 100,000 diploid genomes, including all forms structural variation, could be stored and made searchable for haplotype queries using a single large compute node.

The human reference genome is part of the foundation of modern human biology and a monumental scientific achievement. However, because it excludes a great deal of common human variation, it introduces a pervasive reference bias into the field of human genomics. To reduce this bias, it makes sense to draw on representative collections of human genomes, brought together into reference cohorts. There are a number of techniques to represent and organize data gleaned from these cohorts, many using ideas implicitly or explicitly borrowed from graph-based models. Here, we survey various projects underway to build and apply these graph-based structures-which we collectively refer to as genome graphs-and discuss the improvements in read mapping, variant calling, and haplotype determination that genome graphs are expected to produce., (© 2017 Paten et al.; Published by Cold Spring Harbor Laboratory Press.)

Motivation: Sequence mapping is the cornerstone of modern genomics. However, most existing sequence mapping algorithms are insufficiently general., Results: We introduce context schemes: a method that allows the unambiguous recognition of a reference base in a query sequence by testing the query for substrings from an algorithmically defined set. Context schemes only map when there is a unique best mapping, and define this criterion uniformly for all reference bases. Mappings under context schemes can also be made stable, so that extension of the query string (e.g. by increasing read length) will not alter the mapping of previously mapped positions. Context schemes are general in several senses. They natively support the detection of arbitrary complex, novel rearrangements relative to the reference. They can scale over orders of magnitude in query sequence length. Finally, they are trivially extensible to more complex reference structures, such as graphs, that incorporate additional variation. We demonstrate empirically the existence of high-performance context schemes, and present efficient context scheme mapping algorithms., Availability and Implementation: The software test framework created for this study is available from https://registry.hub.docker.com/u/adamnovak/sequence-graphs/., Contact: anovak@soe.ucsc.edu, Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The world's genomics data will never be stored in a single repository - rather, it will be distributed among many sites in many countries. No one site will have enough data to explain genotype to phenotype relationships in rare diseases; therefore, sites must share data. To accomplish this, the genetics community must forge common standards and protocols to make sharing and computing data among many sites a seamless activity. Through the Global Alliance for Genomics and Health, we are pioneering the development of shared application programming interfaces (APIs) to connect the world's genome repositories. In parallel, we are developing an open source software stack (ADAM) that uses these APIs. This combination will create a cohesive genome informatics ecosystem. Using containers, we are facilitating the deployment of this software in a diverse array of environments. Through benchmarking efforts and big data driver projects, we are ensuring ADAM's performance and utility., (© The Author 2015. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

A significant proportion of enzymes display cooperativity in binding ligand molecules, and such effects have an important impact on metabolic regulation. This is easiest to understand in the case of positive cooperativity. Sharp responses to changes in metabolite concentrations can allow organisms to better respond to environmental changes and maintain metabolic homeostasis. However, despite the fact that negative cooperativity is almost as common as positive, it has been harder to imagine what advantages it provides. Here we use computational models to explore the utility of negative cooperativity in one particular context: that of an inhibitor binding to an enzyme. We identify several factors which may contribute, and show that acting together they can make negative cooperativity advantageous.