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"Novak, M."
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Genotyping structural variants in pangenome graphs using the vg toolkit
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.
Journal Article
Designing rainwater harvesting systems : integrating rainwater into building systems
\"Rainwater Harvesting the first comprehensive book on designing rainwater harvesting systems. It provides practical guidelines for developing a rainwater harvesting strategy, taking into account climate, public policies, environmental impact, and end uses. Case studies are included throughout, and a companion website houses worksheets, calculators, and other resources. Rainwater Harvesting is a valuable reference for architects, landscape architects, and site engineers\"-- Provided by publisher.
Book
Variation graph toolkit improves read mapping by representing genetic variation in the reference
Reducing read mapping bias and improving complex variant detection with a highly scalable computational toolkit that implements variation graphs.
Reference genomes guide our interpretation of DNA sequence data. However, conventional linear references represent only one version of each locus, ignoring variation in the population. Poor representation of an individual′s genome sequence impacts read mapping and introduces bias. Variation graphs are bidirected DNA sequence graphs that compactly represent genetic variation across a population, including large-scale structural variation such as inversions and duplications
1
. Previous graph genome software implementations
2
,
3
,
4
have been limited by scalability or topological constraints. Here we present vg, a toolkit of computational methods for creating, manipulating, and using these structures as references at the scale of the human genome. vg provides an efficient approach to mapping reads onto arbitrary variation graphs using generalized compressed suffix arrays
5
, with improved accuracy over alignment to a linear reference, and effectively removing reference bias. These capabilities make using variation graphs as references for DNA sequencing practical at a gigabase scale, or at the topological complexity of
de novo
assemblies.
Journal Article
Integrated cancer tissue engineering models for precision medicine
Tumors are not merely cancerous cells that undergo mindless proliferation. Rather, they are highly organized and interconnected organ systems. Tumor cells reside in complex microenvironments in which they are subjected to a variety of physical and chemical stimuli that influence cell behavior and ultimately the progression and maintenance of the tumor. As cancer bioengineers, it is our responsibility to create physiologic models that enable accurate understanding of the multi-dimensional structure, organization, and complex relationships in diverse tumor microenvironments. Such models can greatly expedite clinical discovery and translation by closely replicating the physiological conditions while maintaining high tunability and control of extrinsic factors. In this review, we discuss the current models that target key aspects of the tumor microenvironment and their role in cancer progression. In order to address sources of experimental variation and model limitations, we also make recommendations for methods to improve overall physiologic reproducibility, experimental repeatability, and rigor within the field. Improvements can be made through an enhanced emphasis on mathematical modeling, standardized in vitro model characterization, transparent reporting of methodologies, and designing experiments with physiological metrics. Taken together these considerations will enhance the relevance of in vitro tumor models, biological understanding, and accelerate treatment exploration ultimately leading to improved clinical outcomes. Moreover, the development of robust, user-friendly models that integrate important stimuli will allow for the in-depth study of tumors as they undergo progression from non-transformed primary cells to metastatic disease and facilitate translation to a wide variety of biological and clinical studies.
Journal Article
Biochar: A synthesis of its agronomic impact beyond carbon sequestration
Biochar has been recently heralded as an amendment to revitalize degraded soils, improve soil carbon sequestration, increase agronomic productivity and enter into future carbon trading markets. However, scientific and economic technicalities may limit the ability of biochar to consistently deliver on these expectations. Past research has demonstrated that biochar is part of the black carbon continuum with variable properties, due to the net result of production (e.g., feedstock and pyrolysis conditions) and post-production factors (storage or activation). Therefore, biochar is not a single entity, but rather spans a wide range of black carbon forms. Biochar is black carbon, but not all black carbon is biochar. Agronomic benefits arising from biochar additions to degraded soils have been emphasized, but negligible and negative agronomic effects have also been reported. Fifty percent of the reviewed studies reported yield increases following black carbon or biochar additions, with the remainder of the studies reporting alarming decreases to no significant differences. Hardwood biochar (black carbon) produced by traditional methods (kilns or soil pits) possessed the most consistent yield increases when added to soils. The universality of this conclusion requires further evaluation due to the highly skewed feedstock preferences within existing studies. With global population expanding while the amount of arable land remains limited, restoring soil quality to nonproductive soils could be a vital key to meeting future global food production, food security and energy supplies; biochar may play a role in this endeavor. Biochar economics are often marginally viable and are tightly tied to the assumed duration of agronomic benefits. Further research is needed to determine the specific conditions under which biochar can provide real economic and agronomic benefits and to elucidate the fundamental mechanisms responsible for these benefits.
Journal Article
Progressive Cactus is a multiple-genome aligner for the thousand-genome era
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
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, 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.
The Progressive Cactus program can create reference-free alignments of hundreds of large vertebrate genomes efficiently, and is used for the alignment of more than 600 amniote genomes.
Journal Article
Microbiome Composition and Function Drives Wound-Healing Impairment in the Female Genital Tract
The mechanism(s) by which bacterial communities impact susceptibility to infectious diseases, such as HIV, and maintain female genital tract (FGT) health are poorly understood. Evaluation of FGT bacteria has predominantly been limited to studies of species abundance, but not bacterial function. We therefore sought to examine the relationship of bacterial community composition and function with mucosal epithelial barrier health in the context of bacterial vaginosis (BV) using metaproteomic, metagenomic, and in vitro approaches. We found highly diverse bacterial communities dominated by Gardnerella vaginalis associated with host epithelial barrier disruption and enhanced immune activation, and low diversity communities dominated by Lactobacillus species that associated with lower Nugent scores, reduced pH, and expression of host mucosal proteins important for maintaining epithelial integrity. Importantly, proteomic signatures of disrupted epithelial integrity associated with G. vaginalis-dominated communities in the absence of clinical BV diagnosis. Because traditional clinical assessments did not capture this, it likely represents a larger underrepresented phenomenon in populations with high prevalence of G. vaginalis. We finally demonstrated that soluble products derived from G. vaginalis inhibited wound healing, while those derived from L. iners did not, providing insight into functional mechanisms by which FGT bacterial communities affect epithelial barrier integrity.
Journal Article
Understanding the functional basis of moral conviction: Is moral conviction related to personal and social identity expression?
The degree to which one experiences an attitude as a moral conviction is associated with a host of consequences, such as charitable giving, volunteerism, political engagement, resistance to compromise, intolerance of dissenting viewpoints, and acceptance of any means, including violence, to achieve morally preferred ends. Despite these profound ramifications, our understanding of the psychological functions of moral conviction remains limited. In three studies, we tested competing hypotheses about two possible functions of moral conviction: personal identity and social identity expression. Study 1 developed and validated personal and social identity function measures in a U.S. sample and provided an initial test of hypotheses ( N = 320). Study 2 further validated these measures and tested whether cultural mindset moderated the relationship between identity functions and moral conviction in a U.S. sample ( N = 364). Study 3 tested hypotheses cross-culturally (i.e., using U.S. and Indian samples, N = 300). The personal identity function uniquely predicted moral conviction in all three studies and across six issue domains, whereas the social identity function did not (Studies 1–3). Surprisingly, neither cultural mindset (i.e., an independent and interdependent self-construal or endorsement of the individualizing or binding moral foundations) nor culture moderated these results.
Journal Article