The Mastery Rubric for Bioinformatics supporting design and evaluation of career-spanning education and training, bioRxiv, 2019-06-02
AbstractAs the life sciences have become more data intensive, the pressure to incorporate the requisite training into life-science education and training programs has increased. To facilitate curriculum development, various sets of (bio)informatics competencies have been articulated; however, these have proved difficult to implement in practice. Addressing this issue, we have created a curriculum-design and -evaluation tool to support the development of specific Knowledge, Skills and Abilities (KSAs) that reflect the scientific method and promote both bioinformatics practice and the achievement of competencies. Twelve KSAs were extracted via formal analysis, and stages along a developmental trajectory, from uninitiated student to independent practitioner, were identified. Demonstration of each KSA by a performer at each stage was initially described (Performance Level Descriptors, PLDs), evaluated, and revised at an international workshop. This work was subsequently extended and further refined to yield the Mastery Rubric for Bioinformatics (MR-Bi). The MR-Bi was validated by demonstrating alignment between the KSAs and competencies, and its consistency with principles of adult learning. The MR-Bi tool provides a formal framework to support curriculum building, training, and self-directed learning. It prioritizes the development of independence and scientific reasoning, and is structured to allow individuals (regardless of career stage, disciplinary background, or skill level) to locate themselves within the framework. The KSAs and their PLDs promote scientific problem formulation and problem solving, lending the MR-Bi durability and flexibility. With its explicit developmental trajectory, the tool can be used by developing or practicing scientists to direct their (and their team’s) acquisition of new, or to deepen existing, bioinformatics KSAs. The MR-Bi can thereby contribute to the cultivation of a next generation of bioinformaticians who are able to design reproducible and rigorous research, and to critically analyze results from their own, and others’, work.
biorxiv scientific-communication-and-education 200-500-users 2019Rock the Chalk A five-year comparative analysis of a large microbiology lecture course reveals improved outcomes of chalk-talk compared to PowerPoint, bioRxiv, 2019-05-28
AbstractThe rise of electronic assisted presentation programs such as PowerPoint in undergraduate large lecture biology classes has displaced more traditional hand-drawn lectures such as the blackboard or overhead projectors, referred here as “chalk-talk” approaches. But which method is more effective in a large lecture microbiology classroom is unclear. Here I present data from a large microbial genetics lecture course taken during a five-year span comparing PowerPoint to chalk-talk lecturing methods. The results indicate that the chalk-talk approach was preferred by the students and rated higher in all measured metrics including course enjoyment, learning of key concepts, and course outcomes.
biorxiv scientific-communication-and-education 200-500-users 2019Whole-genome deep-learning analysis identifies contribution of noncoding mutations to autism risk, Nature Genetics, 2019-05-27
We address the challenge of detecting the contribution of noncoding mutations to disease with a deep-learning-based framework that predicts the specific regulatory effects and the deleterious impact of genetic variants. Applying this framework to 1,790 autism spectrum disorder (ASD) simplex families reveals a role in disease for noncoding mutations—ASD probands harbor both transcriptional- and post-transcriptional-regulation-disrupting de novo mutations of significantly higher functional impact than those in unaffected siblings. Further analysis suggests involvement of noncoding mutations in synaptic transmission and neuronal development and, taken together with previous studies, reveals a convergent genetic landscape of coding and noncoding mutations in ASD. We demonstrate that sequences carrying prioritized mutations identified in probands possess allele-specific regulatory activity, and we highlight a link between noncoding mutations and heterogeneity in the IQ of ASD probands. Our predictive genomics framework illuminates the role of noncoding mutations in ASD and prioritizes mutations with high impact for further study, and is broadly applicable to complex human diseases.
nature genetics genetics 200-500-users 2019Species-specific oscillation periods of human and mouse segmentation clocks are due to cell autonomous differences in biochemical reaction parameters, bioRxiv, 2019-05-26
AbstractWhile the mechanisms of embryonic development are similar between mouse and human, the tempo is in general slower in human. The cause of interspecies differences in developmental time remains a mystery partly due to lack of an appropriate model system1. Since murine and human embryos differ in their sizes, geometries, and nutrients, we use in vitro differentiation of pluripotent stem cells (PSCs) to compare the same type of cells between the species in similar culture conditions. As an example of well-defined developmental time, we focus on the segmentation clock, oscillatory gene expression that regulates the timing of sequential formation of body segments2–4. In this way we recapitulate the murine and human segmentation clocks in vitro, showing that the species-specific oscillation periods are derived from cell autonomous differences in the speeds of biochemical reactions. Presomitic mesoderm (PSM)-like cells induced from murine and human PSCs displayed the oscillatory expression of HES7, the core gene of the segmentation clock5,6, with oscillation periods of 2-3 hours (mouse PSM) and 5-6 hours (human PSM). Swapping HES7 loci between murine and human genomes did not change the oscillation periods dramatically, denying the possibility that interspecies differences in the sequences of HES7 loci might be the cause of the observed period difference. Instead, we found that the biochemical reactions that determine the oscillation period, such as the degradation of HES7 and delays in its expression, are slower in human PSM compared with those in mouse PSM. With the measured biochemical parameters, our mathematical model successfully accounted for the 2-3-fold period difference between mouse and human. We further demonstrate that the concept of slower biochemical reactions in human cells is generalizable to several other genes, as well as to another cell type. These results collectively indicate that differences in the speeds of biochemical reactions between murine and human cells give rise to the interspecies period difference of the segmentation clock and may contribute to other interspecies differences in developmental time.
biorxiv developmental-biology 200-500-users 2019Enabling high-accuracy long-read amplicon sequences using unique molecular identifiers with Nanopore or PacBio sequencing, bioRxiv, 2019-05-24
AbstractHigh-throughput amplicon sequencing of large genomic regions remains challenging for short-read technologies. Here, we report a high-throughput amplicon sequencing approach combining unique molecular identifiers (UMIs) with Oxford Nanopore Technologies or Pacific Biosciences CCS sequencing, yielding high accuracy single-molecule consensus sequences of large genomic regions. Our approach generates amplicon and genomic sequences of >10,000 bp in length with a mean error-rate of 0.0049-0.0006% and chimera rate <0.022%.
biorxiv molecular-biology 200-500-users 2019A rationally designed and highly versatile epitope tag for nanobody-based purification, detection and manipulation of proteins, bioRxiv, 2019-05-18
AbstractSpecialized epitope tags are widely used for detecting, manipulating or purifying proteins, but often their versatility is limited. Here, we introduce the ALFA-tag, a novel, rationally designed epitope tag that serves an exceptionally broad spectrum of applications in life sciences while outperforming established tags like the HA, FLAG or myc tags. The ALFA-tag forms a small and stable α-helix that is functional irrespective of its position on the target protein in prokaryotic and eukaryotic hosts. We developed a nanobody (NbALFA) binding ALFA-tagged proteins from native or fixed specimen with low picomolar affinity. It is ideally suited for super-resolution microscopy, immunoprecipitations and Western blotting, and also allows in-vivo detection of proteins. By solving the crystal structure of the complex we were able to design a nanobody mutant (NbALFAPE) that permits efficient one-step purifications of native ALFA-tagged proteins, complexes and even entire living cells using peptide elution under physiological conditions.
biorxiv biochemistry 200-500-users 2019