Paired Ends Podcast

About Paired Ends Podcast

Bioinformatics, computational biology, and data science updates from the field. Occasional posts on programming. blog.stephenturner.us (https://blog.stephenturner.us?utm_medium=podcast)

Publisher

Stephen Turner

Category

science · technology

Language

en

Explicit

No

First episode

11 Sept 2024

Latest episode

9 Aug 2025

Latest episodes

10 episodes in the feed.

1. 

   9 Aug 2025

   Moving from biotech to academia

   Moving from biotech to academia I recently wrote a piece about leaving academia for biotech. I left academia for industry in 2019. I spent four years at a consulting firm (https://www.signaturescience.com/) before joining Colossal Biosciences (https://colossal.com/). This week I’m returning to the University of Virginia School of Data Science (https://datascience.virginia.edu/) as a tenured associate professor and dean of research. The transition from academia to industry can be tricky, but it’s also increasingly common. There are far fewer academic jobs available than there are trainees coming out of grad school and postdoc positions. What’s talked about less (because it happens less!) is the return trip. And it’s harder. Much harder. Why? Academia is a prestige economy built around publications, teaching, funding, and visibility. Industry, even at companies doing lots of R&D, operates under a different currency: deliverables, velocity, product, and revenue, with a stronger focus on protecting IP than spreading knowledge. Spend long enough away, and the things that matter in academia begin to atrophy, at least in how they appear on paper. So if you're in industry and even thinking about going back, here are some practical things to focus on now, not later. Publish. No seriously, publish. Publications are the coin of the realm in academia. If you’re not authoring papers, even as middle author, you’re invisible to many academic search committees. Make publication a priority, even if your industry work is proprietary or siloed. Can you spin off a methods paper? Collaborate with a former colleague? Co-author a review? Find a way. If nothing else, consider publishing some of your open-source work as an independent scientist to a preprint server like bioRxiv or arXiv. I did this with a little side project, and I have a few more in mind once I can find the time. Depending on the size of your company you may be able to convince leadership that publication is good for the company. I worked at a multidisciplinary scientific services and technical consulting firm (https://www.signaturescience.com/) for several years after I left academia before joining a biotech startup. No one was coming to my company to buy software like rplanes (https://github.com/signaturescience/rplanes) or pracpac (https://github.com/signaturescience/pracpac). They were coming to my company to buy expertise and time from the people who can build things like rplanes and pracpac, and we could point them to the papers (https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0320442) we published to prove our bona fides. Publications served as a flag in the ground, proven past performance we could cite for new consulting services contract proposals. Keep your academic CV up to date I kept my industry at two pages max, highlighting practical skills and accomplishments over a long list of papers. My academic CV is about 40 pages long. Update your CV regularly. And not just the publications. Make sure you add any abstracts, posters, invited talks, teaching, mentoring, grant writing (even internal grants). List these as you would if you never left. Even if you’ve been managing roadmaps and timelines for years, hiring committees still want to see whether you've kept one foot in the scholarly world. It’s hard to do this years later if you haven’t kept your academic CV updated as you go along, so if returning to academia is even a remote possibility for you, update it regularly. Teach, guest lecture, or mentor Find a way to stay active in education. Adjunct a class, give guest lectures, volunteer to teach a short course or workshop at your local R User Group (https://cvillerusers.github.io/) or PyData meetup (https://www.meetup.com/charlottesvilledatascience/). If teaching is part of the academic role you want, you need receipts. Mentoring interns or postdocs in industry can sometimes count, especially if you can point to outcomes. If you teach a workshop, put your workshop material online (here’s an example of mine (https://stephenturner.github.io/workshops/)). If you teach more than a few workshops and you have your materials written with Quarto, it’s easy to turn this into a book and it takes all of 10 minutes to self-publish on Amazon (https://amzn.to/4lubY1U) or Leanpub (https://leanpub.com/bdsr). Write a blog or newsletter If you’ve been out of academia for a while, a blog or newsletter can do double duty: it’s a portfolio of ideas and a public demonstration that you’re still reading, thinking, and engaging. It doesn’t have to be technical — some of the best academic writing is reflection. Just be present. Along similar lines, maintain your public-facing profile. Keep your GitHub active, your personal website updated, and your LinkedIn, ORCID, and Google Scholar profiles accurate. Collaborate with academics One of the best ways to maintain credibility is to stay close to the source. Collaborate with researchers at universities. Serve on thesis committees. Co-author grant applications. Even SBIRs can count here. In my previous industry/consulting role I was able to partner with James Madison University and Elder Research to get SBIR funding for environmental monitoring for harmful algal blooms (https://www.highergov.com/grant/NA22OAR0210493/), and we published a preprint (https://www.biorxiv.org/content/10.1101/2022.03.12.483776v1) on some of the phase 1 work. While here at Colossal I got to collaborate with researchers at the University of East Anglia, the Globe institute at the University of Copenhagen, the Mauritian Wildlife Foundation, Durrell Wildlife Conservation Trust, the government of Mauritius, and the University of Kent. These kind of academic collaborations count for a lot if you can make them happen. Really go out of your way to try to make this happen, even if it’s not a part of your day job. These connections often open doors back into academia and they lend credibility when you make your case to search committees. Stay current with the literature Reading papers for fun might seem like a luxury you don’t have time for in industry, but if you’re planning to go back to academia, you need to keep current. Read. Annotate. Build a bibliography of stuff you’d cite if you wrote a paper tomorrow (I use Zotero). Maybe even write about what you’re reading. (https://blog.stephenturner.us/t/papers) Understand what you’re giving up Going back to academia almost certainly means a pay cut. If you’re leaving a startup, you’re likely walking away from equity that could potentially turn into life-changing wealth. You’ll also go from short feedback loops and funding decisions to heavier bureaucracy and long grant cycles. And as I write this in August 2025, science funding in the US is under attack from all angles. Be honest with yourself about why you want to go back. If it’s because you miss mentoring students, chasing hard problems, or writing papers with your name at the end, great. But don’t underestimate the cost. Know how your time in industry will be perceived Academia says it values real-world experience, but it’s often suspicious of it too. You may have run large teams and shipped major products, but if you haven’t published recently, haven’t taught, haven’t stayed visible in academic spaces, your experience may be undervalued. Don’t take it personally but do plan for it. This is changing in many places. I landed my new position at UVA SDS in no small part because of my industry and startup experience. They’re really leading the way here with this forward-looking stance on entrepreneurship and public-private partnerships. Check out a few of the links below for more. * Phil Bourne: Entrepreneurism, Data Science and a New Building (https://datascience.virginia.edu/news/deans-blog-entrepreneurism-data-science-and-new-building) * Phil Bourne: This Moment and Beyond (https://datascience.virginia.edu/news/deans-blog-moment-and-beyond) * UVA Data Points Podcast: Venture Meets Mission: A Conversation with Arun Gupta (https://uvadatapoints.castos.com/episodes/venture-meets-mission-a-conversation-with-arun-gupta) Final thoughts Coming back isn’t impossible. But it takes planning. You need to start cultivating your academic shadow long before you try to return. It means publishing when no one’s asking you to, teaching when you don’t have to, and showing up in spaces where your current job might not require you to. If you do that consistently, you’ll demonstrate that your time in industry hasn’t distanced you from the values of academia. You’ll show that you’ve kept your edge, stayed engaged, and have something valuable to offer that blends both rigor and real-world experience. This is a public episode. If you would like to discuss this with other subscribers or get access to bonus episodes, visit blog.stephenturner.us (https://blog.stephenturner.us?utm_medium=podcast&utm_campaign=CTA_1)

2. 

   15 Jan 2025

   AI in data science education

   Data science educator and professor Stephen Turner examines the impact of AI on education, discussing the opportunities and challenges of using Large Language Models in data science teaching and learning.

3. 

   23 Dec 2024

   The Enlightenment Conservatory

   https://blog.stephenturner.us/p/enlightenment-conservatory (https://blog.stephenturner.us/p/enlightenment-conservatory) I had good intentions to give NaNoWriMo (https://en.wikipedia.org/wiki/National_Novel_Writing_Month) a try this year but didn’t get very far. Instead I gave OpenAI’s Creative Writing Coach GPT (https://chatgpt.com/g/g-lN1gKFnvL-creative-writing-coach) a try for a (very) short story I had in mind, inspired by my frustration trying to access closed-access research articles for a review article I’m preparing. I found it to be an excellent writing coach with specific advice for refining the role of the curators, expanding the perspective of the cultivators, deepening the emotional stakes, clarifying the catalyst for change, polishing the resolution, adding complexity, making the revolt more dramatic, and fine-tuning the language. Image created with DALL-E (https://chatgpt.com/g/g-2fkFE8rbu-dall-e). Voiceover with ElevenLabs (https://elevenlabs.io/). In a world not so different from our own, there existed a fabled garden called the Enlightenment Conservatory. Here, ideas took root as seeds of thought, blooming into radiant flowers of discovery and wisdom. Each blossom held the promise of transformation - groundbreaking theories, profound insights, and untold wonders capable of reshaping the world. It was said that no other garden in existence could rival its beauty or its mystery. The Conservatory was tended by a diverse group of dedicated cultivators. These scholars came from all corners of the world, driven by an insatiable curiosity and a passion for nurturing new ideas. They spent their days and nights planting seeds of thought, carefully tending to them, and watching in awe as their conceptual flowers blossomed into vibrant displays of intellectual beauty. Each bloom was unique, representing the culmination of the cultivators' hard work, creativity, and brilliance. However, the Enlightenment Conservatory was not open to all. Surrounding it stood a tall, impenetrable wall, erected long ago by a powerful guild known as the Curators. Through a series of cunning maneuvers and ruthless acquisitions, the Curators had gained control over all the smaller intellectual gardens that once existed independently. Now, they ruled the Enlightenment Conservatory with an iron fist. The Curators enforced one unyielding rule: entry to the Conservatory came at an outrageous price. Even the cultivators - those who had poured their hearts and minds into planting and nurturing each idea - were not spared. To gaze upon their own intellectual blooms, they too had to pay the Curators' steep toll. Many could only catch fleeting glimpses of their creations from outside the towering walls, denied the chance to savor the fruits of their labor. Their brilliance was trapped behind gates they could never afford to open. The Enlightenment Conservatory was meant to be a place where people from all walks of life could come to marvel at the wonders of human thought and insight, where ideas could be shared freely and openly. But under the Curators' rule, it became a bastion of exclusivity. Only the wealthiest patrons and members of the most prestigious institutions could afford to enter and enjoy the intellectual bounty within. These privileged few would stroll through the Conservatory, plucking ideas at will, while the majority remained outside the walls, unable to access the knowledge and insights that had been so carefully cultivated. The Curators defended their dominion by calling themselves the stewards of the Enlightenment Conservatory. They claimed their strict oversight was essential to protect the garden from mediocrity, ensuring only the most refined and worthy ideas took root. Without their watchful gaze, they warned, the Conservatory would drown in a sea of weeds, its beauty choked by chaos. But the cultivators saw through the façade. They knew the Curators tended nothing; they merely harvested the fruits of others’ labor while the true blooms of genius often went unnoticed, left to wither in the shadows. They knew that the Curators did little to actually care for the Conservatory. The intellectual blooms within its walls were almost always unchanged from the moment they had been planted. The Curators did not prune, water, or tend to the flowers of thought; they simply collected fees and claimed ownership of every bloom. Worse still, they often overlooked some of the most extraordinary ideas, leaving them to wither and die, while promoting others simply because they had been paid to do so. But for all the Curators' lofty claims, the Enlightenment Conservatory began to wither. Its once-thriving ecosystem of ideas grew barren, choked by exclusion. Young cultivators from distant lands - those with the boldest, freshest seeds of thought - were turned away, unable to pay the Curators' crushing fees. Some gave up entirely, their unplanted ideas fading like dreams forgotten at dawn. Others tried to nurture their seeds in secret, but without the support of the Conservatory, their efforts bore no fruit. The world would never know the brilliance that had been lost, and the cultivators could only watch as the garden they loved fell into quiet decline. The cultivators' frustration grew into a quiet despair. They had poured their souls into planting seeds of thought, nurturing them with endless care, only to see their work imprisoned behind walls they could not afford to scale. What use was a garden of wisdom if it bloomed in the dark, unseen and unshared? They began to speak out, calling for change. They envisioned an Conservatory where all could enter freely, where the flowers of knowledge and insight could be shared by everyone, regardless of wealth or status. They dreamed of an intellectual paradise that truly reflected the diversity and richness of the world's ideas, unencumbered by the greed and control of the Curators. As the cries for change swelled, a few bold cultivators decided they could wait no longer. They slipped beyond the Conservatory's walls and began planting their seeds of thought in the wild, in open fields where anyone - rich or poor, learned or curious - could come and marvel. These free gardens burst into dazzling bloom, spilling over with ideas as vibrant and diverse as the people who tended them. The movement spread like wildfire, and as more cultivators turned away from the Conservatory, the Curators panicked. They scrambled to suppress the rebellion, but it was too late. The walls that had stood for centuries began to crack. In time, the Enlightenment Conservatory was no longer the sole sanctuary of wisdom. The walls that had once loomed so high crumbled to dust as people discovered they didn't need gates to access the beauty of knowledge. All around, new gardens flourished, each more diverse and vibrant than the last. The Conservatory itself, no longer shrouded in exclusivity, was reborn as a shared space for all. Its paths teemed with visitors, its flowers of insight blooming brighter than ever in the sunlight of collaboration and open exchange. At last, the cultivators' dream had come to life: a world where ideas could roam free, taking root wherever they were needed most. And so, the Enlightenment Conservatory was transformed. No longer a place of exclusion, it became a symbol of what could be achieved when knowledge, discovery, and insight were shared freely and openly, for the benefit of all. The cultivators continued their work, more inspired than ever, knowing that their intellectual blooms would flourish in a world where everyone could enjoy them, without barriers, without walls. This is a public episode. If you would like to discuss this with other subscribers or get access to bonus episodes, visit blog.stephenturner.us (https://blog.stephenturner.us?utm_medium=podcast&utm_campaign=CTA_1)

4. 

   20 Dec 2024

   Weekly Recap (Dec 2024, part 3)

   https://blog.stephenturner.us/p/weekly-recap-dec-2024-part-3 (https://blog.stephenturner.us/p/weekly-recap-dec-2024-part-3) This week’s recap highlights the Evo model for sequence modeling and design, biomedical discovery with AI agents, improving bioinformatics software quality through teamwork, a new tool from Brent Pedersen and Aaron Quinlan (vcfexpress) for filtering and formatting VCFs with Lua expressions, a new paper about the NHGRI-EBI GWAS Catalog, and a review paper on designing and engineering synthetic genomes. Others that caught my attention include a new foundation model for scRNA-seq, a web-based platform for reference-based analysis of single-cell datasets, an AI system for learning how to run transcript assemblers, ATAC-seq QC and filtering, metagenome binning using bi-modal variational autoencoders, analyses of outbreak genomic data using split k-mer analysis, a review on Denisovan introgression events in modern humans, T2T assembly by preserving contained reads, and a commentary on AI readiness in biomedical data. Audio generated with NotebookLM. Subscribe to Paired Ends (free) to get summaries like this delivered to your e-mail. Deep dive Sequence modeling and design from molecular to genome scale with Evo Paper: Nguyen et al., "Sequence modeling and design from molecular to genome scale with Evo," Science, 2024. https://doi.org/10.1126/science.ado9336 (https://doi.org/10.1126/science.ado9336). Before getting to this new paper from the Arc Institute, there’s also a Perspective paper published in the same issue, providing a very short introduction that’s also worth reading (“Learning the language of DNA (https://www.science.org/doi/10.1126/science.adt3007)”). TL;DR: This study introduces Evo, a groundbreaking genomic foundation model that learns complex biological interactions at single-nucleotide resolution across DNA, RNA, and protein levels. This model, trained on a massive set of prokaryotic and phage genomes, can predict how variations in DNA affect functions across regulatory, coding, and noncoding RNA regions. The paper and the Perspective paper above emphasize the innovative use of the StripedHyena architecture, which enables Evo to handle large-scale genomic contexts efficiently, setting a precedent for future advancements in genome-scale predictive modeling and synthetic biology. Summary: The authors present Evo, a 7-billion-parameter language model trained on prokaryotic and phage genomes, designed to capture information at nucleotide-level resolution over long genomic sequences. Evo surpasses previous models by excelling in zero-shot function prediction tasks across different biological modalities (DNA, RNA, protein) and can generate functional biological systems like CRISPR-Cas complexes and transposons. It leverages advanced deep signal processing with the StripedHyena architecture to address limitations faced by transformer-based models, allowing it to learn dependencies across vast genomic regions. Evo's training was validated through experimental testing, including the synthesis of novel functional proteins and genome-scale sequence design, underscoring its potential to transform genetic engineering and synthetic biology. Methodological highlights: * Architecture: Utilized the StripedHyena, a hybrid attention-convolutional architecture, for efficient long-sequence processing at nucleotide-level resolution. * Training: Conducted on 2.7 million genomes, with a maximum context length of 131 kilobases. * Applications: Zero-shot predictions in mutation effects on fitness, and generation of operons, CRISPR systems, and large genomic sequences. * Code and models: Open source (Apache license) and available at https://github.com/evo-design/evo (https://github.com/evo-design/evo). Empowering biomedical discovery with AI agents Paper: Gao et al., "Empowering biomedical discovery with AI agents," Cell, 2024. https://doi.org/10.1016/j.cell.2024.09.022 (https://doi.org/10.1016/j.cell.2024.09.022). I’ve covered AI agents for bioinformatics in the highlights sections of previous weekly recaps (e.g., BioMANIA (https://blog.stephenturner.us/i/149172883/biomania-simplifying-bioinformatics-data-analysis-through-conversation) and AutoBA (https://blog.stephenturner.us/i/150024199/an-ai-agent-for-fully-automated-multi-omic-analyses)). This is an interesting, if speculative, look into the present and future of agentic AI in life sciences research. TL;DR: This perspective paper discusses the potential of AI agents to transform biomedical research by acting as "AI scientists," capable of hypothesis generation, planning, and iterative learning, thus bridging human expertise and machine capabilities. Summary: The authors outline a future in which AI agents, equipped with advanced reasoning, memory, and perception capabilities, assist in biomedical discovery by combining large language models (LLMs) with specialized machine learning tools and experimental platforms. Unlike traditional models, these AI agents could break down complex scientific problems, run experiments autonomously, and propose novel hypotheses, while incorporating feedback to improve over time. This vision extends AI's role from mere data analysis to active participation in hypothesis-driven research, promising advances in areas such as virtual cell simulation, genetic editing, and new drug development. Key ideas: * Modular AI system: Integration of LLMs, ML tools, and experimental platforms to function as collaborative systems capable of reasoning and learning. * Adaptive learning: Agents dynamically incorporate new biological data, enhancing their predictive and hypothesis-generating capabilities. * Skeptical learning: AI agents analyze and identify gaps in their own knowledge to refine their approaches, mimicking human scientific inquiry. Improving bioinformatics software quality through teamwork Paper: Ferenc et al., "Improving bioinformatics software quality through teamwork," Bioinformatics, 2024. https://doi.org/10.1093/bioinformatics/btae632 (https://doi.org/10.1093/bioinformatics/btae632). One of the things this paper argues for is implementing code review. I used to work at a consulting firm, and I started a weekly code review session with me and my two teammates. In addition to improving code quality, it also increased the bus factor (https://en.wikipedia.org/wiki/Bus_factor) on a critical piece of software to n>1. I had a hard time scaling this. As my team grew from two to ~12, our weekly code review session turned into more of a regular standup-style what are you doing, what are you struggling with, etc., with less emphasis on code. I think the better approach would have been to make the larger meeting less frequent or async while holding smaller focused code review sessions with fewer people. On the other hand, I recently attended the nf-core hackathon (https://blog.stephenturner.us/p/nextflow-summit-barcelona-2024) in Barcelona where >140 developers came together to work on Nextflow pipelines, and I thought it was wildly successful. TL;DR: This paper argues that the quality of bioinformatics software can be greatly enhanced through collaborative efforts within research groups, proposing the adoption of software engineering practices such as regular code reviews, resource sharing, and seminars. Summary: This paper argues that bioinformatics software often suffers from inadequate quality standards due to individualistic development practices prevalent in academia. To bridge this gap, they recommend fostering teamwork and collective learning through structured activities such as code reviews and software quality seminars. The paper provides examples from the authors’ own experience at the Centre for Molecular Medicine Norway, where a community-driven approach led to improved coding skills, better code maintainability, and enhanced collaborative potential. This approach ensures researchers maintain ownership of their projects while leveraging the benefits of shared knowledge and collective feedback. Highlights: * Structured teamwork: Adoption of collaborative practices like code review sessions and quality seminars to improve software development culture. * Knowledge sharing: Emphasis on resource sharing to minimize redundant efforts and increase efficiency. * Community building: Cultivating a supportive environment that allows for skill-building across the team. * Resource website: The authors provide practical guidance and tools for fostering collaborative software development, accessible at https://ferenckata.github.io/ImprovingSoftwareTogether.github.io/ (https://ferenckata.github.io/ImprovingSoftwareTogether.github.io/). Vcfexpress: flexible, rapid user-expressions to filter and format VCFs Paper: Brent Pedersen and Aaron Quinlan, "Vcfexpress: flexible, rapid user-expressions to filter and format VCFs," Bioinformatics, 2024. 10.1101/2024.11.05.622129 (https://doi.org/10.1101/2024.11.05.622129). On GitHub I “follow” both Brent (https://github.com/brentp) and Aaron (https://github.com/arq5x) so I get notifications whenever either of them publish a new repo. Brent has published many little utilities that improve a bioinformatician’s quality of life (mosdepth (https://github.com/brentp/mosdepth), somalier (https://github.com/brentp/somalier), vcfanno (https://github.com/brentp/vcfanno), smoove (https://github.com/brentp/smoove), to name a few). TL;DR: Vcfexpress is a new tool for filtering and formatting Variant Call Format (VCF) files that offers high performance and flexibility through user-defined expressions in the Lua programming language, rivaling BCFTools in speed but with extended functionality. Summary: The paper introduces vcfexpress, a powerful new tool designed to efficiently filter and format VCF and BCF files using Lua-based user expressions. Implemented in the Rust programming language, vcfexpress supports advanced customization that enables users to apply detailed filtering logic, add new annotations, and format output in various file types like BED and BEDGRAPH. It stands out by balancing speed and versatility, matching BCFTools in performance while surpassing it in analytical customization. Vcfexpress can handle complex tasks such as parsing fields from SnpEff and VEP annotations, providing significant utility for high-throughput genomic analysis. Methodological highlights: * Lua integration: Unique support for Lua scripting enables precise filtering and flexible output formatting. * High performance: Comparable in speed to BCFTools, yet offers additional, customizable logic. * Template output: Allows specification of output formats beyond VCF/BCF, such as BED files. * Code availability: On GitHub at https://github.com/brentp/vcfexpress (https://github.com/brentp/vcfexpress). Permissively licensed (MIT). The NHGRI-EBI GWAS Catalog: standards for reusability, sustainability and diversity Paper: Cerezo M et al., “The NHGRI-EBI GWAS Catalog: standards for reusability, sustainability and diversity”, bioRxiv 2024. https://doi.org/10.1101/2024.10.23.619767 (https://doi.org/10.1101/2024.10.23.619767). TL;DR: The NHGRI-EBI GWAS Catalog (https://www.ebi.ac.uk/gwas/ (https://www.ebi.ac.uk/gwas/)) has implemented new standards and tools for GWAS summary statistics data submission and harmonization, improving data reusability and interoperability. The Catalog now contains over 625,000 curated SNP-trait associations and 85,000 full summary statistics datasets, with significant growth in molecular quantitative trait studies. The paper highlights important updates in data content, user interface improvements, and thoughtful handling of population descriptors. Summary: The GWAS Catalog serves as the largest public repository for FAIR GWAS data, containing over 625,000 curated SNP-trait associations from nearly 7,000 publications. The paper describes major improvements including implementation of the GWAS-SSF standard format for summary statistics, enhanced data harmonization pipelines, and improved handling of molecular quantitative trait studies. The authors address critical challenges in standardizing data submission and population descriptors while maintaining data interoperability. The Catalog has seen significant growth, particularly in molecular quantitative trait studies (82% of additions in 2023), and has implemented UI improvements to handle large-scale datasets efficiently. The work emphasizes the importance of careful population descriptor usage and the need for greater diversity in GWAS studies. Methodological highlights: * Developed and implemented GWAS-SSF standard format defining mandatory fields (chromosome, position, alleles, effect sizes, etc.) and recommended fields for summary statistics. * Enhanced harmonization pipeline with 75% reduction in processing time through improved computational efficiency and workflow management. This pipeline is Nextflow-based (see figure S1, copied below). * Implemented new trait mapping system using Ontology of Biological Attributes for molecular quantitative traits, enabling better integration with chemistry and protein databases. New tools, data, and resources: * GWAS Catalog web interface: https://www.ebi.ac.uk/gwas/ (https://www.ebi.ac.uk/gwas/). * Project GitHub repository: https://github.com/EBISPOT/goci (https://github.com/EBISPOT/goci) (Apache 2.0 license). * SSF-morph tool for format conversion: https://ebispot.github.io/gwas-sumstats-tools-ssf-morph/ (https://ebispot.github.io/gwas-sumstats-tools-ssf-morph/). * Summary statistics API: http://www.ebi.ac.uk/gwas/summary-statistics/api/ (http://www.ebi.ac.uk/gwas/summary-statistics/api/). * Data availability: All curated data available through web interface and programmatic access. Summary statistics submitted after March 2021 available under CC0 license. Review: The design and engineering of synthetic genomes Paper: James, J. S., et al. "The design and engineering of synthetic genomes" in Nature Reviews Genetics, 2024. https://doi.org/10.1038/s41576-024-00786-y (https://doi.org/10.1038/s41576-024-00786-y). I spend a lot of time thinking about designing large synthetic DNA constructs — how the bioinformatics/design side informs the wet lab processes needed to create these. This was a great review on the history, applications, and practice of synthesizing genes and genomes. TL;DR: This comprehensive review examines how synthetic genomics has evolved from early viral genome synthesis to complex bacterial and eukaryotic genomes. The field is moving from proof-of-concept projects to practical applications in medicine, agriculture, and industry, driven by advances in DNA synthesis, assembly methods, and computational design tools. Summary: The review traces synthetic genomics from early milestones like poliovirus synthesis to recent achievements in building complete synthetic yeast chromosomes. While construction capabilities have grown impressively, our ability to predict how genome modifications will function lags behind. The authors highlight how computational tools, artificial intelligence, and improved DNA synthesis technologies are helping bridge this gap. They explore key applications including viral vaccines, engineered microorganisms for bioproduction, and synthetic chromosomes for various applications including xenotransplantation and enhanced crops. A major theme is the transition from demonstrating technical feasibility to practical real-world applications. Highlights: * Introduction of new approaches for genome design including template-guided design, genetic code alteration, and synthetic circuit-based design to build genomes with novel functions. * Development of integrated computer-aided design and manufacturing platforms that combine sequence design, functional prediction, and automated assembly planning. * Advances in hierarchical genome assembly methods that enable parallel construction and testing of multiple synthetic genome sections. Other papers of note * scLong: A Billion-Parameter Foundation Model for Capturing Long-Range Gene Context in Single-Cell Transcriptomics https://www.biorxiv.org/content/10.1101/2024.11.09.622759v1 (https://www.biorxiv.org/content/10.1101/2024.11.09.622759v1) * archmap.bio (https://www.archmap.bio): A web-based platform for reference-based analysis of single-cell datasets https://www.biorxiv.org/content/10.1101/2024.09.19.613883v1 (https://www.biorxiv.org/content/10.1101/2024.09.19.613883v1) * Data-driven AI system for learning how to run transcript assemblers https://www.biorxiv.org/content/10.1101/2024.01.25.577290v2 (https://www.biorxiv.org/content/10.1101/2024.01.25.577290v2) * Quaqc: Efficient and quick ATAC-seq quality control and filtering https://academic.oup.com/bioinformatics/advance-article/doi/10.1093/bioinformatics/btae649/7852831 (https://academic.oup.com/bioinformatics/advance-article/doi/10.1093/bioinformatics/btae649/7852831) * Binning meets taxonomy: TaxVAMB improves metagenome binning using bi-modal variational autoencoder https://www.biorxiv.org/content/10.1101/2024.10.25.620172v1 (https://www.biorxiv.org/content/10.1101/2024.10.25.620172v1) * Seamless, rapid, and accurate analyses of outbreak genomic data using split k-mer analysis https://genome.cshlp.org/content/34/10/1661.full (https://genome.cshlp.org/content/34/10/1661.full) * Review: A history of multiple Denisovan introgression events in modern humans https://www.nature.com/articles/s41588-024-01960-y (https://www.nature.com/articles/s41588-024-01960-y) * Telomere-to-telomere assembly by preserving contained reads https://genome.cshlp.org/content/early/2024/11/04/gr.279311.124.short (https://genome.cshlp.org/content/early/2024/11/04/gr.279311.124.short) * AI-readiness for Biomedical Data: Bridge2AI Recommendations https://www.biorxiv.org/content/10.1101/2024.10.23.619844v2 (https://www.biorxiv.org/content/10.1101/2024.10.23.619844v2) Subscribe to Paired Ends (free) to get summaries like this delivered to your e-mail. This is a public episode. If you would like to discuss this with other subscribers or get access to bonus episodes, visit blog.stephenturner.us (https://blog.stephenturner.us?utm_medium=podcast&utm_campaign=CTA_1)

5. 

   13 Dec 2024

   Weekly Recap (Dec 2024, part 2)

   https://blog.stephenturner.us/p/weekly-recap-dec-2024-part-2 (https://blog.stephenturner.us/p/weekly-recap-dec-2024-part-2) This week’s recap highlights a new way to turn Nextflow pipelines into web apps, DRAGEN for fast and accurate variant calling, machine-guided design of cell-type-targeting cis-regulatory elements, a Nextflow pipeline for identifying and classifying protein kinases, a new language model for single cell perturbations that integrates knowledge from literature, GeneCards, etc., and a new method for scalable protein design in a relaxed sequence space. Others that caught my attention include commentary on improving bioinformatics software quality through teamwork, targeted nanopore sequencing for mitochondrial variant analysis, a review on plant conservation in the era of genome engineering, a de novo assembly tool for complex plant organelle genomes, learning to call copy number variants on low coverage ancient genomes, a near telomere-to-telomere phased reference assembly for the male mountain gorilla, a method for optimized germline and somatic variant detection across genome builds, a searchable large-scale web repository for bacterial genomes, and an integer programming framework for pangenome-based genome inference. Audio generated with NotebookLM. (The hosts were very excited about this issue!) Subscribe to Paired Ends (free) to get summaries like this delivered to your e-mail. Deep dive Cloudgene 3: Transforming Nextflow Pipelines into Powerful Web Services Paper: Lukas Forer and Sebastian Schönherr. Cloudgene 3: Transforming Nextflow Pipelines into Powerful Web Services. bioRxiv, 2024. DOI: 10.1101/2024.10.27.620456 (https://doi.org/10.1101/2024.10.27.620456). I got to meet both Lukas and Sebastian in person at the Nextflow Summit (https://blog.stephenturner.us/p/nextflow-summit-barcelona-2024). Lukas gave a talk on nf-test (https://www.youtube.com/watch?v=jcxqGCWp71g&list=PLPZ8WHdZGxmVKQga4KE15YVt95i-QXVvE&index=5), while Sebastian gave a talk on the Michigan Imputation Serve (https://www.youtube.com/watch?v=ainEmE6zVbI&list=PLPZ8WHdZGxmVKQga4KE15YVt95i-QXVvE&index=24)r (MIS). MIS is implemented in Nextflow and driven using Cloudgene, and has helped over 12,000 researchers worldwide impute over 100 million samples. This paper describes Cloudgene for turning a Nextflow pipeline into a web service. TL;DR: Cloudgene 3 provides a user-friendly platform to convert Nextflow pipelines into scalable web services, allowing scientists to deploy and run complex bioinformatics workflows without requiring web development expertise. Summary: Cloudgene 3 addresses the challenge of deploying Nextflow pipelines as scalable web services, allowing researchers to leverage computational workflows without the need for technical setup or coding. The platform simplifies the transformation of Nextflow pipelines into “Cloudgene apps,” which include user-friendly interfaces and allow for seamless dataset management, job monitoring, and data security. By supporting features like workflow chaining and dataset integration, Cloudgene 3 enables collaborative and flexible use of pipelines across various scientific domains, from genomics to proteomics. This tool expands accessibility to complex analyses, facilitating data sharing and enhancing reproducibility, and has already been implemented in large-scale services like the Michigan Imputation Server. Its open accessibility and adaptable deployment model (cloud or local infrastructure) highlight its utility for bioinformatics workflows. Methodological highlights: * Converts Nextflow pipelines into web services with a few simple steps, creating portable “apps” that include metadata, input/output parameters, and multi-step workflows. * Integrates real-time status updates and error handling for Nextflow tasks, leveraging a unique secret URL for each task to monitor progress. * Supports cloud platforms and local installations, providing compatibility with engines like Slurm and AWS Batch and storage options like AWS S3. New tools, data, and resources: * Cloudgene 3 platform: Free platform available at cloudgene.io (https://www.cloudgene.io/). * Cloudgene 3 source code: https://github.com/genepi/cloudgene3 (https://github.com/genepi/cloudgene3). Comprehensive genome analysis and variant detection at scale using DRAGEN Paper: Behera, S., et al. Comprehensive genome analysis and variant detection at scale using DRAGEN. Nature Biotechnology, 2024. DOI: 10.1038/s41587-024-02382-1 (https://doi.org/10.1038/s41587-024-02382-1). DRAGEN was a godsend in a previous job. I needed a turnkey variant calling solution that was fast. I bought an on-prem DRAGEN FPGA server, which was capable of taking you from FASTQ files to VCF in ~30 minutes for a 30X human whole genome. Illumina has previously published white papers on DRAGEN’s speed and accuracy. The publication in Nature Biotechnology engendered some interesting discussion (https://x.com/nomad421/status/1849977588539642161) online. On one hand, the paper was a pleasure to read, and the benchmarks are compelling and well done. On the other, the method isn’t available to explore, reproduce, understand in detail, or build upon. Which raises the question — should this have been a peer-reviewed publication in the scientific record? Or should this just have been another white paper? At some point “papers” hawking some new and improved closed source method are thinly veiled advertisements stamped with the approval of peer review. I think there should be some place in the scientific literature for papers like this describing a closed-source method, but where benchmarks are independently evaluated by a team of peer reviewers. I just don’t know what that looks like in the current landscape of peer reviewed papers versus a vendor’s white paper. TL;DR: DRAGEN is a high-speed, highly accurate genomic analysis platform for variant detection, leveraging hardware acceleration, pangenome references, and machine learning. It outperforms traditional tools across variant types (SNVs, indels, SVs, CNVs, STRs) and is designed for large-scale, clinical genomics applications. Summary: This study presents DRAGEN, a platform that uses accelerated hardware and sophisticated algorithms to enable comprehensive variant detection at unprecedented speed and accuracy. By integrating pangenome references and optimizing for all major variant classes, DRAGEN achieves high concordance in identifying complex and diverse genomic variants, even in challenging regions. Benchmarking across 3,202 genomes from the 1000 Genomes Project highlights DRAGEN’s scalability and its advantages over traditional methods like GATK and DeepVariant, especially for clinically relevant genes. The platform’s robust performance across SNVs, SVs, CNVs, and STRs allows for large-cohort analyses critical for population-scale genomics and clinical diagnostics, facilitating variant discovery in diseases with both common and rare genetic underpinnings. Methodological highlights: * Uses pangenome references to enhance alignment accuracy and variant detection across diverse populations. * Optimized for rapid, parallel processing of SNVs, indels, CNVs, and STRs with an average processing time of ~30 minutes per genome. * Employs machine learning-based filtering to reduce false positives and improve accuracy in variant calling. * Integration of ExpansionHunter for STR analysis and specialized callers for pharmacogenomic variants (e.g., CYP2D6, SMN) ensures reliable detection in medically significant genes. Machine-guided design of cell-type-targeting cis-regulatory elements Paper: Gosai, S. J., et al. Machine-guided design of cell-type-targeting cis-regulatory elements. Nature, 2024. DOI: 10.1038/s41586-024-08070-z (https://doi.org/10.1038/s41586-024-08070-z). TL;DR: This paper introduces a platform for designing synthetic cis-regulatory elements (CREs) with programmed cell-type specificity using a deep-learning-based model called Malinois, combined with a computational design tool, CODA, and massively parallel reporter assays (MPRAs) for validation. Summary: This study presents a framework for designing synthetic CREs that drive gene expression specifically in desired cell types. Using Malinois, a deep convolutional neural network trained on MPRA data from human cells, the researchers predict CRE activity and design synthetic elements targeting specific cell lines. The CODA (Computational Optimization of DNA Activity) platform then iteratively refines these designs to achieve high specificity, which is validated in vitro across multiple cell types and in vivo in mice and zebrafish. By outperforming natural CREs in specificity and robustness, these synthetic elements could significantly enhance targeted gene therapy approaches, especially by providing tools for precise gene expression control in therapeutic and research applications. The framework expands our capacity to engineer regulatory DNA for complex tissue-specific requirements, advancing possibilities for both biomedical research and gene therapy. Methodological highlights: * Malinois CNN model predicts cell-type-specific CRE activity directly from DNA sequences, validated with MPRA-based data in K562, HepG2, and SK-N-SH cells. * CODA optimization platform iteratively adjusts CRE sequences to increase cell-type specificity, employing algorithms such as Fast SeqProp for efficient sequence design. * High-throughput MPRA validates the activity of 77,157 synthetic and natural CRE sequences across cell types, showing superior specificity in synthetic CREs. New tools, data, and resources: * Code availability: https://github.com/sjgosai/boda2 (https://github.com/sjgosai/boda2) (yes, this is the CODA repo, which is named “boda2” for “legacy reasons”). * Data availability: All the data used in the study is described in the data availability section (https://www.nature.com/articles/s41586-024-08070-z#data-availability) of the paper. KiNext: a portable and scalable workflow for the identification and classification of protein kinases Paper: Hellec, E., et al. KiNext: A Portable and Scalable Workflow for the Identification and Classification of Protein Kinases. BMC Bioinformatics, 2024. DOI: 10.1186/s12859-024-05953-w (https://doi.org/10.1186/s12859-024-05953-w). TL;DR: KiNext is a Nextflow-based pipeline for identifying and classifying protein kinases (kinome) from annotated genomes, enabling reproducible analysis and classification of kinase families across species. Summary: Protein kinases are crucial for cellular signaling and adaptation, and identifying the full kinome of an organism can reveal insights into its physiological and adaptive capabilities. KiNext automates this process, applying Hidden Markov Models (HMMs) to detect both eukaryotic and atypical protein kinases from genomic data and classifying them into known kinase families. Validated against two model species, Crassostrea gigas and Ostreococcus tauri, KiNext identified previously unclassified kinases and achieved enhanced classification accuracy compared to earlier methods. The tool is particularly valuable for large-scale genome projects, such as the Earth BioGenome Project, as it ensures reproducible kinome analysis in alignment with FAIR data principles. By allowing user-provided HMMs, it can be adapted for diverse taxa, making it versatile for comparative kinome studies. Methodological highlights: * Uses Nextflow and Singularity containers for reproducible, scalable analysis of kinomes across computing environments. * Combines HMM models for specific kinase groups with automatic phylogenetic analysis of ePKs and aPKs using IQTree, facilitating precise classification. * Outputs include detailed summary tables of identified kinases, with options for further validation using structural prediction tools like AlphaFold and Foldseek. New tools, data, and resources: * Code availability: On GitLab at https://gitlab.ifremer.fr/bioinfo/workflows/kinext (https://gitlab.ifremer.fr/bioinfo/workflows/kinext). Note that this is licensed under the AGPL, not the regular GPL. Meaning that the source code availability trigger in the GPL also applies if the pipeline is offered over a network as a service. scGenePT: Is language all you need for modeling single-cell perturbations? Paper: Istrate, A.-M., et al. scGenePT: Is language all you need for modeling single-cell perturbations? bioRxiv, 2024. https://doi.org/10.1101/2024.10.23.619972 (https://doi.org/10.1101/2024.10.23.619972). This work from researchers at the Chan Zuckerberg Initiative was also covered a recent issue (https://bitsinbio.substack.com/p/bits-in-bio-weekly-october-29th-2024) of the Bits In Bio Weekly newsletter (which, by the way, if you haven’t subscribed to the newsletter or joined the BiB Slack (https://join.slack.com/t/bitsinbio/shared_invite/zt-1zm9rebti-7CmMNhMImVcUuFmwjkscIA), you should). Of note the text embeddings use GPT 3.5, which is already outdated. Unfortunately the code and model checkpoints aren’t available, and “will be made available upon publication.” TL;DR: This study introduces scGenePT, an enhanced single-cell gene perturbation model combining biological and language-based representations to predict gene expression outcomes. By incorporating gene knowledge from scientific literature, it improves over traditional models like scGPT in complex perturbation settings. Summary: In advancing single-cell biology, predicting the effects of gene perturbations is essential. Traditional models rely on experimental data, such as single-cell RNA sequencing counts, but scGenePT integrates language embeddings from scientific resources (e.g., NCBI, UniProt, Gene Ontology) to enrich gene representations. The findings suggest that adding textual gene representations enhances the predictive power for single- and two-gene perturbations, especially where gene interactions yield non-additive effects. This approach is crucial for handling diverse perturbation scenarios, with significant implications for precision medicine, as it facilitates a more nuanced understanding of gene interactions under various conditions. The study validates the integration approach with superior performance over models relying solely on experimental data, demonstrating that language representations can serve as a valuable prior in biological modeling. Methodological highlights: * scGenePT extends scGPT by adding gene-specific language embeddings sourced from scientific literature, providing both additive and complementary information for perturbation modeling. * Uses GPT-3.5 embeddings to align knowledge sources like NCBI gene summaries, UniProt protein data, and Gene Ontology annotations. * Employs a Transformer-based architecture where language and experimental data embeddings converge at the gene representation level, followed by a Transformer encoder-decoder setup for predictive modeling. * Code availability: Unfortunately the code and model checkpoints aren’t available, and “will be made available upon publication.” Scalable protein design using optimization in a relaxed sequence space Paper: Frank, C., et al. Scalable Protein Design Using Optimization in a Relaxed Sequence Space. Science, 2024. DOI: 10.1126/science.adq1741 (https://doi.org/10.1126/science.adq1741). Protein design is important in medicine and biotechnology because it enables the creation of synthetic proteins tailored for specific functions, such as therapeutic agents that can target diseases more effectively or robust enzymes for diagnostics. In the area I work in (de-extinction), designed proteins can help reconstitute essential biological functions in revived or closely related species, potentially aiding in biodiversity restoration and ecological balance. TL;DR: This paper presents a new pipeline for protein design using relaxed sequence optimization (RSO), which enables efficient gradient-based design of large and complex protein structures. This approach yields high-quality protein backbones and supports applications in synthetic protein-protein interactions. Summary: The study introduces Relaxed Sequence Optimization (RSO), a gradient-descent method applied in a “relaxed” sequence space that enables rapid convergence in protein design without the constraints of one-hot encoding. By iteratively optimizing loss functions within AlphaFold2’s predictive space, RSO creates diverse protein backbones, later refined by ProteinMPNN to ensure foldability into intended structures. This approach was experimentally validated with over 100 designed proteins, including large monomers and heterodimers, highlighting its scalability and structural accuracy for de novo proteins up to 1000 amino acids. The RSO pipeline, which allows for custom loss functions tailored to specific design goals, represents a significant advance in both design speed and application scope, facilitating the development of stable, large-scale proteins relevant to fields like structural biology and synthetic biochemistry. Methodological highlights: * RSO operates in a relaxed sequence space, optimizing backbones without forcing discrete amino acid representations, allowing for smooth gradient transitions. * Integrates ProteinMPNN for generating foldable protein sequences that match RSO-designed backbones, achieving stable high-resolution structures in experimental validation. * Customizable loss functions support specific design tasks, such as helical content reduction and binder-targeting configurations, without retraining. New tools, data, and resources: * Code availability: Available on GitHub: github.com/sokrypton/ColabDesign (https://github.com/sokrypton/ColabDesign) * Data availability: Experimental data, including TEM images and crystal structures, are archived on Figshare at doi.org/10.6084/m9.figshare.27009724 (https://figshare.com/articles/dataset/Data_for_Relaxed_Sequence_Optimization_Paper/27009724), with additional cryo-EM and crystal models in PDB and EMDB. Other papers of note * Improving bioinformatics software quality through teamwork https://academic.oup.com/bioinformatics/advance-article/doi/10.1093/bioinformatics/btae632/7831429 (https://academic.oup.com/bioinformatics/advance-article/doi/10.1093/bioinformatics/btae632/7831429) * Targeted nanopore sequencing using the Flongle device to identify mitochondrial DNA variants https://www.nature.com/articles/s41598-024-75749-8 (https://www.nature.com/articles/s41598-024-75749-8) * Review: Plant conservation in the age of genome editing: opportunities and challenges https://genomebiology.biomedcentral.com/articles/10.1186/s13059-024-03399-0 (https://genomebiology.biomedcentral.com/articles/10.1186/s13059-024-03399-0) * Oatk: a de novo assembly tool for complex plant organelle genomes https://www.biorxiv.org/content/10.1101/2024.10.23.619857v1 (https://www.biorxiv.org/content/10.1101/2024.10.23.619857v1) * LYCEUM: Learning to call copy number variants on low coverage ancient genomes https://www.biorxiv.org/content/10.1101/2024.10.28.620589v2 (https://www.biorxiv.org/content/10.1101/2024.10.28.620589v2) * A near telomere-to-telomere phased reference assembly for the male mountain gorilla https://www.biorxiv.org/content/10.1101/2024.10.28.620258v1 (https://www.biorxiv.org/content/10.1101/2024.10.28.620258v1) * StableLift: Optimized Germline and Somatic Variant Detection Across Genome Builds https://www.biorxiv.org/content/10.1101/2024.10.31.621401v1 (https://www.biorxiv.org/content/10.1101/2024.10.31.621401v1) * BakRep – a searchable large-scale web repository for bacterial genomes, characterizations and metadata https://doi.org/10.1099/mgen.0.001305 (https://doi.org/10.1099/mgen.0.001305) * Integer programming framework for pangenome-based genome inference https://www.biorxiv.org/content/10.1101/2024.10.27.620212v1.full (https://www.biorxiv.org/content/10.1101/2024.10.27.620212v1.full) Subscribe to Paired Ends (free) to get summaries like this delivered to your e-mail. This is a public episode. If you would like to discuss this with other subscribers or get access to bonus episodes, visit blog.stephenturner.us (https://blog.stephenturner.us?utm_medium=podcast&utm_campaign=CTA_1)

6. 

   5 Dec 2024

   Weekly Recap (Dec 2024, part 1)

   Stephen Turner's Paired Ends podcast recaps the latest advancements in computational workflows, AI-powered virtual cells, and bioinformatics methods for prioritizing causal genetic variants and predicting gene expression in diverse cellular and disease states.

7. 

   22 Nov 2024

   Weekly Recap (Nov 2024, part 3)

   Full recap: https://blog.stephenturner.us/p/weekly-recap-nov-2024-part-3 (https://blog.stephenturner.us/p/weekly-recap-nov-2024-part-3) This week’s recap highlights pangenome graph construction with nf-core/pangenome, building pangenome graphs with PGGB, benchmarking algorithms for single-cell multi-omics prediction and integration, RNA foundation models, and a Nextflow pipeline for characterizing B cell receptor repertoires from non-targeted bulk RNA-seq data. Others that caught my attention include benchmarking generative models for antibody design, improved detection of methylation in ancient DNA, differential transcript expression with edgeR, a pipeline for processing xenograft reads from spatial transcriptomics (Xenomake), public RNA-seq datasets and human genetic diversity, a review on bioinformatics approaches to prioritizing causal genetic variants in candidate regions, quantifying constraint in the human mitochondrial genome, a review on sketching with minimizers in genomics, and analysis of outbreak genomic data using split k-mer analysis. Deep dive Cluster-efficient pangenome graph construction with nf-core/pangenome Paper: Heumos, S. et al. Cluster-efficient pangenome graph construction with nf-core/pangenome. Bioinformatics, 2024. DOI: 10.1093/bioinformatics/btae609 (https://doi.org/10.1093/bioinformatics/btae609). Benchmarking in bioinformatics typically involves some measure of accuracy (precision, recall, F1 score, MCC, ROC, etc.), and compute requirements (CPU time, peak RAM usage, etc.). A metric I’ve been seeing more recently is the carbon footprint of a particular bioinformatics analysis. In the benchmarks performed here (detailed below), the authors calculated the CO2 equivalent (CO2e) emissions for running both nf-core/pangenome and another commonly used tool, showing that nf-core/pangenome took half the time for an analysis without increasing CO2e. It looks like the authors are using the nf-co2footprint (https://github.com/nextflow-io/nf-co2footprint) plugin to do this. TL;DR: This paper introduces nf-core/pangenome, a Nextflow-based pipeline for constructing reference-unbiased pangenome graphs, offering improved scalability and computational efficiency compared to existing tools like the PanGenome Graph Builder (PGGB is highlighted next in this post!). Summary: The nf-core/pangenome pipeline offers a scalable and efficient method for building pangenome graphs by distributing computations across multiple cluster nodes, overcoming the limitations of PGGB, a widely used tool in the field. Pangenome graphs model the collective genomic content across populations, reducing biases associated with traditional reference-based approaches. This work showcases the pipeline’s power by constructing a graph for 1000 chromosome 19 human haplotypes in just three days and processing over 2000 E. coli sequences in ten days—tasks that would take PGGB much longer or fail due to computational limitations. The nf-core/pangenome pipeline emphasizes portability and seamless deployment in high-performance computing (HPC) environments using biocontainers. With these features, it enables population-scale genomic analyses for various organisms, supporting biodiversity and personalized genomics research. Methodological highlights: * Uses Nextflow for efficient workflow management and resource distribution, ensuring parallel processing and modular flexibility. * Avoids reference biases by aligning each sequence against all others with WFMASH, followed by graph induction with SEQWISH and graph simplification with SMOOTHXG. * The pipeline integrates ODGI for quality control and MultiQC for generating summary reports, ensuring comprehensive analyses. New tools, data, and resources: * GitHub repository: https://github.com/nf-core/pangenome (https://github.com/nf-core/pangenome). * Documentation/tests: https://nf-co.re/pangenome (https://nf-co.re/pangenome). * Code for the paper: https://github.com/subwaystation/pangenome-paper (https://github.com/subwaystation/pangenome-paper). Here’s a talk from last year’s Nextflow summit where Simon Heumos (lead author on this paper) talks about the workflow in detail. Building pangenome graphs Paper: Garrison, E. et al. Building pangenome graphs. Nature Methods, 2024. DOI: 10.1038/s41592-024-02430-3 (https://doi.org/10.1038/s41592-024-02430-3) (read free: https://rdcu.be/dXDTo (https://rdcu.be/dXDTo)) The benchmarking paper above discusses nf-core/pangenome in contrast to PGGB, the subject of this paper. This paper was originally published in April 2023, and this updated version of the preprint contains new experimental data. The authors from this paper and the previous nf-core/pangenome paper overlap substantially. TL;DR: This paper introduces PanGenome Graph Builder (PGGB), a reference-free tool that constructs unbiased pangenome graphs to capture both small and large-scale genetic variations. It avoids reference bias by using all-to-all alignments and provides scalable, lossless representations of genomic data. Summary: PGGB addresses limitations in traditional genome graph tools, which often rely on a single reference genome, leading to biases and loss of complex variation. The pipeline performs unbiased, reference-free alignments of multiple genomes using the WFMASH tool, followed by graph construction with SEQWISH and graph simplification with SMOOTHXG. This modular approach captures SNPs, structural variants, and large sequence differences across multiple genomes in a unified framework. The study demonstrates PGGB’s ability to scale efficiently, building complex pangenome graphs for datasets such as human chromosome 6 and primate assemblies. PGGB is validated against existing tools, showing superior performance in accurately representing small and structural variants. Its output facilitates downstream analyses such as phylogenetics, population genetics, and comparative genomics, supporting large-scale projects like the Human Pangenome Reference Consortium (HPRC). Methodological highlights: * Reference-free alignment: Uses WFMASH for all-to-all sequence alignment, enabling unbiased graph construction. * Graph induction and normalization: Constructs graphs with SEQWISH and smooths complex motifs with SMOOTHXG, improving downstream compatibility. * Sparsified alignment approach: Implements random sparsification to reduce computational costs while maintaining accurate genome relationships. New tools, data, and resources: * GitHub repository: https://github.com/pangenome/pggb (https://github.com/pangenome/pggb). * Data: Example pangenomes and validation datasets available at https://doi.org/10.5281/zenodo.7937947 (https://doi.org/10.5281/zenodo.7937947). * Documentation: https://pggb.readthedocs.io (https://pggb.readthedocs.io). Benchmarking algorithms for single-cell multi-omics prediction and integration Paper: Hu, Y. et al. Benchmarking algorithms for single-cell multi-omics prediction and integration. Nature Methods, 2024. DOI: 10.1038/s41592-024-02429-w (https://doi.org/10.1038/s41592-024-02429-w). (Read free: https://rdcu.be/dW01n (https://rdcu.be/dW01n)). The idea behind integration of single cell data is to combine multiple types of single cell omics data (genomics, transcriptomics, epigenomics, etc) to get a more complete understanding of individual cell states. An example: maybe you use Seurat (https://satijalab.org/seurat/articles/integration_introduction.html) to map scRNA-seq data onto something like scATAC-seq obtained from the same tissue to identify nearest neighbor cells for a given cell across data types, and use the mapping to predict protein abundance or chromatin accessibility. This paper benchmarks many different integration approaches, making the distinction between vertical integration (different modalities), horizontal integration (batch correction across datasets), and mosaic integration (multi-omic datasets sharing one type of omics data). TL;DR: This study benchmarks 14 prediction algorithms and 18 integration algorithms for single-cell multi-omics, highlighting top performers such as totalVI, scArches, LS_Lab, and UINMF. It also provides a framework for selecting optimal algorithms based on specific prediction and integration tasks. Summary: Single-cell multi-omics technologies enable simultaneous profiling of RNA expression, protein abundance, and chromatin accessibility. This paper evaluates 14 algorithms that predict protein abundance or chromatin accessibility from scRNA-seq data and 18 algorithms for multi-omics integration. totalVI and scArches consistently excel in protein abundance prediction, while LS_Lab demonstrates superior performance in predicting chromatin accessibility. For multi-omics integration tasks, Seurat and MOJITOO lead in vertical integration, while UINMF and totalVI excel in horizontal and mosaic integration scenarios, respectively. The study uses 47 datasets across diverse tissues and experimental setups to provide robust recommendations for algorithm selection in different single-cell workflows. Methodological highlights: * Two evaluation scenarios: Intra-dataset (same dataset split into train/test) and inter-dataset (train on one dataset, test on another). * Six performance metrics: cell‒cell Pearson correlation coefficient (PCC), protein-protein PCC, cell-cell correlation matrix distance (CMD), protein-protein CMD, AUROC and RMSE. * Evaluation framework: Compares prediction and integration algorithms across single-cell RNA + protein and RNA + chromatin datasets. * Top-performing tools: no single algorithm consistently outperformed the others in every metric and dataset. Generally, performance was better for: * totalVI and scArches for protein abundance prediction. * LS_Lab for chromatin accessibility prediction. * Seurat and MOJITOO for merging RNA expression with protein abundance. * UINMF for integrating batches of scRNA+scATAC data. New tools, data, and resources: * Benchmarking pipeline: Available on GitHub at https://github.com/QuKunLab/MultiomeBenchmarking (https://github.com/QuKunLab/MultiomeBenchmarking). * Datasets: 47 multi-omics datasets (CITE-seq, REAP-seq, SNARE-seq, 10x Multiome) were used to benchmark algorithm performance. Links to relevant resources provided in the Data availability section (https://www.nature.com/articles/s41592-024-02429-w#data-availability). Orthrus: Towards Evolutionary and Functional RNA Foundation Models Paper: Fradkin, P. et al. Orthrus: Towards Evolutionary and Functional RNA Foundation Models. bioRxiv 2024. DOI: doi.org/10.1101/2024.10.10.617658 (https://doi.org/10.1101/2024.10.10.617658). I discovered this from the Bits in Bio newsletter (https://bitsinbio.substack.com/p/bits-in-bio-weekly-october-15th-2024) (which I highly recommend subscribing to). There are plenty of protein and DNA language models around, but this paper describes a new RNA foundation model that can help predict mRNA properties important for therapy and mRNA vaccine development. TL;DR: Orthrus is a new RNA foundation model using contrastive learning, leveraging biological augmentations like splice isoforms and orthologous sequences to predict RNA properties like half-life and protein localization, outperforming existing models in low-data regimes. The code is available at https://github.com/bowang-lab/Orthrus (https://github.com/bowang-lab/Orthrus). Summary: Orthrus introduces a novel approach to RNA property prediction by utilizing contrastive learning based on biological principles. It clusters RNA sequences with functional and evolutionary similarities, using data from 10 species for alternative splicing and over 400 mammalian species for orthology through the Zoonomia project. This strategy enables Orthrus to outperform other RNA foundation models, especially in low-data settings, where it requires minimal fine-tuning to achieve state-of-the-art predictions. Orthrus was evaluated on multiple tasks, including RNA half-life and protein localization, and outperformed supervised models in these areas. The model's ability to generalize well in such scenarios makes it an important tool for predicting RNA functions and understanding alternative splicing’s role in cellular processes. bcRflow: a Nextflow pipeline for characterizing B cell receptor repertoires from non-targeted transcriptomic data Paper: Schlegel, B. T. et al. bcRflow: a Nextflow pipeline for characterizing B cell receptor repertoires from non-targeted transcriptomic data. NAR Genomics and Bioinformatics, 2024. DOI: https://doi.org/10.1093/nargab/lqae137 (https://doi.org/10.1093/nargab/lqae137). Targeted B cell sequencing (bulk or single cell) gives you in-depth profiling of the B cell receptor repertoire. The method described here is used for BCR profiling from nontargeted bulk RNA-seq data. TL;DR: bcRflow is a Nextflow pipeline designed to analyze B cell receptor (BCR) repertoires from non-targeted transcriptomic data. It supports bulk and single-cell RNA-seq data and integrates tools for alignment, assembly, and downstream analysis. Summary: bcRflow is a versatile, scalable Nextflow pipeline for profiling B cell receptor repertoires using bulk or single-cell RNA-seq data. It automates the extraction of immunoglobulin (Ig) sequences and their downstream analysis, which typically requires targeted immune sequencing. By leveraging the MiXCR algorithm for BCR assembly and germline sequence imputation, bcRflow identifies unique clonotypes and characterizes V(D)J recombination patterns, somatic hypermutation rates, class-switch recombination, and repertoire diversity. The pipeline is demonstrated on RNA-seq data from COVID-19 patients, revealing disease-associated shifts in BCR repertoires. bcRflow facilitates immune repertoire studies in diverse biological and clinical contexts, including infectious diseases and vaccine responses, without incurring the costs of targeted sequencing approaches. Methodological highlights: * MiXCR-based alignment: Uses MiXCR for V(D)J gene segment alignment and BCR assembly, supporting both bulk and single-cell RNA-seq data. * Germline sequence imputation: Imputes germline sequences for assessing somatic hypermutation and immune repertoire diversity. * Modular Nextflow design: Offers high scalability, portability, and flexibility across various computational environments, including HPC clusters and cloud-based resources. New tools, data, and resources: * Source code: https://github.com/Bioinformatics-Core-at-Childrens/bcRflow (https://github.com/Bioinformatics-Core-at-Childrens/bcRflow). * Docker: https://hub.docker.com/r/bioinformaticscoreatchildrens/bcrflow (https://hub.docker.com/r/bioinformaticscoreatchildrens/bcrflow) (docker pull bioinformaticscoreatchildrens/bcrflow). * Data availability: RNA-seq data used in this study is from GSE206263 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE206263) (Differential chromatin accessibility in peripheral blood mononuclear cells underlies COVID-19 disease severity prior to seroconversion [bulkRNA-Seq]). Other papers of note * Benchmarking Generative Models for Antibody Design https://www.biorxiv.org/content/10.1101/2024.10.07.617023v2 (https://www.biorxiv.org/content/10.1101/2024.10.07.617023v2) * Improved detection of methylation in ancient DNA https://genomebiology.biomedcentral.com/articles/10.1186/s13059-024-03405-5 (https://genomebiology.biomedcentral.com/articles/10.1186/s13059-024-03405-5) * Faster and more accurate assessment of differential transcript expression with Gibbs sampling and edgeR v4 https://www.biorxiv.org/content/10.1101/2024.06.25.600555v2 (https://www.biorxiv.org/content/10.1101/2024.06.25.600555v2) * Xenomake: A pipeline for processing and sorting xenograft reads from spatial transcriptomic experiments https://academic.oup.com/bioinformatics/advance-article/doi/10.1093/bioinformatics/btae608/7821183 (https://academic.oup.com/bioinformatics/advance-article/doi/10.1093/bioinformatics/btae608/7821183) * Public RNA-seq data are not representative of global human diversity https://www.biorxiv.org/content/10.1101/2024.10.11.617967v2 (https://www.biorxiv.org/content/10.1101/2024.10.11.617967v2) * (Review) A bioinformatics toolbox to prioritize causal genetic variants in candidate regions https://www.cell.com/trends/genetics/fulltext/S0168-9525(24)00215-4 (https://www.cell.com/trends/genetics/fulltext/S0168-9525(24)00215-4) * Quantifying constraint in the human mitochondrial genome https://www.nature.com/articles/s41586-024-08048-x (https://www.nature.com/articles/s41586-024-08048-x) (free: https://rdcu.be/dXhc2 (https://rdcu.be/dXhc2)) * (Review) When less is more: sketching with minimizers in genomics https://genomebiology.biomedcentral.com/articles/10.1186/s13059-024-03414-4 (https://genomebiology.biomedcentral.com/articles/10.1186/s13059-024-03414-4) * Seamless, rapid, and accurate analyses of outbreak genomic data using split k-mer analysis https://genome.cshlp.org/content/early/2024/10/10/gr.279449.124.short (https://genome.cshlp.org/content/early/2024/10/10/gr.279449.124.short) Subscribe to Paired Ends (free) to get summaries like this delivered to your e-mail. This is a public episode. If you would like to discuss this with other subscribers or get access to bonus episodes, visit blog.stephenturner.us (https://blog.stephenturner.us?utm_medium=podcast&utm_campaign=CTA_1)

8. 

   14 Oct 2024

   Inciteful+Zotero to find relevant literature

   https://blog.stephenturner.us/p/inciteful-zotero-biologpt-semantic-scholar (https://blog.stephenturner.us/p/inciteful-zotero-biologpt-semantic-scholar) I am in the middle of writing a review / perspectives paper. One that I’m confident will be exciting once we get it published. Some sections of the review cover subject matter at the outer periphery of my expertise. These are areas where I don’t have as strong of a command of the relevant literature as my collaborators do. In my Zotero (https://www.zotero.org/) library I have a collection of a few relevant papers in these areas published by my co-authors, but I needed a way to quickly find other relevant papers in this field based on the small collection of papers I already have. Inciteful + Zotero was a perfect combination. I also found BioloGPT and Semanitic Scholar to be useful for other related tasks. Inciteful A colleague introduced me to Inciteful ( https://inciteful.xyz/ ), and at first glance it seemed to fit the bill perfectly. And, it’s free (really free, not freemium free, not free for now free — truly free, with no sign-up required). What does Inciteful do and why would you use it? From the general documentation: [Inciteful] builds a network of papers from citations, uses network analysis algorithms to analyze the network, and gives you the information you need to quickly get up to speed on that topic. You can find the most similar papers, important papers as well as prolific authors and institutions. And from the Use Cases documentation (https://help.inciteful.xyz/use-cases.html): Getting Familiar With a Body of Literature The first and most basic is familiarizing yourself with a body of literature. This happens all the time, you become interested in a topic that is not directly related to your current work and it’s tough to get a handle on the current state of that topic. Inciteful makes that easy. Finding Literature for a Paper in Progress As you are writing a paper it’s good to periodically check to be sure the what you are writing addresses the most recent literature in the topic. Rounding Out a Literature Review Literature reviews tend to start with keyword based searches using your academic search engine of choice. You often end up using complicated search strategies …Even after all these complicated searches, you have no way of knowing if anything slipped through the cracks. This is where Inciteful shines. You can go to inciteful.xyz (https://inciteful.xyz/) and start building out a collection of papers by entering DOIs, PMIDs, arXiv URLs, etc., but I found the most effective way to do this was to seed my Inciteful search from a collection of papers I already have in my Zotero library. Using Inciteful with Zotero I’ve been using Zotero for reference management since the 2000s when it was initially only a Firefox browser extension. I used Mendeley for a period until it was acquired by Elsevier, then switched back to Zotero. Zotero is the only reference manager I’m aware of that works with MS Word, Google Docs, and integrates seamlessly with RStudio (https://posit.co/blog/rstudio-1-4-preview-citations/) to insert BiBTeX citations in RMarkdown/Quarto. The Inciteful plugin for Zotero (https://github.com/inciteful-xyz/inciteful-zotero-plugin) was clutch here. This allows you to highlight papers in your Zotero library, right click, and start a graph search, right from Zotero. Let’s take a look. Demo The literature review I’m writing isn’t a review on gene editing, but I work with a lot of brilliant genome engineers at Colossal. When I first got started here I read all the literature in this area I could get my hands on, because I came to Colossal with little background in synthetic biology. This demo uses a subset of papers in my CRISPR / genome engineering collection in Zotero. First, you can highlight all the papers you want to seed your search with. With the Inciteful plugin installed, right click, and start a graph search. This opens Inciteful in your browser and the first thing you’ll see is a citation graph. It’s a nice visual, but I personally never find these kinds of graphs all that useful. The real benefit comes from the tables below. The first table is a list of similar papers which tend to cite the papers I used as input from my Zotero library. Next you can see a list of the most important papers, by PageRank. Some of these I already have in my library. Others I don’t, but I can add these to the existing search with the “+” sign. Obvious missing paper here was the landmark 2012 paper from Emmanuelle Charpentier’s lab. Next I can get a list of papers that cite the largest number of papers I have in my collection, which are likely review papers. Finally, there are four sections that aren’t immediately useful for expanding my literature search. I’m glad the developer included these, because it’s interesting to see things like the top authors, institutions, journals, etc. The “Upcoming Authors” section was interesting to me. How are these found? See the little “SQL” button at the bottom of each panel? Clicking it you can actually see the SQL code that’s running behind the scenes. And you can modify and re-execute it! Here’s the SQL for the Upcoming Authors section. Other tools Inciteful isn’t the only tool that occupies this space. I spent a little time with BioloGPT and Semantic Scholar. Both of these are more AI-forward than Inciteful. BioloGPT BioloGPT (biologpt.com (https://biologpt.com/)) is an interesting one. It’s less of a research discovery tool and more of a Biology-focused AI research tool. That is, you start from research questions rather than from a stack of papers you already have. From the documentation: BioloGPT is engineered to be a highly-detailed, evidence-based, and skeptical AI committed to truth-seeking and answering biology questions as accurately as possible. It rigorously cites all used papers to ensure reliability, and can even generate novel hypothesis, code, art, and experiments. By citing relevant data and maintaining a critical, empirical stance, BioloGPT directly counters potential research biases such as positive result bias, framing bias, ideologies, censorship, scientific corruption, and industry influence. I asked about current best practices for analyzing single-cell ATAC seq data (link (https://biologpt.com/?q=What%20are%20the%20current%20best%20bioinformatics%20approaches%20for%20single%20cell%20ATAC%20seq)). You get back a short summary answer, followed by a longer answer. At first this might seem like something you can get out of ChatGPT or other tools with a recent knowledge limit. The first place BioloGPT differs from a generic AI chatbot is that assertions are backed by citations, and hoving over them gives you a preview of the paper, a very short summary, citation counts, and an evidence assertion. BioloGPT then provides a code snippet. I’ve never actually used scanpy so I can’t verify the accuracy of this code, but it at least would help point you in the right direction of tools to take a look at, if nothing else. Here’s where BioloGPT helps with literature discovery to some degree. Next you’ll see a list of top search results, showing you recent literature relevant to your query. The next section presents potential hypotheses, a hypothesis graveyard, and potential experiments. This might be a little speculative, but I think the idea could help guide your research into areas you might not have explored, especially if it’s an area you’re not already intimately familiar with. Another interesting feature of BioloGPT is its ability to create plots based on an input query. The example query Graph of CD4 expression across all immune cell types (https://biologpt.com/?q=Graph%20of%20CD4%20expression%20across%20all%20immune%20cell%20types) produces the following result. The interactive graphic it produces is made with Plotly, and BioloGPT provides the sources it used to create the plot. Finally, BioloGPT saves your queries, and in your account page, you can fill in additional areas of interest. With this you’ll get a weekly roundup email pointing out new literature relevant to the questions you’ve asked and the topics you claim interest in. Semantic Scholar Semantic Scholar (semanticscholar.org (https://www.semanticscholar.org/)) is a free AI-driven search and discovery tool. You start by searching for a subject or paper. Each paper has an AI-generated TLDR, with some citation information available on the side. Once you find a paper, you can save it to your Semantic Scholar library, and you can save papers into different collections. Once you do so, you can opt in to receiving regular emails with newly published research that’s highly related to papers in one or more of your collections. This is the feature I love most about Semantic Scholar. Where Inciteful doesn’t have a login or session persistence, Semantic Scholar helps with staying on top of recently published literature relevant to literature you’ve already collected. Others I didn’t try There are plenty of other tools that occupy this space. I haven’t had a chance yet to use Elicit (elicit.com (https://elicit.com/)) or Research Rabbit (researchrabbit.ai (https://www.researchrabbit.ai/)). There’s also PaperQA2 (“superhuman scientific literature search”) — see the blog post (https://www.futurehouse.org/research-announcements/wikicrow) and GitHub page (https://github.com/Future-House/paper-qa) (Apache license). There’s Google’s NotebookLM ( https://notebooklm.google/ ), which is more of a research assistant tool than a literature discovery tool. I imagine we’ll see many more AI-driven research support tools like this in the near future. This is a public episode. If you would like to discuss this with other subscribers or get access to bonus episodes, visit blog.stephenturner.us (https://blog.stephenturner.us?utm_medium=podcast&utm_campaign=CTA_1)

9. 

   16 Sept 2024

   Illuminate preprints with an AI-generated podcast discussion

   Full post at https://blog.stephenturner.us/p/illuminate-preprints-with-an-ai-generated-podcast (https://blog.stephenturner.us/p/illuminate-preprints-with-an-ai-generated-podcast) Google has a new experimental tool called Illuminate (illuminate.google.com (https://illuminate.google.com/)) that takes a link to a preprint and creates a podcast discussing the paper. When I tested this with a few preprints, the podcasts it generated are about 6-8 minutes long, featuring a male and female voice discussing the key points of the paper in a conversational style. There are some obvious shortcomings. It doesn’t know how to pronounce words that aren’t real words (for example, bioRxiv, or Heng Li’s new Ropebwt3), and like many text-based genAI tools, it overuses the word “delve.” And, when I gave it my recent paper describing biorecap (blog post (https://blog.stephenturner.us/p/biorecap-r-package-for-summarizing-biorxiv-preprints-local-llm), paper (https://arxiv.org/abs/2408.11707)), it delved into a discussion on generative AI ethics that I never wrote about in the paper. But, aside from these few quirks, I actually enjoyed listening to the audio it produced. I used Illuminate to generate podcasts discussing a few preprints on arXiv quantitative biology that caught my attention lately, or in the case of biorecap and pracpac, those that I authored. The full podcast at the top of this post has all six of these preprints together, timestamped with chapters if you’re listening to this in a podcast app. Alternatively, you can listen to each individual paper below. biorecap: an R package for summarizing bioRxiv preprints with a local LLM (https://arxiv.org/abs/2408.11707 (https://arxiv.org/abs/2408.11707)) BWT construction and search at the terabase scale (https://arxiv.org/abs/2409.00613 (https://arxiv.org/abs/2409.00613)) Genomic Language Models: Opportunities and Challenges (https://arxiv.org/abs/2407.11435 (https://arxiv.org/abs/2407.11435)) Near to Mid-term Risks and Opportunities of Open-Source Generative AI (https://arxiv.org/abs/2404.17047 (https://arxiv.org/abs/2404.17047)) Guidelines for releasing a variant effect predictor (https://arxiv.org/abs/2404.10807 (https://arxiv.org/abs/2404.10807)) pracpac: Practical R Packaging with Docker (https://arxiv.org/abs/2303.07876 (https://arxiv.org/abs/2303.07876)) This is a public episode. If you would like to discuss this with other subscribers or get access to bonus episodes, visit blog.stephenturner.us (https://blog.stephenturner.us?utm_medium=podcast&utm_campaign=CTA_1)

10. 

    11 Sept 2024

    Paired Ends Podcast

    This is an experiment. I’m not if or when I’ll ever do anything with it. In the meantime, subscribe to my newsletter at https://blog.stephenturner.us/ (https://blog.stephenturner.us/). This is a public episode. If you would like to discuss this with other subscribers or get access to bonus episodes, visit blog.stephenturner.us (https://blog.stephenturner.us?utm_medium=podcast&utm_campaign=CTA_1)

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