https://phys.org/news/2025-01-complex-human-cell-lines-reveals.html Phys.org Topics * Week's top * Latest news * Unread news * Subscribe [ ] Science X Account [ ] [ ] [*] Remember me Sign In Click here to sign in with or Forget Password? Not a member? Sign up Learn more * Nanotechnology * Physics * Earth * Astronomy & Space * Chemistry * Biology * Other Sciences * Medical Xpress Medicine * Tech Xplore Technology [INS::INS] * * share this! * 113 * Tweet * Share * Email 1. Home 2. Biology 3. Cell & Microbiology 1. Home 2. Biology 3. Biotechnology * * * --------------------------------------------------------------------- January 30, 2025 The GIST Editors' notes This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: fact-checked peer-reviewed publication trusted source proofread Complex engineering of human cell lines reveals genome's unexpected resilience to structural changes by Wellcome Trust Sanger Institute CRISPR-Cas Credit: Pixabay/CC0 Public Domain The most complex engineering of human cell lines ever has been achieved by scientists, revealing that our genomes are more resilient to significant structural changes than was previously thought. Researchers from the Wellcome Sanger Institute, Imperial College London, Harvard University in the US and their collaborators used CRISPR prime editing to create multiple versions of human genomes in cell lines, each with different structural changes. Using genome sequencing, they were able to analyze the genetic effects of these structural variations on cell survival. The research, published in Science, shows that as long as essential genes remain intact, our genomes can tolerate significant structural changes, including large deletions of the genetic code. The work opens the door to studying and predicting the role of structural variation in disease. Structural variation is a change in the structure of an organism's genome, such as deletions, duplications and inversions of the genetic sequence. These structural changes to the genome can be significant, sometimes affecting hundreds to many thousands of nucleotides--the basic building blocks of DNA and RNA. Structural variants are associated with developmental diseases and cancer. However, our ability to study the effects of structural variation in the genomes of mammals, and the role they play in disease, has been difficult due to the inability to engineer these genetic changes. To overcome this challenge, Sanger Institute researchers and their collaborators set out to develop new approaches for creating and studying structural variation. [INS::INS] In a new study, the team used a combination of CRISPR prime editing and human cell lines--groups of human cells in a dish--to generate thousands of structural variants in human genomes within a single experiment. To do this, researchers used prime editing to insert a recognition sequence into the genomes of the human cell lines to target with recombinase--an enzyme that enabled the team to 'shuffle' the genome. By inserting these recombinase handles into repetitive sequences, which are hundreds and thousands of identical sequences in the genome, with a single prime editor they were able to integrate up to almost 1,700 recombinase recognition sites into each cell line. This resulted in more than 100 random large-scale genetic structural changes per cell. This is the first time that it's been possible to 'shuffle' a mammalian genome, especially at this scale. The team then studied the impacts of the structural variation on the human cell lines. Using genomic sequencing, the team was able to take 'snapshots' of the human cells and their 'shuffled' genomes over the course of a few weeks, watching which cells survived and which died. As expected, they found that when structural variation deleted essential genes, this was heavily selected against and the cells died. However, they found that groups of cells with large-scale deletions in the genomes that avoided essential genes survived. Discover the latest in science, tech, and space with over 100,000 subscribers who rely on Phys.org for daily insights. Sign up for our free newsletter and get updates on breakthroughs, innovations, and research that matter--daily or weekly. [ ] Subscribe The team also conducted RNA sequencing of the human cell lines, which measures gene activity, known as gene expression. This revealed that large-scale deletions of the genetic code, especially in non-coding regions, did not seem to impact the gene expression of the rest of the cell. The researchers suggest that human genomes are extremely tolerant of structural variation, including variants that change the position of hundreds of genes, as long as essential genes are not deleted4. Plus, they query whether much of the non-coding DNA in human genomes is dispensable, but further research that engineers additional deletions in more cell lines is needed. In a related paper, also published in published in Science, researchers from the University of Washington had a similar goal of creating structural variants at large scale and studying their effects on the human genome. This team used a different approach, adding recombinase sites to transposons--mobile genetic elements--that randomly integrated in the genomes of human cell lines and mouse embryonic stem cells. Using their method, they demonstrated that the effects of the induced structural variants can be read out using single-cell RNA sequencing. This advance paves the way for large screens of structural variant impact, potentially improving the classification of structural variants found in human genomes as benign or clinically significant. [INS::INS] Both studies came to similar conclusions that human genomes are surprisingly tolerant to some substantial structural changes, although the full extent of this tolerance remains to be explored in future studies enabled by these technologies. Overall, this research presents the most engineered human cell lines to date. For the first time, researchers are able to create structural variants in human genomes, at large scales in a single experiment, and analyze the many random versions of our genomes. This work will increase our understanding of the role of structure variants in disease, which may eventually lead to predictions being made around how damaging structural variants could be in an individual. This research also helps narrow the range of the genome for exploring structural variation that leads to disease, especially if non-coding DNA can be discounted. Plus, with this new tool, scientists can generate new, streamlined cell lines with evolved properties, such as being optimized for growth, studying drug resistance, or bioengineered to create medicines. "If the genome was a book, you could think of a single nucleotide variant as a typo, whereas a structural variant is like ripping out a whole page. These structural variants are known to play roles in developmental diseases and cancer, but it has been difficult to study them experimentally," says Dr. Jonas Koeppel, co-first author previously at the Wellcome Sanger Institute, and now at the University of Washington. "Through creative and collaborative thinking, we've been able to do complex engineering in human cells that no-one has done before. By shuffling the genomes of human cell lines at large scale, we've shown that our genomes are flexible enough to tolerate significant structural changes. These tools will help focus future studies into structural variations and their roles in disease." "Our studies were only made possible because the right mix of ingredients came together at the right time: the scale of genome sequencing, cutting-edge genome engineering, and the use of recombinases. And importantly, the open and collaborative nature of our science across global borders. Our teams independently had similar ideas and came together to make these pioneering studies happen," says Dr. Raphael Ferreira, co-first author and a postdoctoral researcher in the Church Lab at Harvard Medical School. "Ten years ago, people thought it would take decades of work and hundreds of millions of dollars to engineer a rearrangeable human genome that scientists could use to study genome structure, but this work shows a way to make this possible right now. It's exciting to think about what new biology we can learn from rearrangeable genomes and where this might go next," says Professor Tom Ellis, an author of the study and Associate Faculty at the Wellcome Sanger Institute, based at the Department of Bioengineering at Imperial College London. "These studies represent a step change in the parallel creation and evaluation of structural variation in human genomes. The tools to create a single variant at a time had been available for decades, but we have demonstrated that interrogating variants and making randomized human genomes at scale is now doable. This gives new entry points both into the study of disease-associated variation, as well as opportunities for bioengineering," says Dr. Leopold Parts, co-lead author at the Wellcome Sanger Institute. More information: Jonas Koeppel et al, Randomizing the human genome by engineering recombination between repeat elements, Science (2025). DOI: 10.1126/science.ado3979. www.science.org/doi/10.1126/ science.ado3979 Science (2025). DOI: 10.1126.science.ado5978 Journal information: Science Provided by Wellcome Trust Sanger Institute Citation: Complex engineering of human cell lines reveals genome's unexpected resilience to structural changes (2025, January 30) retrieved 19 February 2025 from https://phys.org/news/ 2025-01-complex-human-cell-lines-reveals.html This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only. --------------------------------------------------------------------- Explore further Researchers map structural variants in 17,795 sequenced human genomes --------------------------------------------------------------------- 113 shares * Facebook * Twitter * Email Feedback to editors * Featured * Last Comments * Popular Dogs blink more in response to other dogs doing the same, hinting at social connection 7 hours ago 0 Synthetic diamond with hexagonal lattice outshines the natural kind with unprecedented hardness 8 hours ago 0 Two distinct superconducting states found in Bernal bilayer graphene challenge current models 8 hours ago 0 Observations investigate long-term X-ray variability of young stellar object HL Tauri 10 hours ago 0 The evolving pigment palette of European skin, eyes and hair as seen through ancient DNA Feb 18, 2025 0 --------------------------------------------------------------------- [gif] 10 new sponge species discovered in Hawaii's Kane'ohe Bay 28 minutes ago [gif] Fossil study reveals that palm trees once thrived in subarctic Canada 42 minutes ago [gif] Bacteria on marine particles play key role in ocean nitrogen cycle 56 minutes ago [gif] Proactively exposing ecosystems to mild environmental stressors offers protection, study finds 1 hour ago [gif] Ultrafast vortex electron diffraction: A new way to observe electrons in motion 1 hour ago [gif] Chlorine plus UV light can detoxify water affected by harmful algae blooms 2 hours ago [gif] CRISPR manipulation of UFO gene reveals complex plant flowering dynamics 2 hours ago [gif] Disrupting parasite gene regulation reveals new malaria intervention strategy 2 hours ago [gif] Blocking plant immune responses gives colonizing bacteria a competitive advantage 3 hours ago [gif] Alaska's lakes and ponds reveal effects of permafrost thaw 3 hours ago --------------------------------------------------------------------- Relevant PhysicsForums posts US Government Shuts Down NIH Grant Reviews and More 22 hours ago Is there a link between poultry consumption and longevity? Feb 16, 2025 Heat transfer and body temperature regulation in Huskies Feb 8, 2025 Here comes COVID-19 version BA.2, BA.4, BA.5,... Feb 8, 2025 Biochemical effects of switching to dairy-free foods Feb 7, 2025 Rolling Review of HIPRA COVID-19 Vaccine: Booster for Adults Feb 5, 2025 More from Biology and Medical --------------------------------------------------------------------- [INS::INS] * Related Stories [gif] Researchers map structural variants in 17,795 sequenced human genomes May 28, 2020 [gif] Researchers disclose genome-wide variations in secondary structure of human DNA May 24, 2021 [gif] New structural variant detection tool could significantly advance genomic analysis and precision medicine Oct 10, 2024 [gif] Genetic germline variations influence expression of cancer cell genes, finds study Mar 4, 2024 [gif] A thorough characterization of structural variants in human genomes Apr 16, 2019 [gif] Complex genomic variants are related to psychiatric diseases, study finds Oct 21, 2024 * Recommended for you [gif] Disrupting parasite gene regulation reveals new malaria intervention strategy 2 hours ago [gif] Blocking plant immune responses gives colonizing bacteria a competitive advantage 3 hours ago [gif] Circular mRNA produces 200 times more protein, enhancing precision therapy potential 11 hours ago [gif] Resilient algae darken glacier surface and may speed up Greenland ice melt, study finds 6 hours ago [gif] Time to update textbooks on electron transport chain in mitochondria, researchers say 6 hours ago [gif] Cancer cells cooperate to scavenge for nutrients, scientists discover 7 hours ago Load comments (0) Get Instant Summarized Text (Gist) The engineering of human cell lines has demonstrated that human genomes are more resilient to structural changes than previously believed. Using CRISPR prime editing, researchers created numerous structural variants in human genomes, revealing that genomes can tolerate significant alterations as long as essential genes remain intact. This work enhances the understanding of structural variants' roles in diseases and suggests that much non-coding DNA may be dispensable. The findings pave the way for future studies on structural variation and its implications in disease, potentially leading to new bioengineering applications. This summary was automatically generated using LLM. Full disclaimer Let us know if there is a problem with our content Use this form if you have come across a typo, inaccuracy or would like to send an edit request for the content on this page. For general inquiries, please use our contact form. For general feedback, use the public comments section below (please adhere to guidelines). Please select the most appropriate category to facilitate processing of your request [-- please select one -- ] [ ] [ ] [ ] [ ] [ ] Your message to the editors [ ] Your email (only if you want to be contacted back) [ ] Send Feedback Thank you for taking time to provide your feedback to the editors. Your feedback is important to us. However, we do not guarantee individual replies due to the high volume of messages. E-mail the story Complex engineering of human cell lines reveals genome's unexpected resilience to structural changes Your friend's email [ ] Your email [ ] [ ] I would like to subscribe to Science X Newsletter. Learn more Your name [ ] Note Your email address is used only to let the recipient know who sent the email. Neither your address nor the recipient's address will be used for any other purpose. The information you enter will appear in your e-mail message and is not retained by Phys.org in any form. [ ] [ ] [ ] [ ] [ ] [ ] [ ] Your message [ ] Send Newsletter sign up Get weekly and/or daily updates delivered to your inbox. You can unsubscribe at any time and we'll never share your details to third parties. [ ] Subscribe More information Privacy policy Donate and enjoy an ad-free experience We keep our content available to everyone. Consider supporting Science X's mission by getting a premium account. Remove ads Maybe later Medical Xpress Medical Xpress Medical research advances and health news Tech Xplore Tech Xplore The latest engineering, electronics and technology advances Science X Science X The most comprehensive sci-tech news coverage on the web Newsletters [ ] Subscribe Science X Daily and the Weekly Email Newsletter are free features that allow you to receive your favorite sci-tech news updates in your email inbox Follow us * * * * * * * * Top * Home * Search * Mobile version * Help * FAQ * About * Contact * Science X Account * Premium Account * Archive * News wire * Android app * iOS app * RSS feeds * Push notification (c) Phys.org 2003 - 2025 powered by Science X Network Privacy policy Terms of use E-mail newsletter [ ] Subscribe Follow us * * * * It appears that you are currently using Ad Blocking software. What are the consequences? x Quantcast