Category Archives: Genome

Arlene O. Siefker-Radtke, MD: What Im hearing, Scott, is, "Use all the resources at hand, our APNs, [advanced practice nurses] are fantastic at getting things done, and keeping the process moving forward," and, I might even argue, are our urologic oncology colleagues because getting that tissue is important. And as you mentioned, there are sites that may be more challenging than others. I agree with you. We can get good core needle biopsies from lymph nodes, from liver, from the bladder, etc. A good transurethral resection by our urologist can yield a very nice, and sometimes the most robust, piece of tissue. We are more challenged, though, when we start talking about lung metastases, where perhaps due to location or concomitant emphysema, we end up with smaller tissue specimens. And then the bone is particularly challenging because the process of decalcifying the bone often leads to reduction in RNA and DNA. So once bone is decalcified, we have destruction of what we're trying to look for. Getting that optimal tissue from the bladder, lymph nodes, liver, and well-located lung nodules in a patient without emphysema can be most helpful in achieving the diagnosis. Additionally, it can make a difference based on where the tumor is and how easily we can detect the mutation. I know we've talked about FGFR3 since we have FGFR3-targeted therapy. We've talked about PD-L1 expression levels, how they may fluctuate, and how they're sometimes used in urothelial cancer, but not really used in most patients with urothelial cancer. Are there any other biomarkers that you feel look promising for our patients with urothelial cancer?

Scott T. Tagawa, MD, MS, FACP: Yes, I would say that there are additional, mostly genomic, biomarkers. Some of them will be grouped, for instance, if you look at TCGA [The Cancer Genome Atlas] subsets to put them into categories, and some of them are more specific; they may not be quite prime-time today, but they may be helpful in the future. Some of them are taking a drug that may be already approved in another cancer, and then we're studying it in urothelial cancer. There's a lot of back and forth, for instance, between lung cancer and urothelial cancer. It's one of the reasons I will always advocate for panel testing when its available, rather than single gene testing. However, I don't really know of a case, at least in our country, where panel testing is not available if the single gene test is available. I realize there may be some issues in terms of insurance coverage. Luckily, what I have found, at least here in New York, is that sometimes, some of the platforms don't go after we do in-house testing. But, if I'm sending out, many of the platforms don't go after copays, at least. But in diseases, such as urothelial carcinoma, where there is a validated biomarker, such as FGFR3 alterations, billing for that test in the overall panel basically pays for the panel itself. And we first identified this in lung cancer, so if we're looking for EGFR, or RAS, or ALK, just obtaining the financial money from those testing. The rest of it comes for free. Different commercial panels are going to do it differently, but overall, it's not that much more expensive to do a panel than it is a single gene.

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Genomic Profiling Assays in Metastatic Urothelial Cancer - OncLive

DUBLIN, Nov. 25, 2021 /PRNewswire/ -- The "Flow Cytometry Markets: Forecasts by Technology, Product and Application, with Executive and Consultant Guides and Including Customized Forecasting - 2021 to 2025" report has been added to ResearchAndMarkets.com's offering.

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The technology is moving faster than the market. Find the opportunities and the pitfalls. Understand growth expectations and the ultimate potential market size.

Flow Cytometry is a mainstay of analytical methods to study cells, but growth is now accelerating as new immuno-oncology and liquid biopsy markets create unprecedented investment in the race to cure cancer. Research vs. Clinical, Bead vs. Gel, it's all here in this comprehensive report.

On top of this new genome-based knowledge is fostering a new generation of scientific exploration of single cells. This market just keeps on growing with no end in sight. The workhorse of the pharmaceutical industry is becoming a central player in biotechnology.

This is a complex area but this readable report will bring the entire management team up to speed, on both the technology and the opportunity.

Key Topics Covered:

1 Market Guides1.1 Situation Analysis1.2 Guide for Executives and Marketing Staff1.3 Guide for Investment Analysts and Management Consultants

2 Introduction and Market Definition2.1 What is Flow Cytometry?2.1.1 Cell Sorting2.1.2 Academic Use2.2 Market Definition2.2.1 Market Size.2.2.2 Currency2.2.3 Years2.3 Methodology2.3.1 Authors2.3.2 Sources2.4 U.S. Medical Market and Pharmaceutical Research Spending Perspective2.4.1 Expenditures for Pharmaceutical Research

3 Flow Cytometry - Guide to Technology3.1 Flow Cytometers3.2 Hardware3.2.1 Fluidics3.2.1.1 Hydrodynamic Focusing3.2.1.2 Acoustic Focusing3.2.2 Optics and electronics3.2.2.1 Optical filters3.2.2.2 Prisms, gratings, and spectral flow cytometry3.2.2.3 Imaging flow cytometry3.3 Data analysis3.3.1 Compensation3.3.2 Gating3.3.3 Computational analysis3.3.4 FMO controls3.4 Cell Sorting3.5 Labels3.5.1 Fluorescent labels3.5.2 Quantum dots3.5.3 Isotope labeling3.6 Bead Array3.7 Impedance flow cytometry3.8 Flow Cytometry Applications3.9 Cell Viability Assays3.10 Cell Proliferation Assays3.11 Cytotoxicity Assays3.12 Cell Senescence Assays3.13 Apoptosis3.14 Autophagy3.15 Necrosis3.16 Oxidative Stress3.17 Signalling Pathways, GPCR3.18 Immune Regulation & Inhibition3.19 Reporter Gene Technology

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4 Industry Overview4.1 Players in a Dynamic Market4.1.1 Academic Research Lab4.1.2 Contract Research Organization4.1.3 Genomic Instrumentation Supplier4.1.4 Cell Separation and Viewing Supplier4.1.5 Cell Line and Reagent Supplier4.1.6 Pharmaceutical Company4.1.7 Audit Body4.1.8 Certification Body

5 Market Trends5.1 Factors Driving Growth5.1.1 The Move to Cell Based Analytics5.1.2 Immuno-oncology5.1.3 Genomic Blizzard5.1.4 Technology Convergence5.2 Factors Limiting Growth5.2.1 Genomic Technology Competition5.2.2 Instrument Integration5.2.3 Maturity5.3 Technology Development5.3.1 Software5.3.2 Instrument Size5.3.3 Larger Panels5.3.4 The Next Five Years

6 Flow Cytometry Recent Developments6.1 Recent Developments - Importance and How to Use This Sectio6.1.1 Importance of These Developments6.1.2 How to Use This Section6.2 Beckman Coulter launches CytoFLEX SRT benchtop cell sorter6.3 Thermo Fisher Acquires Cell Sorting Technology From Propel Labs6.4 Thermo Fisher Acquires Programmable Dye Platform Pioneer Phitonex6.5 NGS Bests Flow Cytometry for MRD-Based Prediction6.6 Bio-Rad Launches New StarBright Dyes6.7 Cytek Biosciences Closes $120M Financing Round6.8 Cellular Analytics Detects Early Mesothelioma Using Liquid Biopsy6.9 Cytek Biosciences Gets CE Mark for Flow Cytometer6.10 Aigenpulse launches suite to automate flow cytometry6.11 Sysmex Partec to Distribute De Novo Flow Cytometry Software

7 Profiles of Key Flow Cytometry Companies7.1 Agilent7.2 Amphasys7.3 Apogee Flow Systems7.4 Applied Cytometry7.5 Astrolabe Diagnostics7.6 Beckman Coulter Diagnostics7.7 Becton, Dickinson and Company7.8 BennuBio7.9 bioMerieux Diagnostics7.10 Bio-Rad Laboratories, Inc.7.11 Cytek Biosciences7.12 Cytognos7.13 Cytonome7.14 De Novo Software7.15 Fluidigm Corp7.16 Gemini Bio7.17 Kinetic River7.18 Logos Biosystems7.19 Luminex7.20 Miltenyi Biotec7.21 Molecular Devices7.22 Namocell7.23 Nanion7.24 NanoCellect Biotechnology7.25 Omiq7.26 On-Chip Biotechnologies7.27 Partek7.28 Sartorius7.29 sbtinstruments.com7.30 Sony Biotechnology7.31 Stratedigm7.32 Sysmex7.33 Sysmex Partec7.34 Tecan7.35 Tercen Data7.36 Thermo Fisher Scientific Inc.7.37 TissueGnostics7.38 Union Biometrica7.39 Verity Software House7.40 Yokogawa Fluid Imaging Technologies

8 Flow Cytometry Global Market Overview8.1 Global Market Overview by Country8.2 Global Market Size by Product - Overview8.3 Global Market Size by Application - Overview8.4 Global Market Size by Technology - Overview

9 Global Market by Product9.1 Reagent Market9.2 Instrument Market9.3 Services Market9.4 Software Market

10 Global Market by Application10.1 Research Market10.2 Clinical Market10.3 Industrial Market10.4 Other Application Market

11 Global Market by Technology11.1 Gel Market11.2 Bead Market

12 Appendices12.1 United States Medicare System: 2021 Clinical Laboratory Fees Schedule12.2 FDA Cancer Drug Approvals by Year12.3 Clinical Trials Started 2010 to 201612.4 Share of Pharma R&D by Country

For more information about this report visit https://www.researchandmarkets.com/r/yigb6x

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Research and Markets Laura Wood, Senior Manager press@researchandmarkets.com

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Global Flow Cytometry Markets Report 2021-2025 - The Move to Cell Based Analytics / Immuno-oncology / Genomic Blizzard / Technology Convergence -...

The Earlham Institute (EI) has boosted its capability in high-fidelity long-read sequencing with a twin set of the cutting-edge Pacific Biosciences Sequel IIe platforms to support the Earth BioGenome projects, providing the UK bioscience community with critical technologies for biodiversity genomics.

As theEarth BioGenome Project (EBP)is gaining momentum to sequence, catalogue, and characterise the genomes of all eukaryotic biodiversity on Earth within the next ten years, global efforts are under way to deploy the technology and infrastructure capable of rapidly delivering large numbers of high quality genome sequences.

The Sequel IIe platform empowers scientists to take genomic analysis to a higher level of accuracy by producing high-fidelity long reads (HiFi) to resolve genomes and transcriptomes.

The Sequel IIe platforms allow us to scale up our existing infrastructure in our contribution to BioGenome sequencing,said Head ofGenomics Pipelinesat the Earlham InstituteDr Karim Gharbi.Demand from the UK bioscience community for higher-quality genome references is growing rapidly, with requests to access HiFi sequence data at an all-time high.

Feedback from early adopters of the Sequel IIe across the genomics community has been extremely positive with HiFi genomes, outperforming existing resources by at least one order of magnitude. The additional platform will immediately double our genome sequence capability capacity, enabling continued, cost-effective access to HiFi reads for EI researchers and UK bio-scientists.

In the past few years, the Earlham Institute has made strategic investments in genome-enabling technologies, setting the path for a new era in biology where high-quality, richly-annotated genome sequences are no longer the exception but increasingly the norm.

Director of the Earlham Institute Prof Neil Hall, added:The Earth BioGenome project initiatives are highly collaborative but the technology and infrastructure capable of producing high-quality genomes at scale need to be ensured. The additional HiFi capacity at the Earlham Institute for the analysis of protist genomes strengthens our position in the global initiative as a leader in genome sequencing.

These sequencing technologies support several national and international initiatives with the Earlham Institute as a core research partner including the Vertebrate Genomes Project,Darwin Tree of Life (DTOL) Project, and European Reference Genome Atlas (ERGA) delivering key sequencing data and analyses for a wide range of organisms, and underpinning ambitious programme to catalogue the biodiversity of single-cell eukaryotes (protists).*

Key to this investment was the early adoption of the long, high-quality (HiFi) sequencing platform (Pacific Biosciences Sequel II) in 2019, before the Earlham Institute permanently acquired the instrument with support from BBSRC funding,added Dr Gharbi. This technology allowed the Institutes researchers to secure early success in delivering high-quality genome references for key target species and establish EI as a leading centre in BioGenome research .

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New HiFi Platform Increases Sequencing Power To Help Decode Genome Of All Life On Earth - Eurasia Review

SAN DIEGO, Nov. 22, 2021 (GLOBE NEWSWIRE) -- Bionano Genomics, Inc. (BNGO), provider of optical genome mapping (OGM) solutions on the Saphyr system and the leading software for genomic data visualization, interpretation and reporting, today announced the publication of a study by Johns Hopkins University in the Journal of Clinical & Anatomic Pathology outlining a stepwise approach to adoption of OGM for cancer analysis in the cytogenetics lab.

This publication is by an outstanding team at Johns Hopkins University and we believe it represents the type of foundational work needed to establish where OGM fits in the cancer analysis lab and the types of subjects and samples that should be analyzed with OGM, commented Dr. Alka Chaubey, chief medical officer of Bionano Genomics. Knowing how different samples perform with OGM and the variants it detects can allow us to build a paradigm for working with OGM alongside other powerful tools in molecular pathology and cytogenomics as we push forward in our mission to transform the way the world sees the genome.

Conducted as a blinded comparison to a comprehensive collection of tools, this study compared results from OGM to those from whole-genome chromosomal microarrays (CMA) from Illumina, fluorescence in-situ hybridization (FISH) probes from Abbott, a targeted panel by next-generation sequencing (NGS) from Illumina, a gene fusion panel by gene expression on the nCounter from NanoString and traditional g-banding by karyotyping. The cohort comprised five different cancer subjects and multiple sample types: four leukemia/lymphoma subjects and one solid tumor subject across three bone marrow samples, one peripheral blood sample and one solid tumor sample (kidney tissue from a Wilms tumor subject).

The findings by OGM were concordant with those obtained by CMA and NGS for copy number variants (CNVs) and FISH and karyotyping for balanced structural variations (SVs) such as inversions and translocations. Sensitivity compared to CMA was 96% (22/23 CNVs detected) excluding copy neutral loss of heterozygosity calls. Sensitivity compared to karyotyping and FISH was 100% (98/98 loci detected). OGM also revealed substantially more SVs than the traditional methods, including an additional 51 CNVs and 20 SVs. Of the variants revealed by OGM that were not detected by the standard methods, 52% involved genes and 7.7% of them involved known cancer genes. The other 48% were classified as variants of unknown significance (VOUSs). The authors point out that these VOUSs have the potential to play a role in further refining patient diagnosis and identifying novel proteins that could be therapeutic targets.

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OGM was also used in the study to provide high resolution analysis of subjects with complex karyotypes exhibiting chromothripsis. Chromothripsis, or chromosome shattering, results in highly complex chromosomal structures that are typically very challenging to unravel by CMA, FISH and karyotyping. OGM provides a more comprehensive view across the genome that targeted methods like FISH cannot give and it has been shown to have a higher resolution than traditional methods as well. Compared to karyotyping, which has a resolution of 5 Mbp, OGMs resolution is 10,000 times higher and compared to CMA, OGMs resolution is 20-100 times higher, depending on the probe density used on the array. The authors used OGM to reveal and characterize chromothripsis (complex genome structures) in leukemia subjects with unprecedented scope and resolution, which they said can be extremely helpful in determining if there are druggable variants present, markers consistent with aggressive disease or disease thats treatment refractory.

The principal conclusions of this publication is that OGM provides an alternative workflow that provides valuable genomic information often with higher resolution than traditional methods without sacrificing sensitivity. OGM is complementary to methods like NGS, which reveal sequence variants, and provides an opportunity to simplify and consolidate workflows for SV analysis by using OGM as an alternative to CMA, FISH and karyotyping.

This publication is available at http://www.clinpathology.com/wp-content/uploads/2021/05/JCAP-6-117.pdf.

About Bionano Genomics

Bionano is a provider of genome analysis solutions that can enable researchers and clinicians to reveal answers to challenging questions in biology and medicine. The Companys mission is to transform the way the world sees the genome through OGM solutions, diagnostic services and software. The Company offers OGM solutions for applications across basic, translational and clinical research. Through its Lineagen business, the Company also provides diagnostic testing for patients with clinical presentations consistent with autism spectrum disorder and other neurodevelopmental disabilities. Through its BioDiscovery business, the Company also offers an industry-leading, platform-agnostic software solution, which integrates next-generation sequencing and microarray data designed to provide analysis, visualization, interpretation and reporting of copy number variants, single-nucleotide variants and absence of heterozygosity across the genome in one consolidated view. For more information, visit http://www.bionanogenomics.com, http://www.lineagen.com or http://www.biodiscovery.com.

Forward-Looking Statements of Bionano Genomics

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as may, will, expect, plan, anticipate, estimate, intend and similar expressions (as well as other words or expressions referencing future events, conditions or circumstances) convey uncertainty of future events or outcomes and are intended to identify these forward-looking statements. Forward-looking statements include statements regarding our intentions, beliefs, projections, outlook, analyses or current expectations concerning, among other things: our ability to build a paradigm for working with OGM alongside other tools in molecular pathology and cytogenomics; the potential role of VOUSs, including those detected by OGM, in refining patient diagnosis and identifying possible therapeutic targets; and OGMs ability to simplify workflows for SV analysis as compared to CMA, FISH and karyoptyping and be complementary to NGS. Each of these forward-looking statements involves risks and uncertainties. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the risks and uncertainties associated with: the impact of the COVID-19 pandemic on our business and the global economy; general market conditions; changes in the competitive landscape and the introduction of competitive products or improvements on existing methods, such as CMA, FISH, karyotyping and NGS; failure of future study results to support those demonstrated in the study referenced in this press release; changes in our strategic and commercial plans; inability to obtain sufficient financing to fund our strategic plans and commercialization efforts; the ability of medical and research institutions to obtain funding to support adoption or continued use of our technologies; the loss of key members of management and our commercial team; and the risks and uncertainties associated with our business and financial condition in general, including the risks and uncertainties described in our filings with the Securities and Exchange Commission, including, without limitation, our Annual Report on Form 10-K for the year ended December 31, 2020 and in other filings subsequently made by us with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on managements assumptions and estimates as of such date. We do not undertake any obligation to publicly update any forward-looking statements, whether as a result of the receipt of new information, the occurrence of future events or otherwise.

CONTACTSCompany Contact:Erik Holmlin, CEOBionano Genomics, Inc.+1 (858) 888-7610eholmlin@bionanogenomics.com

Investor Relations:Amy ConradJuniper Point+1 (858) 366-3243amy@juniper-point.com

Media Relations:Michael SullivanSeismic+1 (503) 799-7520michael@teamseismic.com

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Bionano Genomics Announces Peer-Reviewed Publication from Johns Hopkins University Outlining a Stepwise Approach to the Adoption of Optical Genome...

In recent years, many have considered how best to govern increasingly powerful genome editing technologies. Since 2015, more than 60 statements, declarations, and other codes of practice have been published by international organizations and scientific institutions (1). In particular, the 2018 birth of two twins, Lulu and Nanawhose HIV-receptors CCR5 were altered by biophysics researcher He Jiankuitriggered widespread condemnation from the scientific community, the public, and even legal institutions. Eminent organizations that have opined on the matter include the World Health Organizations Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing (WHO committee) and the International Commission on the Clinical Use of Human Germline Genome Editing (the international commission).

To date, reports have expressed common concerns over various issues in the governance of human genome editingfor example, whether to impose moratoriums on basic research and clinical activities in human heritable genome editing. They have also agreed on some general actions, such as encouraging public input and implementing regulations on preclinical and clinical research in human heritable genome editingin particular as it pertains to the transparent disclosure of experiments underway and the documenting of protocols and patient consent responsibly.

When it comes to genome editing technologies, we need to acknowledge and account for very different points of view from researchers and regions around the world. Image credit: Shutterstock/vchal.

The ethical implications of genome editing seemingly exacerbate the divergent views among stakeholders, especially those with different cultural backgrounds, ideologies, religious views, and commercial interests.

But although most of the opinions, guidelines, and issues discussed in these reports are noteworthy and defensible, we argue that their effectiveness in guiding global governance is limited. Genome editing technology has grown too quickly, and stakeholders in the debate are too diverse, for current approaches to establish a robust, credible, and lasting regulatory regime. We need to acknowledge and account for very different points of view from researchers and regions around the world.

Existing governance mechanisms share features with the Asilomar statement in 1975, which is generally seen as providing effective regulation on recombinant DNA technologies (2). Features of that approach include 1) a governance body led by a commission of leading experts from one or a few countries and supported by several influential international and professional organizations; 2) proposed governance tools that are nonbinding; 3) guidelines implemented either through direct regulation and restraining the behaviors of the global research community, or having the guidelines absorbed into government regulations and funding agency policies.

Such a governance model has its merits. Indeed, a small group of leading experts can reach consensus quickly and effectively. And if academic journals and funding agencies adopt and adhere to such guidelines, scientists will follow. In such cases, the strong network of leading experts frequently allows guidelines they produce to influence government regulations (3). For instance, the final statement of Asilomar conference later served as a template for the future recommendation of the NIH Recombinant DNA Advisory Committee (4).

However, we are far from achieving a consensus on critical governing issues related to human genome editing at the global level, as illustrated by the divergence of existing guidelines (1). In the case of moratorium on heritable genome editing, for example, some guidelines (e.g., the one developed by European Group on Ethics in Science and New Technologies) suggested broad prohibition on gene editing of human embryos or gametes which would result in the modification of the human genome (5), whereas others (e.g., the one developed by the United States National Academies of Sciences, Engineering, and Medicine Committee) tentatively supported germline editing under certain specified conditions (6). Debate and critiques have continued, especially after the gene editing fiasco spearheaded by researcher He Jiankui (7).

Notably, diverse opinions emerged among the scientific community regarding the moratorium on heritable human genome editing. For instance, some leading scientists, such as Eric Lander (8), called for a global moratorium on clinical use of human heritable genome editing for a defined period of time to enable the development of international guidelines. In contrast, some prestigious researchers expressed objections to such a proposal, arguing that it would be open-ended in duration and could impede scientific research and delay the deployment of life-saving technologies for patients who cannot wait (9).

The global scientific community did engage in fierce debates on how to regulate recombinant DNA technology when the Asilomar statement was developed. However, the current landscape of human genome editing is very different. It renders a global governance model led by a small group of scientists and scientific organizations outdated and counter to an inclusive framework that encompasses views and opinions of a diverse set of stakeholders reaching both inside and outside of academia.

When the Asilomar statement was put forward in 1975, there were around 30 authors who had related scientific publications, far fewer than the 140 participants who attended the Asilomar meeting. Moreover, although the total number of authors grew to around 900 in 1978, more than 70% of their affiliated institutions are based in the United States. In other words, the recombinant DNA research community was much smaller and far less diverse, making it relatively easy for the Asilomar conference to reach a consensus and then convince others in the community to agree.

Today, the scientific community is very diverse geographically and culturally. Between 2012 and 2018, there were more than 8,000 publications on genome editing, carrying the names of more than 36,000 authors. Around 4,000 institutions across 94 countries/regions in all major continents are involved in the field of genome editing (see Table 1). The ethical implications of genome editing seemingly exacerbate the divergent views among stakeholders, especially those with different cultural backgrounds, ideologies, religious views, and commercial interests.

The global distribution of publications, countries/regions, institutions, and authors for recombinant DNA (19721978) and genome editing (20122018)

To investigate further, we conducted a global online survey with the corresponding authors of human genome editing-related publications. We sent out questionnaires to 3,326 authors and received 201 validated responses. We do note limitations for our survey, including the potentially biased opinions of corresponding authors and a relatively low response rate (6%). Nevertheless, we gleaned some insights into researchers attitudes toward current guidelines and their opinions regarding basic and clinical research of human somatic and germline editing and enhancement research. We also asked for their preference for global governance models in this field.

Specifically, we selected five representative governance guidelines developed by the most authoritative institutions and asked the scientists about their familiarity with these guidelines. Around 40% of the respondents said they had never heard of them, and less than 20% said they had read the guidelines in detail. More importantly, we find very different attitudes toward some crucial issues. For instance, around 30% of respondents wanted to see a moratorium on even basic research in the field. Some 56% disagreed with this idea, and 14% were neutral. There were important regional differences. For instance, scientists from North America and Europe were the least conservative and tended to disagree with imposing moratoriums. Those from Asia were more likely to take a neutral stand, whereas those from other regions (e.g., Africa and South America) were more conservative, tending to agree with the need for a moratorium.

For our part, we believe that a global moratorium is not warranted, but that it is necessary to impose certain restrictions on the research and on clinical trials directed at human genome editing. However, the question of when and how the restrictions should be implemented requires discussions on a global scale and consensus among a broad range of stakeholders from different regions.

That group of stakeholders includes many based in or working with the private sector, which makes the context for global governance quite different from that of the Asilomar period. In the 1970s, most of the scientists engaged in recombinant DNA research were working in public institutions; today, many scientists working in genome editing have conflicts of interest over intellectual property or act as advisors for commercial companies (10). These conflicts are not systematically declared in the guidelines they produce.

Public engagement is also extremely important, as some existing efforts appreciate. For example, the international commission recommends that extensive social dialogue should be undertaken before a country makes a decision on whether to permit clinical use of heritable human genome editing and recognize the efforts by civil society on the global level to promote international cooperation on approaches to responsible development (11). We agree with the commissions suggestion that organizations like WHO and the United Nations Educational, Scientific and Cultural Organization (UNESCO) take the responsibility to evaluate and make recommendations. In particular, we appreciate the new framework developed by the WHO committee (12), which highlights the role of various tools, institutions, and processes for the governance of human genome editing.

Key to achieving these goals is more inclusive engagement of the global scientific community. First, effective public engagement and discussion require basic information on this subject, such as the differences between human genome editing in somatic cells and the germ line. This condition is particularly hard to fulfill in the less-developed regions where access to education and information are more limited. If experts in these regions have more opportunities to engage in global dialogues, they could bring back up-to-date information and various arguments to inform public debates in these countries.

Second, most guidelines and frameworks being suggested by international bodies have no legal authority or jurisdiction. The effectiveness of such approaches therefore depends on national regulators willingness to voluntarily follow these global rules, creating an enforcement challenge that fails to account for nonadopters. If researchers and representatives of professional institutions from more countries could be involved in global policymaking, they could serve as policy entrepreneurs to inform the national policymakers and provide policy suggestions based on their first-hand experience in the global arena, for a more authoritative local framework. Third, the establishment of stringent global rules requires a high degree of consensus around the worldwide stakeholders. Therefore, inclusive dialogue and the effort to achieve global consensus within the global scientific community are indispensable.

For all these reasons, it is time we go beyond the traditional governance model in the field of biotechnology and draw lessons from broader global governance practices. This can be done in several ways.

First, leading academic journals as well as professional conferences with international influence should serve as more open and inclusive platforms for dialogue on contentious governance issues related to human genome editing. More scientists and experts from less developed countries should be invited to express their views in these journals and speak at international conferences; their opinions need to be seriously considered. Notably, the conference known as CRISPRcon has provided such an inclusive venue for diverse opinions to be shared. There is a silent majority of researchers and stakeholders who have not had the chance to provide meaningful input.

Previous experiences in global governance reveal that ensuring voices are heard is a critical first step towards global governance improvement. One example is the policy-making process of the UN Sustainable Development Goals (SDGs). To generate a consensus on the new set of global sustainable development goals for the period of 2015 to 2030, the UN developed various open platforms for institutions and individuals around the world to provide their opinions. For instance, the UN Sustainable Development Solution Network (UNSDSN) was established to bring together global experts from all regions and all sectors to promote practical solutions for sustainable development (13). They also initiated the UN My World survey to invite voices from around the world into policymaking at the global level (14).

Second, the international professional organizations developing standards and rules for human genome editing should expand their networks to include more historically neglected countries and regions. For example, the international commission is poised to play an important role in the field, but there are only 10 countries academies of sciences and medicines involved thus far. Efforts should be made to bring in more leading experts from less developed countries; right now, leaders in influential international professional organizations, such as the International Society for Stem Cell Research, are mostly from developed countries. A good model is the World Medical Association, which represents the national associations of physicians of more than 110 countries. Over the years, the association has developed many successful and inclusive standards and rules, including the influential Declaration of Helsinki on research ethics.

Third, public and private funding agencies of science and medicine around the world should work together to initiate collective actions to govern human genome editing. If influential funders could jointly recognize basic principles and standards that strengthen ethical review, accountability, and transparency, large numbers of researchers around the world who have received or wish to receive funding could be incentivized to heed these principles and standards. The Human Genome Project illustrates the impact of funding agencies in forging a community spirit (15). In 1996, the Wellcome Trust sponsored a leadership gathering of the largest labs in the publicly funded genome project coordinated by the NIH. The outcome of this meeting is the famous Bermuda Agreement, in which scientists pledged to release human sequence data as soon as possible and submit their data to a public database. Because of the substantial power of these funders, this rule successfully reshaped practice nearly instantly in the field, even without any legal authority (16).

Science is evolving at a feverish pace. Technological development is no longer the purview of a few leading academic institutes and a handful of entrepreneurial forerunners, as illustrated with the rise of CRISPR-based technologies driving the democratization of genome editing. Accordingly, governance by the few for all is no longer appropriate nor acceptable. Each approach suggested above has seen some historical success and has potential to improve governance of human genome editing. We must combine these tools into an integrated network. Standards and agreements independently launched by academic journals, funding agencies, and international professional organizations could mutually reinforce each other. Key individuals and organizations could play the critical role as the bridges connecting different approaches. The global governance of human genome editing urgently needs the wisdom of the entire global scientific community as well as those in related fields and interested members of the general public.

The work was supported by the National Natural Science Foundation of China (Grant 72004169).

Competing interest statement: R.B. is a cofounder of Intellia Therapeutics, Locus Biosciences, TreeCo, Ancilia Biosciences, and CRISPR Biotechnologies, and is a shareholder of Caribou Biosciences and Inari Ag.

Any opinions, findings, conclusions, or recommendations expressed in this work are those of the authors and have not been endorsed by the National Academy of Sciences.

This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2118540118/-/DCSupplemental.

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Opinion: Toward inclusive global governance of human genome editing - pnas.org

Genomic and Proteomic Tools Market: Introduction

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Key Players Operating in Global Genomic and Proteomic Tools Market

The global genomic and proteomic tools market is consolidated due to the presence of small number of key players. These players hold major share in their respective regions. Growth strategies adopted by leading players are likely to drive the global genomic and proteomic tools market.

Major players operating in the global genomic and proteomic tools market are:

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Surgical Navigation Systems Market: The demand within the global surgical navigation systems market is expected to rise in the coming times. The importance of digital and visual technologies in the field of medicine and healthcare has created fresh opportunities for market growth and maturity. In the contemporary times, the healthcare industry has stayed abreast with the latest advances in technology. The integration of digital systems in the healthcare fabric has helped in expediting, accelerating, and improving the process of treatment.

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Genomic and Proteomic Tools Market: Rise in the number of cancer patients across the world to drive the market - BioSpace

Image credit: Miroslaw Miras, via Pixabay.

You may have heard that all the DNA in your body, if stretched out, could reach to the Sun and back more than 70 times. What is even more amazing is that all this DNA occupies only a tiny fraction of the space within your body it is packed away inside the tiny nucleus of each cell. Furthermore, the DNA is not merely packed away and sitting idly; rather, it is a dynamic molecule taking part in several active processes including gene expression and cell division. Three new scientific papers have been published in recent weeks that reveal exquisite patterns of design in the DNA and nucleus in which it is housed.

The human genome is organized in 23 pairs of chromosomes. Most of the pairs are of similar length, but in the final 23rd pair, the first chromosome designated X is much longer than the second chromosome designated Y. That is not the only unique characteristic of the 23rd pair. These so-called sex chromosomes differ between the genders. While males have both an X and Y chromosome, females have two X chromosomes. As if to avoid a double dose of X chromosome genes, females inactivate one of their two X chromosomes during embryonic development. As for which of the two X chromosomes is inactivated, this appears to be done randomly in each cell. This means that females, unlike males, have two different functional genomes operating in their bodies, making for a fascinating twist to female genetics. That is, in some cells of the female, the first X chromosome is active whereas in the remainder of the cells the other X chromosome is active. A classic example is the colorful calico cat whose two X chromosomes code for two different colors.

Exactly how the developing female embryo inactivates one of the X chromosomes has not been well understood. What has been clear is that the story involves a region on the X chromosome itself, and information in that region that codes for a long RNA molecule, known as Xist. The name Xist stands forX-inactive specific transcript, a direct reference to its function of inactivating the X chromosome. But a genetic region that, ultimately, causes the inactivation of the entire chromosome must be handled very carefully. It is present on all X chromosomes but causes inactivation not of the single male X chromosome, and not of one of the two female X chromosomes. Importantly it causes inactivation only of the other female X chromosome.

In addition to the fact that Xist must be very carefully controlled, new research1is shedding light on how this single molecule can produce such a significant result. While it seemed that a very large number of Xist molecules must be required to inactivate the much larger X chromosome, the researchers studied mouse embryonic stem cells and found that only about one hundred Xists are required. The Xists, operating in pairs, recruit a large number of proteins. The result is about 50 complexes, each consisting of two Xists and an army of proteins, spaced along the X chromosome. Some of the proteins twist and condense the overall chromosome, compressing it so that most of the genes are close to one of the 50 complexes. Other proteins act to silence those nearby genes, thus essentially inactivating the entire X chromosome. Obviously, there are many important, coordinated, steps in this inactivation process, allowing for a small number of Xists to manage this big job. As the papers lead author remarked, It was kind of shocking to us that from just 50 sites, Xist manages to silence a thousand genes.2

X chromosome inactivation is not the only function that RNA molecules perform in the nucleus. They also, for example, help to maintain the overall three-dimensional structure of the various macromolecules in the nucleus, including the DNA. This is important because otherwise in the crowded nucleus, molecules can inadvertently chemically bond, or link, to one another. DNA crosslinking, for example, can result from environmental toxins and radiation. Such crosslinking, whether between DNA or other molecules, can cause cell death and is the goal in some chemotherapies. But crosslinking also is proving to be a valuable research tool. As another new paper reports,3crosslinking is now being used, along with several other complicated steps, to map out the three-dimensional structure of the DNA, various RNAs, and many proteins, within the nucleus. Simply put, the general idea is to link together molecules that are in close proximity. The cell is then broken down into clusters of linked molecules which can be identified and mapped out to reconstruct the structures within the nucleus.

The researchers found the certain RNA molecules serve to recruit and organize other RNA and protein molecules. Those recruited RNA and protein molecules, which otherwise would randomly move about, then serve important regulatory roles in accessing and processing the DNAs genetic information. The researchers also found that several high-concentration territories are formed within the nucleus, where these molecules cluster and function. As the paper explains, the organizing RNA molecules recruit diffusible RNA and protein regulators into precise 3D structures. What we are seeing is a much more detailed, elegant, and exacting picture of the nucleus than textbooks have ever envisioned.

The problem of organizing and maintaining the molecular structures within the nucleus becomes even more intriguing when one considers cellular division. When a cell divides, producing two daughter cells, the precise 3D nucleus structure discussed above must somehow be reestablished in the new cells. Certain proteins have been known to be important in this process, and another new study4has now identified a single protein that is particularly important in this cell division process. The protein, called lamin C, is, according to the paper, uniquely required for large-scale chromosome organization, and global 3D genome organization in the daughter cells.

During the process lamin C is phosphorylated, meaning a phosphoryl group is attached by special proteins. The phosphoryl group is removed when lamin C is done with its job, which is just one part of a larger, more complex process. As the lead researcher explained, There is this exquisite choreography of the different lamin proteins and DNA to get things just as they should be.5

Beyond this exquisite choreography, the crucial role of lamin C highlights another hallmark of design; namely, the teleology implicit when a part is required for its own production. Because lamin C, a protein, is produced by cellular protein synthesis. That is a process that begins with the genome in the nucleus, which is maintained by lamin C. In other words, lamin C is required for the production of lamin C.

These three studies of the structures within the cells nucleus continue to reveal a natural world that gives evidence design in many different ways.

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Studies Reveal Designs of Nucleus and DNA - Discovery Institute

Newswise A five-year partnership being launched by the InnovativeGenomicsInstitute (IGI) a non-profit founded by Nobel Laureate Jennifer Doudna andCGIAR, the worlds largest publicly-funded agricultural research partnership, will harness the power of science to help millions of people overcome poverty, hunger, and malnutrition.

One in four people globally, and rising, are unable to afford a healthydiet.COVID-19 has exacerbated this trend by disrupting food production and distribution, driving upby 20 percentthe number of people threatened by hunger in 2020. The pandemic is unfolding amidst an environmental and climate crisis which is undermining food production andour ability to nourish the world.

According to Barbara Wells, Global Director for Genetic Innovation at CGIAR: World-class science is vital for facilitating farmer adaptation and mitigating our food systems contribution to climate change. Plant-breeding innovations can help ramp up food production while making farms more climate resilient, profitable, and environmentally friendly.

Technologies such asgene editing,which enable scientists tomaketargeted changes to a cropsDNA, can accelerate the development ofmore disease-resistant,water-efficientvarieties that can improve food production and nutrition in areas that are especially vulnerable to climate change,Dr.Wellsexplained.

CGIAR has produced and promoted innovations that are boosting thesustainableproduction of nutritious foodin Africa, Asia and Latin America.Over the past five decades, CGIAR scientists and national partners have developed and disseminatedrobust and highly productive crop varieties and livestock breedstailored to theneedsoflocalmen and women. Those innovationshavehelped hundreds of millions of peopleacross the Global Southovercome hunger and poverty.

TheIGIis a collaboration ofthe University of California, Berkeley andtheUniversity of California, San Francisco with amissiontodeveloprevolutionarygenome-editing tools that enableaffordable and accessible solutions in human health, climate, and agriculture.The IGIs Climate & Sustainable Agriculture program focuses ondeveloping crops that are resistant to pestsanddiseases,resilient toa changing climate, and less dependent onfarmer inputs.Whereas the IGIis a pioneer inappliedgenomic research, CGIAR focuses ontranslatingdiscoveries intoimproved crop varieties and cropping systems.This partnership provides an accelerated pipeline from upstream innovation to real-world impact.

The IGI is testing technologies with great potential to benefit people in the countries where CGIAR is active, such as a way of removing the cyanide found in cassavaa staple upon which nearly a billion people depend and fighting diseases in economically important crops like wheat, rice, and bananas, said Dr. Brian Staskawicz, the IGI Director of Sustainable Agriculture.

The IGI is also pioneering new ways to reduce methane emissions from rice farming, which accounts for 2.5 percent of humanitys contribution to global warming, by using genomic approaches to reduce methane production by soilmicrobes, he added.

By partnering with CGIAR, the IGI can ensure that the products of its research will benefit farmers and consumers in some of the worlds poorest countries, where CGIAR has been working for 50 years and has extensive partner networks, said Dr. Melinda Kliegman, Director of Public Impact at the IGI. Together we can accelerate the development and delivery of more climate-resilient, productive and nutritious crops for resource-poor farmers and consumers.

Over the next five years, the IGI andCGIARwillusethe latest breakthroughs in genomic sciencetoenhancethe resilience and productivity of farmers inlow- and middle-incomecountries andimprove thewellbeing andlivelihoods ofwomen and men insome of the worlds poorestcommunities.

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Harnessing the Power of CRISPR to Reduce Poverty and Malnutrition - Newswise

Retinoic acid affects the transcriptome of zebrafish endodermal cells

To identify genes regulated by RA in zebrafish endodermal cells, we used the transgenic Tg(sox17:GFP) line which drives GFP expression in endodermal cells and allows their selection by fluorescence activated cell sorting (FACS). Tg(sox17:GFP) embryos were treated either with RA, BMS493 (pan-RAR inverse-agonist) or DMSO (control) from 1.25 to 11hpf, a time window that covers the whole blastula and gastrula periods. Endodermal GFP+ cells were next selected by FACS from embryos at 3-somites (3-S) and 8-somites (8-S) stages (11 hpf and 13 hpf, respectively). Non-endodermal (GFP) cells were also selected from the DMSO-treated control embryos in order to compare with GFP+ endodermal cells and identify genes displaying endodermal enriched expression. RNA-seq was performed on all these FACS-isolated cells prepared in triplicate (24 samples in total) and transcriptomes were analysed using the bioinformatic pipeline as described in Materials and methods. Principal component analysis of all RNA-seq data (Fig.1A) shows (i) a tight clustering of all triplicate samples confirming a high reproducibility in the experiment, (ii) a strong difference between the transcriptome of endodermal and non-endodermal (NE) cells (discriminated along the first axis of the PCA plot), (iii) relatively similar transcriptomes of cells isolated at 3-S and 8-S stages, and (iv) a clustering of BMS493 samples near DMSO samples indicating a much weaker effect of BMS493 treatments compared to the RA treatments. These conclusions were further confirmed by the differential gene expression analyses between the different conditions. Indeed, more differentially expressed genes were identified between endodermal and non-endodermal cells (1370 and 1410 differentially expressed genes at 3-S and 8-S stages, respectively with a FDR<0.01) than between endodermal cells treated with RA versus DMSO (756 and 514 RA-regulated genes at 3-S and 8-S stages, respectively with FDR<0.01) or with BMS493 versus DMSO (32 and 71 BMS493-regulated genes at 3-S and 8-S stages, respectively). We found a large overlap among the sets of genes having an endodermal-enriched expression at 3-S and at 8-S stages (Fig. S1A; list of genes given in Table S1) and these sets include all known endodermal markers including sox17, gata5/6 and foxa1/2/3, validating the accurate sorting of endodermal cells. RA-regulated genes consist of a large set of up- and down-regulated genes (Table S2), many of them being regulated at both 3-S and 8-S stages (Fig. S1B). These RA-regulated genes include known RAR-direct targets such as cyp26b1/a1, dhrs3a, nr2f2 and several hox genes, validating our protocol and the of RA treatments. Interestingly, BMS493 treatment led mostly to down-regulation of gene expression. Indeed at 3-S stage, the 32 BMS493-regulated genes were all repressed, and, at 8-S stage, 68 genes were repressed while only 3 genes were up-regulated by BMS493 treatment (Tables S3). A large overlap was also observed between the genes down-regulated by BMS493 at 3-S and at 8-S stage (Fig. S1C). As expected, a large proportion of genes down-regulated by BMS493 were up-regulated by RA treatment, this observation being evident mostly at 3-S stage where 72% of genes repressed by the RAR inverse-agonist were induced by RA, while this proportion decreased to 40% at 8-S stage (Fig.1B,C). Tables 1 and 2 show the genes significantly up-regulated by RA and down-regulated by BMS493 as well as those enriched in the endoderm at 3- and 8-somites stage, respectively (shown in bold). gata6, insm1a and ascl1b are the only known pancreatic regulatory genes which were regulated by both RA and BMS493 (Table 1). Other pancreatic transcription factors, like mnx1, insm1b, hnf1ba, nr5a2 or neuroD1, were induced by the RA-treatment but not significantly repressed by BMS493. Inversely, other pancreatic regulators were inhibited by BMS493 but not significantly induced by RA like pdx1, rfx6 and myt1b (Tables S3 and S6). We can assume that the induction of pancreatic fate by RA (and the absence of pancreas upon BMS439 treatment) is mediated, at least in part, by the direct or indirect regulation of these pancreatic regulatory factors. In conclusion, these RNA-seq data highlight all the genes with an enriched expression in zebrafish endodermal cells and which are regulated by RA signalling. This gene set notably includes regulators involved in the AP patterning of the endoderm, such as hox genes, and known factors involved in the specification of pancreatic progenitors.

Effect of RA and BMS493 on the transcriptome of endodermal cells. (A) Principle component analysis (PCA) of the 24 RNA-seq data obtained on cells isolated at 3-somites stage (circle) and 8-somites stage (triangle). The colors indicate the data for non-endodermal cells (NE) (grey), and endodermal cells treated with RA (purple), BMS493 (red) and DMSO as control (green). The plot shows high reproducibility between triplicates. The strongest transcriptomic differences occur between endodermal and non-endodermal cell (along PC1), then between endodermal cells treated with RA and DMSO (along PC2), while BMS493 treatment has minimal influences. Consistent with the inverse-agonist action of BMS493 and with the agonist action of RA, these samples are located far from each other, the DMSO-samples being located between them. (B,C) Venn diagram displaying the number of genes up-regulated by RA (purple), down-regulated by BMS493 (red) and endodermal enriched (green) at 3-somites (B) and 8-somites stage (C).

To further identify the genes directly regulated by RAR and determine if some pancreatic regulatory genes are direct targets of RA signalling, we performed ChIP-seq experiments at the end of gastrulation. In absence of validated commercialized ChIP-grade antibody recognizing zebrafish RAR, we chose to express a tagged RARaa in zebrafish gastrulae by injecting zebrafish fertilized eggs with the mRNA coding for the zebrafish RARaa protein fused to a Myc-tag at its C-terminal end. RARaa was chosen as the RNA-seq data indicated that it is the most highly expressed RA receptor in zebrafish endodermal cells. We injected very small amount of this mRNA (about 30pg) in order to avoid high non-physiological levels of RARa protein within embryos; the development of embryos were not affected by these injections. Chromatin was prepared at 11.5 hpf (3 somites stage) from about 2000 injected zebrafish embryos and immunoprecipitation was performed with a ChIP-grade Myc antibody. Comparison of reads obtained with the Myc-RAR ChIP and the input negative control led to the identification of 4858 RAR peaks. In order to identify bona fide RAR binding sites showing strong affinity, we selected all peaks with a height score above 50 (Table S4). By choosing such criteria, 2848 robust RAR binding sites were identified in the zebrafish genome. As shown in Fig.2A, a majority of these sites are located near or within genes: 8% were found in promoters (i.e. 1kb upstream of the gene TSS, Transcription Start Site), 30% in upstream sequences (from 1 to 10kb), 22% in introns, 4% in exons, and only 33% in intergenic regions. Sequence analysis of all RAR peaks revealed that the highest represented motif corresponds to the Direct Repeat of the RGKTCA motif separated by 5 bases (reported as DR5) and being the RAR/RXR consensus binding sequence (present in 39% of identified RAR peaks) (Fig.2B)1. The next most abundant motifs are also repetitions of the RGKTCA motif with different spacings (TR4 being a Direct Repeat separated by 1 and 2 bases : DR1/DR2) and orientations (Rxra being an Inverted Repeat with no base separation : IR0). Furthermore, many RAR peaks were found near genes reported to be RAR-direct target genes in other species, such as cyp26a1, dhrs3, nr2f2 or the hoxb1a-hoxb4a genomic region (Fig.2C and data not shown). All these observations confirm the accuracy of the ChIP-seq data. Interestingly, many identified zebrafish RAR sites are located in evolutionary conserved genomic sequences as shown by the fish PhastCons track (Fig.2C and see below).

Identification of RAR binding sites in the zebrafish endoderm. (A) Distribution of ChIP-seq peaks to the different regions of the zebrafish genome. (B) Top 3 motifs overrepresented in all ChIP-seq peak sequences with the percentage of sites containing the motifs and the p-value of enrichment. The three motifs consist to a repetition of the A/GGGTCA sequence; the first corresponds to the classical DR5 recognized by the RARA:RXR complex, the second (TR4) is a superposition of DR1 and DR2, and the third is a IR0. (C) Visualization of RARaa binding sites around the dhrs3a gene (upper panel), cyp26a1 (middle panel) and hoxb1a-hoxb4a genomic region (below panel). Tracks in gold correspond to RARaa ChIP-seq reads and identified RARaa peaks. The track in blue shows the location of conserved genomic sequences (from the UCSC Genome Browser obtained from comparison of 5 fish species).

The RAR ChIP-seq peaks located within 250kb from the TSS of a gene were assigned to this gene and when several genes were lying in the vicinity of a RAR site, the closest gene was considered as the putative RAR-regulated gene. Using this strategy, amongst the 2848 RAR sites, 2144 were linked to a gene. Correlation analysis between RA gene expression regulated by RA and the number of RAR sites near the gene showed that RAR acts mainly as a transcriptional activator (Fig.3A), supporting the classical model where RAR/RXR heterodimers mainly recruit co-activators upon RA ligand binding1. However, this correlation is not very high and genes down-regulated by RA can harbour nearby RAR sites. Indeed, from the gene set having RAR sites, 61 were down-regulated and 94 genes were up-regulated by RA at 3-S stage (Fig.3B, Tables S5). Among the genes up-regulated by RA and harbouring a RAR site, we identified the pancreatic regulatory genes hnf1ba/b, gata6, insm1b, jag2b and mnx1 indicating that these genes are direct targets of RA. As for the genes down-regulated by BMS493, we found that a large number of them (i.e. 18 genes out of 32) contain RAR sites and amongst them 13 are also upregulated by RA (Fig.3B, see legends for gene names). In conclusion, the ChIP-seq data allowed us to define the zebrafish RAR cistrome at the end of gastrulation and identify putative RAR direct target genes.

Integrated analysis of the ChIP-seq and RNA-seq data. (A) Correlation of RA gene regulation (log2 fold change of expression RA versus DMSO) according to the number of neighbouring RARaa ChIP-seq peaks. Only RA-regulated genes were included in the plot. (B) Venn diagram showing the overlap of genes harbouring nearby RARa binding sites (yellow) and those up-regulated by RA (purple), or down-regulated by RA (blue). The below panel also shows the overlap with the genes down-regulated by BMS493 (red). The 13 genes showing up-regulation by RA, down-regulation by BMS493 and harbouring a RAR site are tshz1, nr6a1b, foxg1b, nr2f5, gata6, dhrs3a, hoxb1b, slc22a3, ppm1h, nrip1a, col7a1l, hoxc1a and hoxb5b.

Functionally important regulatory regions are expected to be conserved during evolution. To determine which RAR binding sites are conserved in vertebrates, we compared our zebrafish ChIP-seq data with those of Chatagon and colleagues19 who identified RAR binding sites in the murine genome using the F9 embryonal carcinoma cells whose differentiation into primitive endodermal cell is induced by RA treatment. This comparison revealed that, among the 2144 zebrafish genes harbouring a RAR site, 722 have also a RAR site near the murine orthologous genes. This list of conserved RAR-bound genes comprises notably cyp26a1/b1, dhrs3a, nr2f2, many hox genes, raraa/b as well as pancreatic genes gata6, hnf1ba, insm1 and mnx1. We next determined which of these RAR binding sites are located in conserved regulatory sequences. To that end, we retrieved the list of conserved non-coding elements (CNEs) identified in zebrafish by comparing multiple fish and tetrapod genomes34. Amongst the 722 conserved RAR-bound genes, 116 RAR binding sites were located in CNEs, supporting a regulatory function (Table S6). Amongst them, 24 CNEs were even conserved from fish to mouse and are called here HCNE for highly conserved non-coding elements. They are found for example near the meis1/2, srsf6, qki, nrip1 and ncoa3 genes (Table S6). As already reported, several RAR sites controlling the expression of hox genes are located in these HCNEs17. Interestingly, we identified here a novel RAR site in a HCNE located 25kb downstream of the zebrafish hoxb cluster in the fourth intron of the skap1 gene. This intron contains 4 strong RAR sites in the zebrafish and murine sequences (green boxes in Fig.4A,B) and the sequence of the second RAR site has been maintained throughout vertebrate evolution and shows a motif similar to a DR5 RARE (Fig.4C). The transcriptional regulatory function of this HCNE was tested by transgenesis by inserting one copy of this element upstream of a minimal cfos promoter driving GFP. As shown in Fig.5A, this reporter transgene is expressed in the gut and in the neural tube. Highest GFP levels were detected in the posterior hindbrain, in a pattern highly reminiscent of hoxb1b gene expression (shown on Fig.5D). Furthermore, when transgenic embryos were treated with exogenous RA, GFP expression was drastically increased and detected in the whole morphologically affected embryos in a similar manner to hoxb1b (Fig.5B,E). Conversely, treatments with the RA inverse-agonist BMS493 turned off the expression of this DR5-RAR-skap1:GFP transgene (Fig.5C) as well as of hoxb1b, except in the tailbud region (Fig.5F). This confirms the RARE function of this element and indicates a role in hoxbb cluster regulation.

Examples of RARa binding sites conserved among vertebrates. (A,B) Genome browser views around HoxB-Skap1 locus in mouse (A) and zebrafish (B) showing the RAR binding sites detected by ChIP-seq (in gold) in both species. All RAR sites are located in CNEs but only the RAR sites located in skap1 gene 4th intron (green box) display sequence conservation from zebrafish to human. Other RAR sites located at similar places in the murine and zebrafish loci (red boxes) are probable orthologous RAR sites but their sequences cannot be aligned between zebrafish and mice. Conserved regions from the UCSC genome browser is shown below the murine RAR ChIP-seq peaks in panel (A). (C) Alignment of 9 vertebrate sequences corresponding to the second RAR sites located in skap1 gene 4th intron, showing the conservation of a DR5-like motif (blue boxes; inverse orientation) recognized by the RARRXR complex. Sequences highlighted in green are identical in all 9 species.

The conserved RAR site from skap1 gene 4th intron is a functional RARE. Pictures of the DR5-RAR-skap1:GFP transgenic embryos treated with DMSO (control, panel A), with RA (panel B) or with BMS493 (panel C). Upper panels display GFP fluorescent expression and lower panels (A, B and C) display embryo morphology. GFP Expression in the posterior endoderm gut is indicated by yellow arrows.

We also verified the regulatory role of some other RAR sites identified near zebrafish pancreatic regulatory genes. For example, we tested the activity of a RAR site located near a CNE downstream of the zebrafish mnx1 gene. A RAR binding site is also found at a similar location downstream of the murine Mnx1 gene (Fig. S2A). This RAR element was able to target GFP expression to the posterior endoderm at low level and in the dorsal pancreatic bud at higher levels (Fig. S2BD). When the RAR-mnx1:GFP transgenic embryos were treated with RA, GFP expression was slightly increased in whole endoderm; conversely, treatment with BMS493 abolished GFP expression (Fig. S2DF).

In conclusion, these analyses show that a large fraction of RAR sites has been conserved during evolution and transgenic assays confirm that some elements are sufficient to drive expression in endoderm and confer a RA-response.

RARRXR complexes control gene expression through the recruitment of corepressors (e.g. NCoR/Smart) and coactivators (NCoA) which control chromatin compaction via HDACs and HATs, respectively2, 3. Thus, one possible strategy to identify functional RAREs is to perform a genome-wide analysis of chromatin accessibility modifications following RA or RA inverse-agonist treatments by ATAC-seq assays33 allowing the identification of open chromatin and nucleosome-free regions induced or repressed by RA signaling. As most nucleosome-free regions correspond to regulatory sequences, ATAC-seq can also highlight the enhancers or promoters whose accessibility is modified by RA signalling indirectly, i.e. through the binding of transcription factors whose expression is induced by RA. Thus, sequence analysis of all RA-induced ATAC-seq peaks can give clues on the identity of transcription factors acting in the subsequent steps of the RA-induced regulatory cascade.

As for the RNA-seq assays, zebrafish embryos were treated with RA, BMS493 and DMSO during blastula and gastrulation and about 10,000 endodermal cells were selected by FACS at 3-somites stage (11 hpf). Non-endodermal cells from control DMSO-treated embryos were also analysed in parallel. Cell preparations and ATAC-seq experiments were done in triplicate for each condition and analysed as described in Materials and methods. We first verified the accuracy of the data by several quality control analyses. First, for all samples, the analysis of the ATAC-seq fragment size distribution revealed the expected pattern with abundant short (<150bp) fragments corresponding to nucleosome-free regions and larger fragments of about 200 and 400bp corresponding to mono- and bi-nucleosome regions, respectively (Fig. S3A). Secondly, as reported previously33, 35, genome mapping of the nucleosome-free fragments showed a clear enrichment in promoter regions immediately upstream of transcriptional start sites (TSSs), while mono-nucleosomes were depleted from TSSs and rather mapped just downstream of the TSSs in a periodic manner (Fig. S3B). Thirdly, we verified that the ATAC-seq fragments correspond to many zebrafish regulatory regions by comparing them with regions harbouring the histone modifications H3K4me3 and H3K27ac marks identified in zebrafish embryos at 10hpf36. Heatmap plots of ATAC-seq reads from all samples showed an obvious enrichment at loci harbouring these two histone modifications (Fig.6A and Fig. S4). As regulatory regions often display sequence conservation, we also compared our ATAC-seq reads to the collection of zebrafish evolutionary-conserved non-coding elements (zCNEs)34. Heat-maps of ATAC-seq reads from each sample also showed a strong correlation with zCNEs (Fig.6A and Fig. S4). These observations confirm that regions identified by ATAC-seq exhibited hallmarks of active regulatory elements. The reproducibility of ATAC-seq data was also analysed by PCA (Fig.6B). This PCA showed that (i) triplicate samples are tightly clustered, and (ii) endodermal and non-endodermal (NE) cell clusters are separated along the PC2 axis, while the RA-treated cluster is separated from the DMSO- and BMS-cell cluster along the PC3 axis. Thus, as observed for the RNA-seq data (Fig.1A), stronger differences are observed between GFP+ and GFP cells compared to the differences between RA-treated and DMSO-treated endodermal cells. The samples corresponding to the BMS493-treated cells and DMSO-treated cells were not clearly segregated and did not reveal significant effects of BMS493 on the chromatin accessibility.

Identification of nucleosome-free regions in zebrafish endodermal cells and following RA treatments by ATAC-seq assays. (A) Heat maps showing enrichment of ATAC-seq reads at the middle of chromatin regions harbouring H3K4me3 and H3K27Ac epigenetic marks and at genomic areas corresponding to zCNE. The maps display intervals flanking 10kb up and downstream of the features. The heat map plots shown on this figure corresponds to the ATAC-seq data obtained with control endodermal cells (DMSO-treated). Similar results were obtained for the other samples (see Suppl. Fig.4). (B) PCA plots obtained for the ATAC-seq libraries. ATAC-seq data from endodermal and non-endodermal cells are separated along the PC2 axis, while those from RA-treated versus control and BMS493 are separated along the PC3 axis. The plot shows clustering of triplicates and no obvious separation of the DMSO- and BMS493- treated cells. (C,D) Top 3 enriched motifs found in nucleosome-free regions detected specifically in endoderm (C) and detected following RA-treatments (D). (E) Plot showing the correlation of RA-induced gene expression (log2 fold change) and the number of RA-induced nucleosome-free elements located nearby the genes. Only genes showing significant RA gene induction were included.

From all 12 ATAC-seq samples, a total of 156,604 nucleosome-free regions were identified within the zebrafish genome. Differential peak intensity analyses revealed that 9722 and 12,974 regions are more accessible in endodermal and non-endodermal cells, respectively (with FDR<0.05, Tables S7). Interestingly, sequence analysis of all endodermal-specific ATAC-seq regions highlight a significant enrichment of the binding site motifs for the Gata, Fox and Sox protein families (Fig.6C), in accordance with the well-known function of Gata4/5/6, Foxa1/2/3 and Sox32/17 in endodermal cell differentiation6. Also, these endoderm-enriched ATAC-seq peaks are often identified near endodermal and pancreatic regulatory genes, such as in the foxa2, nkx6.1, hnf4g, sox17 or mnx1 loci (Fig. S5 and data not shown), suggesting the presence of endoderm-specific enhancers at these locations.

As expected, the RA treatments had less influence on ATAC-seq peaks compared to the cell type identity (i.e. endoderm versus non-endoderm). Still, 1240 genomic regions were found to be more accessible and 749 regions were less accessible in the RA-treated endoderm compared to the DMSO-treated controls (with FDR<0.05). If the RA-treated samples were directly compared with the BMS493-treated samples, more peaks were detected as treatment-dependent: 3277 regions were more accessible in RA-treated while 1762 were more accessible in the BMS493-treated cells (Tables S8). Annotation of the RA-induced ATAC-seq peaks to the closest gene revealed that they were often located near RA-upregulated genes identified above by RNA-seq. Moreover, we found a significant correlation between the level of RA-induced gene expression and the number of RA-induced ATAC-seq elements (Fig.6E). Interestingly, 11% of RA-induced ATAC-seq peaks corresponded to RAR binding sites identified by ChIP-seq and possess the DR5 motif recognized by the RAR/RXR complex (Fig.6D). This was the case for RA-induced peaks in the dhrs3a, cyp26a1/b1 and insm1b genes (see black boxes in Fig. S6 and data not shown). However, many identified RAR sites did not display a significant increase in accessibility, such as those located in the hoxba locus (see green boxes in Fig. S6). Furthermore, the majority of RA-induced ATAC-seq peaks did not harbour RAR binding sites although they were usually found near RA-upregulated genes; instead, such peaks often harbour Gata or Hnf1b binding motifs (38% and 13% of all RA-induced elements, respectively; Fig.6D). Thus, it can reasonably be assumed that these genes are indirectly stimulated by RA signalling. For example, the pancreatic regulatory genes pdx1, insm1a, rfx6 or neurod1, all upregulated by RA-treatment but devoid of RAR binding sites, had RA-induced ATAC-seq peaks located in their genomic neighbourhood and contained either Hnf1b or Gata binding motifs in such peaks (Fig. S7 and data not shown). To identify the GATA and Hnf1b family members involved in these indirect RA-regulations, we searched in the list of RA-stimulated genes (Table S2) for these 2 types of transcription factors and we also determined if RAR sites are detected in their genomic loci (Tables S4 and S5). hnf1ba and hnf1bb were both induced by RA but the level of expression of hnf1ba was about 200-fold higher than hnf1bb in endodermal cells. Furthermore, hnf1ba contains three RAR binding sites located in evolutionary-conserved and nucleosome-free regions (Fig.7A), while hnf1bb has only one weak RAR site (data not shown). Out of the 10 members of the GATA family, only gata4 and gata6 were significantly induced by RA but gata6 was expressed in the endoderm at about 40-fold higher level compared to gata4. Furthermore, gata6 has a high affinity RAR binding site in a nucleosome-free region located about 30kb upstream from its TSS (Fig.7B) while no such RAR site was present around the gata4 gene locus (data not shown). Thus, all these analyses strongly suggest that, upon RA induction, RARRXR complexes directly activate expression of Gata6 and Hnf1ba, which in turn will open regulatory chromatin regions of many genes, including those coding for several pancreatic regulatory factors.

Location of RARa binding sites and of nucleosome-free regions in the hnf1ba (panel A) and gata6 (panel B)gene loci. Visualization of ATAC-seq reads from the merged 3 replicates obtained from endoderm treated with BMS493, DMSO or RA and from non-endodermal cells (NE), in addition to tracks showing RARaa binding sites, H3K27Ac and H3K3me3 marks determined by ChIP-seq. Regions showing conservation of genomic sequences among 5 fish species are also shown by blue boxes below the tracks. The RAR binding sites are highlighted by gold boxes.

Read more:
Identification of downstream effectors of retinoic acid specifying the zebrafish pancreas by integrative genomics | Scientific Reports - Nature.com

To do their lab work, Laura Ross and her team must conduct an itty-bitty surgery. First, they dissect out the reproductive tissues of the black-winged fungus gnat, a diminutive black fly about one-sixteenth to one-eighth of an inch long. Then they home in on particular cells in that tissue: the germ cells, which produce eggs and sperm and so hold the keys to the genome of the next generation.

Ross, an evolutionary biologist at the University of Edinburgh in Scotland, roots around in fungus-gnat parts because theres something odd about the cells in these flies: They dont follow the textbook rules. In sexually reproducing creatures, one full copy of the mothers genetic material generally fuses with one full copy of the fathers to create the complete, doubled-up set of DNA found in cells throughout the body.

But the fungus gnat does something bizarre. Early in the embryos development, most of the cells jettison two specific chromosomes enormous ones, compared with the others so the pair never ends up in the lions share of the gnats body. Only the cells that become germ cells retain the bonus DNA and pass it on to the next generation.

How and why this feature evolved remains largely mysterious, though biologists first spotted it a century ago. And black-winged fungus gnats arent the only genetic screwballs. A surprisingly wide array of creatures, all the way up to some vertebrates, dump significant stretches of DNA during early development, so the stretches dont end up in most of their body cells.

To date, scientists have observed the phenomenon in various insects, in lampreys and hagfish, in hairy one-celled life forms called ciliates, in parasitic roundworms and tiny crustaceans called copepods. Theyve seen it in rat-like marsupials called bandicoots and in songbirds probably all songbirds, according to recent work. And they expect to find many more cases.

A lot of these weird genomic features tend to be fairly rare, but they do evolve repeatedly, Ross says. Its not just one freak event. Presumably, then, there must be some selective advantage to the creatures that go down that evolutionary route. But what is it?

J. WANG & R.E. DAVIS / CURRENT OPINION IN GENETICS & DEVELOPMENT 2014

From copepods and worms to lampreys and bandicoots, programmed DNA elimination crops up all over the multicellular treeof life, with more cases likely waiting to be found. The standout stars of this odd show are songbirds, which all appearto display the phenomenon. Animal groups in which cases have been documented are noted in red, as are dates when thediscoveries in a given group were first reported. (Ciliates are noted in blue to indicate the trees root:the most recent common ancestor of all the creatures shown.)

Beyond their fascinating oddness, these quirks may hold broader lessons on how genomes work the way they do, scientists think, and how and why the DNA in germ cells is treated differently from the DNA in the rest of the developing critters body.

Its a fundamental difference between the DNA thats going on to the next generation and the DNA thats in all the other cell types, says Jeramiah Smith, a geneticist at the University of Kentucky who studies the phenomenon in lampreys and described it in the 2020 Annual Review of Animal Biosciences.

Starting in the late 1800s, well before scientists nailed down the link between DNA and heredity, biologists peering down microscopes used dyes to study tiny, twig-like bodies inside dividing cells, watching as the twigs grouped together and then separated. German anatomist Wilhelm von Waldeyer-Hartz named these structures chromosomes in 1888, for the ease with which they took up dye.

Around the same time, cell biologists observed chunks of chromosomes being discarded in a parasitic roundworm called Parascaris univalens that infects horses a much-studied worm because its pair of huge chromosomes were easy to view under a microscope. In later decades, researchers described other worm species that dropped segments from several chromosomes during early rounds of cell division in embryos. But they didnt have the technology to really explore it, says Richard Davis, an emeritus molecular biologist at the University of Colorado School of Medicine in Aurora.

Davis, who dedicated the last decade of his career to studying how this casting-off happens in a handful of roundworms, initially thought that the DNA being eliminated carried no blueprint for any genes. Most biologists (those whove heard of the phenomenon, anyway) have assumed the same thing, he says.

WIKIMEDIA COMMONS / PUBLIC DOMAIN

The earliest noted case of programmed DNA loss was reported in the late 19th century in a species of nematode worm. The observation was made by German scientist Theodor Boveri (right), who was renowned for his careful examination of chromosomes as cells divided and for linking this chromosomal behavior to the inheritance of traits, among other work. The drawing on the left is one of many by Boveri, who also drew and painted in his youth. It documents chromosome loss in early embryonic divisions of the worm.

It turned out, though, that this ditched DNA contains genes lots of them. Roundworms from the genus Ascaris, which infect pigs and people, dump about 5 percent of their genes, while those of the genus Parascaris cast off about 10 percent. Only the cells that are destined to form the worms body do the DNA ditching: Just like the black-winged fungus gnat, the full set of genes remain in the cells destined to form eggs and sperm. The worms offspring, and its offsprings offspring, repeat the exact same process.

Davis also noticed something else: Most of the genes that are retained in the germ cells are active in those cells, implying theyre needed there. And so Davis thinks that tossing the genes away in all the other body cells may be the worms ironclad method of making sure the genes dont become active where they arent meant to.

Guaranteeing that genes are active at certain times but not others, or in some tissues but not others, is a critical function for any living thing. Think of the many different cell types in our bodies: All contain the same DNA sequence, but our heart cells produce different proteins than our skin cells do, so that each can do its specialized job. And even within a particular type of cell, the proteins that are produced vary during a creatures lifespan.

Perhaps what these dropped genes do would be so damaging to adult cells that eliminating them is a better-safe-than-sorry device, Davis says. Its total speculation, though because theres no proof of anything.

But that also presents a puzzler thats yet to be solved. Most living things already have ways to silence specific genes by adding chemical tags. So why do they choose to do this? Davis says.

Smith thinks the same type of extreme gene silencing may be at play in lampreys. His lab stumbled upon DNA elimination in these ancient jawless fish while working with colleagues on decoding the lamprey genome. Smith had seen research from the 1980s reporting chromosome loss in the closely related hagfish. He decided to see if lampreys were doing the same thing.

Lamprey physiology makes it easy to extract eggs and sperm from the animals Smith likens it to milking a cow or squeezing toothpaste out of a tube. He then fertilized the eggs and watched the embryos develop and found that they were dropping chromosomes 1.5 to 3 days after fertilization.

Lampreys lose 12 entire chromosomes out of their initial set of 96, and perhaps some bits and pieces from the chromosomes that remain. The losses are pre-programmed to occur in almost all the cells of the embryo except for a small handful of cells destined to soon become germ cells. Ultimately, those bits end up in sperm and egg cells, but not in any other lamprey cells.

Using advanced sequencing methods that were just coming online at the time, Smith and his colleagues identified many genes in the eliminated DNA. Intriguingly, about 60 percent to 70 percent of the genes are similar to ones that, in our species, are thought to boost cancer when their activity gets out of control. Whatever their normal function is, those genes might be especially dangerous ones to keep around in body cells. We think lamprey are getting rid of these genes as a means of permanently silencing them, Smith says.

Early in development, the sea lamprey loses genetic material as shown in this diagram. Most of the chromosomes segregate neatly to the poles during cell division but 12 do not, and as a consequence dont end up in the two new nuclei that result from a division. They form their own micronuclei, and the genes they contain are silenced and ultimately degraded. The result: The lamprey haploid chromosome count of 96 ends up as 84 in body cells.

Rosss fungus gnats, Bradysia ( Sciara) coprophila, have their own special mystery. They have been bred and maintained for decades, passing from lab to lab. Researchers in the 1920s studying how chromosomes behave in the cell noticed that these flies lose two chromosomes in some cells. (Some insects, its now known, have more than 80 chromosomes to dispose of.) But these chromosomes called germline restricted chromosomes because they are only retained in the germline are almost as large as the rest of the gnats genome.

In fact, they are basically an entire genome, as they contain an entire extra set of the genes a gnat has. But fungus gnats are weirder still. When Ross and her team sequenced the chromosomes, she found that the genes they bear arent especially similar to ones of the species they reside in. It looks like the genome of a completely different species, Ross says of an entirely different group of flies.

Rosss best guess is that during a rare mating event between two different species eons ago, the genome of one got integrated into the genome of the other and somehow got shunted to the germline alone. For her, this still-hypothetical freak event along with other weirdnesses over how flies pass on their genetic material points to a fundamental mystery. The definition of life is being able to copy and paste your genetic material into future generations, she says. Why is this process so variable, and what drives that variation?

That same question drives Alexander Suh, an evolutionary biologist at the University of East Anglia in the UK and Uppsala University in Sweden, who studies a germline-restricted chromosome in the zebra finch, a songbird. Researchers first reported its existence in 1998. As a zebra finch embryo develops, this chromosome somehow magically, says Suh, and I say that with quotes just because I have no explanation yet, gets dropped from all cells except the germ cells.

This bizarre chromosome, too, is chock-full of genes, many of them present in multiple sometimes hundreds of copies. And many are active in the germline. Suh and colleagues and another group independently reported in 2019 that the chromosome dates back to the common ancestor of songbirds, and that all songbirds about half of all birds carry it.

Whatever it is, its been around for 50 million years, Suh says. Its somehow made sure that the host cannot exist without it.

Now Suhs team and others are puzzling out the possible role of this chromosome by looking at the function of the genes it contains. In the zebra finch at least, many of them seem related to development of the female gonad. Others appear to be involved in other aspects of early development.

But its a head scratcher, Suh says, why these genes get passed down in a roundabout way that differs from the standard system of heredity. Smith, Ross and Davis are similarly pondering the reasons for the systems that they study in lampreys, flies and worms.

Perhaps the chromosomes (or bits of chromosomes) are selfish just in it for themselves and have engineered ways to be retained. Or maybe these germline-restricted chromosomes have a benefit for example, by serving as incubators where newly evolved genes are safely housed until it can be determined if theyre beneficial or damaging to the organism.

Alternatively, the processes could be holdovers from earlier evolutionary events. Maybe, says Smith, this silencing technique evolved before or in parallel with some of the silencing methods that vertebrates use today. Is this something that at one period of time defined our ancestors biology?

But whatever the answer or answers turns out to be, its striking, Suh says, how few people, even among biologists, are aware that genes and heredity so often work in peculiar ways.

Maybe, he says, this is something we need to start teaching earlier on: how even more fascinating the genome is than we already thought.

This article originally appeared in Knowable Magazine, an independent journalistic endeavor from Annual Reviews.

More:
The curious case of the shrinking genome - American Society for Biochemistry and Molecular Biology