The Human Pangenome Project: a global resource to map genomic diversity
Ting Wang, Lucinda Antonacci-Fulton, David Haussler
Perspective | 20 April 2022
Nature, Volume 604 Issue 7906, 21 April 2022
The Human Pangenome Reference Consortium aims to offer the highest quality and most complete human pangenome reference that provides diverse genomic representation across human populations.
Abstract
The human reference genome is the most widely used resource in human genetics and is due for a major update. Its current structure is a linear composite of merged haplotypes from more than 20 people, with a single individual comprising most of the sequence. It contains biases and errors within a framework that does not represent global human genomic variation. A high-quality reference with global representation of common variants, including single-nucleotide variants, structural variants and functional elements, is needed. The Human Pangenome Reference Consortium aims to create a more sophisticated and complete human reference genome with a graph-based, telomere-to-telomere representation of global genomic diversity. Here we leverage innovations in technology, study design and global partnerships with the goal of constructing the highest-possible quality human pangenome reference. Our goal is to improve data representation and streamline analyses to enable routine assembly of complete diploid genomes. With attention to ethical frameworks, the human pangenome reference will contain a more accurate and diverse representation of global genomic variation, improve gene–disease association studies across populations, expand the scope of genomics research to the most repetitive and polymorphic regions of the genome, and serve as the ultimate genetic resource for future biomedical research and precision medicine.
Month: May 2022
Uganda Genome Resource: A rich research database for genomic studies of communicable and non-communicable diseases in Africa
Uganda Genome Resource: A rich research database for genomic studies of communicable and non-communicable diseases in Africa
Segun Fatumo, Joseph Mugisha, Opeyemi Soremekun, Allan Kalungi, Richard Mayanja, Christopher Kintu, Ronald Makanga, Ayoub Kakande, Andrew Abaasa, Gershim Asiki, Robert Kalyesubula, Robert Newton, Moffat Nyirenda, Manjinder S Sandhu, Pontiano Kaleebu
medRxiv, 2022.05.05.22274740; doi: https://doi.org/10.1101/2022.05.05.22274740
Abstract
The Uganda Genome Resource (UGR) is a well characterised genomic database, with a range of phenotypic communicable and non-communicable diseases and risk factors generated from the Uganda General Population Cohort (GPC) – a population-based open cohort study established in 1989 by the Medical Research Council (MRC) UK in collaboration with the Uganda Virus Research Institute (UVRI).
In 2011, UGR was launched with genotype data on ∼5000 and whole genome sequence data on ∼2000 Ugandan individuals from 9 ethno-linguistic groups. Leveraging other available platforms at the MRC Uganda such as Biorepository centre for sample storage, Clinical Diagnostic Laboratory Service (CDLS) for sample diagnostic testing, sequencing platform for DNA extraction, Uganda Medical informatics Unit (UMIC) for large-scale data analysis, GPC for additional sample collection, UGR is strategically poised to expand and generate scientific discoveries.
Here, we describe UGR and highlight the important genetic findings thus far including how UGR is providing opportunities to: (1) discover novel disease susceptibility genetic loci; (2) refine association signals at new and existing loci; (3) develop and test Polygenic Risk Score (PRS) to determine individual’s disease risk; 4) assess how some risk factors including infectious diseases are causally related to non-communicable diseases (NCDs) in Africa; (5) develop research capacity for genomics in Africa; and (6) enhance African participation in the global genomics research arena. Leveraging established research infrastructure, expertise, local genomic leadership, global collaboration and strategic funding, we anticipate that UGR can develop further to a comparable level of European and Asian large-scale genomic initiatives.
Participant recall and understandings of information on biobanking and future genomic research: experiences from a multi-disease community-based health screening and biobank platform in rural South Africa
Participant recall and understandings of information on biobanking and future genomic research: experiences from a multi-disease community-based health screening and biobank platform in rural South Africa
Authors: Manono Luthuli, Nothando Ngwenya, Dumsani Gumede, Resign Gunda, Dickman Gareta, Olivier Koole, Mark J. Siedner, Emily B. Wong and Janet Seeley
Research Open Access
BMC Medical Ethics, 2022 23:43 Published on: 18 April 2022
Abstract
Background
Limited research has been conducted on explanations and understandings of biobanking for future genomic research in African contexts with low literacy and limited healthcare access. We report on the findings of a sub-study on participant understanding embedded in a multi-disease community health screening and biobank platform study known as ‘Vukuzazi’ in rural KwaZulu-Natal, South Africa.
Methods
Semi-structured interviews were conducted with research participants who had been invited to take part in the Vukuzazi study, including both participants and non-participants, and research staff that worked on the study. The interviews were transcribed, and themes were identified from the interview transcripts, manually coded, and thematically analysed.
Results
Thirty-nine individuals were interviewed. We found that the research team explained biobanking and future genomic research by describing how hereditary characteristics create similarities among individuals. However, recollection and understanding of this explanation seven months after participation was variable. The large volume of information about the Vukuzazi study objectives and procedures presented a challenge to participant recall. By the time of interviews, some participants recalled rudimentary facts about the genetic aspects of the study, but many expressed little to no interest in genetics and biobanking.
Conclusion
Participant’s understanding of information related to genetics and biobanking provided during the consent process is affected by the volume of information as well as participant’s interest (or lack thereof) in the subject matter being discussed. We recommend that future studies undertaking biobanking and genomic research treat explanations of this kind of research to participants as an on-going process of communication between researchers, participants and the community and that explanatory imagery and video graphic storytelling should be incorporated into theses explanations as these have previously been found to facilitate understanding among those with low literacy levels. Studies should also avoid having broader research objectives as this can divert participant’s interest and therefore understanding of why their samples are being collected.
Gene Editing, Animal Disenhancement and Ethical Debates: A Conundrum for Business Ethics?
Gene Editing, Animal Disenhancement and Ethical Debates: A Conundrum for Business Ethics?
N Thomas, A Langridge
Animals and Business Ethics
Book Chapter
Springer. 25 April 2022
The Palgrave Macmillan Animal Ethics Series. Palgrave Macmillan, Cham.
https://doi.org/10.1007/978-3-030-97142-7_10
Abstract
Despite the potential of genetic disenhancement to create livestock incapable of pain and thus reduce animal suffering in industrial farming, ethical theorists have rejected disenhancement as intuitively unethical or as part of a broader dismissal of industrial farming. Although criticisms of industrial farming may be valid, the suffering of animals involved still needs to be addressed, and business ethics is specially placed to do so. In this chapter, a brief overview of the related ethical issues of industrial farming and disenhancement are outlined, and practical steps businesses should make to address animal suffering are provided. Explicit Corporate Social Responsibility policies that reflect the interest of animals, workers and consumers as stakeholders should be put in place, which would provide a mechanism to make businesses accountable for genetic modification and animal welfare more generally.
Governing Gene Drive Technologies: A Qualitative Interview Study
Governing Gene Drive Technologies: A Qualitative Interview Study
de Graeff, Karin R. Jongsma, Jeantine E. Lunshof & Annelien L. Bredenoord
Article
AJOB Empirical Bioethics, Volume 13, 2022 Issue 2
Abstract
Background
Gene drive technologies (GDTs) bias the inheritance of a genetic element within a population of non-human organisms, promoting its progressive spread across this population. If successful, GDTs may be used to counter intractable problems such as vector-borne diseases. A key issue in the debate on GDTs relates to what governance is appropriate for these technologies. While governance mechanisms for GDTs are to a significant extent proposed and shaped by professional experts, the perspectives of these experts have not been explored in depth.
Methods
A total of 33 GDT experts from different professional disciplines were interviewed to identify, better understand, and juxtapose their perspectives on GDT governance. The pseudonymized transcripts were analyzed thematically.
Results
Three main themes were identified: (1) engagement of communities, stakeholders, and publics; (2) power dynamics, and (3) decision-making. There was broad consensus amongst respondents that it is important to engage communities, stakeholders, and publics. Nonetheless, respondents had diverging views on the reasons for doing so and the timing and design of engagement. Respondents also outlined complexities and challenges related to engagement. Moreover, they brought up the power dynamics that are present in GDT research. Respondents stressed the importance of preventing the recurrence of historical injustices and reflected on dilemmas regarding whether and to what extent (foreign) researchers can legitimately make demands regarding local governance. Finally, respondents had diverging views on whether decisions about GDTs should be made in the same way as decisions about other environmental interventions, and on the decision-making model that should be used to decide about GDT deployment.
Conclusions
The insights obtained in this interview study give rise to recommendations for the design and evaluation of GDT governance. Moreover, these insights point to unresolved normative questions that need to be addressed to move from general commitments to concrete obligations.
Proceedings of an expert workshop on community agreement for gene drive research in Africa – Co-organised by KEMRI, PAMCA and Target Malaria
Proceedings of an expert workshop on community agreement for gene drive research in Africa – Co-organised by KEMRI, PAMCA and Target Malaria
Gates Open Research
Open Letter metrics AWAITING PEER REVIEW
[version 1; peer review: awaiting peer review]
Delphine Thizy, Lea Pare Toe, Charles Mbogo, Damaris Matoke-Muhia, Vincent Pius Alibu, S. Kathleen Barnhill-Dilling, Tracey Chantler, Gershom Chongwe, Jason Delborne, Lydia Kapiriri, Esther Nassonko Kavuma, Sethlomo Koloi-Keaikitse, Ana Kormos, Katherine Littler, Dickson Lwetoijera, Roberta Vargas de Moraes, Noni Mumba, Lilian Mutengu, Sylvia Mwichuli, Silvia Elizabeth Nabukenya, Janet Nakigudde, Paul Ndebele, Carolyne Ngara, Eric Ochomo, Simon Odiwuor Ondiek, Stephany Rivera, Aaron J. Roberts, Rodrick Sambakunsi, Abha Saxena, Naima Sykes, Brian B. Tarimo, Nicki Tiffin, Karen H. Tountas
Peer Reviewers Invited
Funders: Bill and Melinda Gates Foundation, Silicon Valley Community Foundation, Open Philanthropy Project
PUBLISHED 29 Jan 2021
Abstract
Gene drive research is progressing towards future field evaluation of modified mosquitoes for malaria control in sub-Saharan Africa. While many literature sources and guidance point to the inadequacy of individual informed consent for any genetically modified mosquito release, including gene drive ones, (outside of epidemiological studies that might require blood samples) and at the need for a community-level decision, researchers often find themselves with no specific guidance on how that decision should be made, expressed and by whom. Target Malaria, the Kenya Medical Research Institute and the Pan African Mosquito Control Association co-organised a workshop with researchers and practitioners on this topic to question the model proposed by Target Malaria in its research so far that involved the release of genetically modified sterile male mosquitoes and how this could be adapted to future studies involving gene drive mosquito releases for them to offer reflections about potential best practices. This paper shares the outcomes of that workshop and highlights the remaining topics for discussion before a comprehensive model can be designed.
Genome-edited crops for improved food security of smallholder farmers
Genome-edited crops for improved food security of smallholder farmers
Kevin V. Pixley, Jose B. Falck-Zepeda, Neal Gutterson
Comment | 07 April 2022
Nature Genetics, Volume 54 Issue 4, April 2022
[Excerpt]
Widespread enthusiasm about potential contributions of genome-edited crops to address climate change, food security, nutrition and health, environmental sustainability and diversification of agriculture is dampened by concerns about the associated risks. Analysis of the top seven risks of genome-edited crops finds that the scientific risks are comparable to those of accepted, past and current breeding methods, but failure to address regulatory, legal and trade framework, and the granting of social license, squanders the potential benefits…
Many countries are still uncertain about whether to grow and how to regulate genome-edited crop varieties12. Scientific, political and social considerations impact these decisions, which are complicated by the rapidly evolving features of the science and inconsistent use of genome-editing terminology13. For example, genome editing may or may not involve the transitory introduction of foreign DNA sequences, may or may not result in transgenic products, and may or may not generate products that substantially differ from varieties bred through conventional breeding. Precise consistent use of accurate terminology (for instance, as proposed by the National Academies of Sciences Engineering and Medicine14) to transparently explain the process, products, benefits and potential risks and mitigation strategies is essential to build public trust and consistent regulatory oversight of technologies, including genome editing.
Global landscape of SARS-CoV-2 genomic surveillance and data sharing
Global landscape of SARS-CoV-2 genomic surveillance and data sharing
Analyses on the global diversity of SARS-CoV-2 genomic surveillance across 118 countries and the extent of public availability of genomic data provide evidence to better inform SARS-CoV-2 surveillance policy.
Zhiyuan Chen, Andrew S. Azman, Hongjie Yu
Analysis | 28 March 2022 | Open Access
Nature Genetics, Volume 54 Issue 4, April 2022
Abstract
Genomic surveillance has shaped our understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. We performed a global landscape analysis on SARS-CoV-2 genomic surveillance and genomic data using a collection of country-specific data. Here, we characterize increasing circulation of the Alpha variant in early 2021, subsequently replaced by the Delta variant around May 2021. SARS-CoV-2 genomic surveillance and sequencing availability varied markedly across countries, with 45 countries performing a high level of routine genomic surveillance and 96 countries with a high availability of SARS-CoV-2 sequencing. We also observed a marked heterogeneity of sequencing percentage, sequencing technologies, turnaround time and completeness of released metadata across regions and income groups. A total of 37% of countries with explicit reporting on variants shared less than half of their sequences of variants of concern (VOCs) in public repositories. Our findings indicate an urgent need to increase timely and full sharing of sequences, the standardization of metadata files and support for countries with limited sequencing and bioinformatics capacity.
Ethical and practical considerations for cell and gene therapy toward an HIV cure: findings from a qualitative in-depth interview study in the United States
Ethical and practical considerations for cell and gene therapy toward an HIV cure: findings from a qualitative in-depth interview study in the United States
Authors: Karine Dubé, John Kanazawa, Hursch Patel, Michael Louella, Laurie Sylla, Jeff Sheehy, Lynda Dee, Jeff Taylor, Jen Adair, Kim Anthony-Gonda, Boro Dropulić, John A. Sauceda, Michael J. Peluso, Steven G. Deeks and Jane Simoni
Content type: Research
BMC Medical Ethics, 9 April 2022
Abstract
Background
HIV cure research involving cell and gene therapy has intensified in recent years. There is a growing need to identify ethical standards and safeguards to ensure cell and gene therapy (CGT) HIV cure research remains valued and acceptable to as many stakeholders as possible as it advances on a global scale.
Methods
To elicit preliminary ethical and practical considerations to guide CGT HIV cure research, we implemented a qualitative, in-depth interview study with three key stakeholder groups in the United States: (1) biomedical HIV cure researchers, (2) bioethicists, and (3) community stakeholders. Interviews permitted evaluation of informants’ perspectives on how CGT HIV cure research should ethically occur, and were transcribed verbatim. We applied conventional content analysis focused on inductive reasoning to analyze the rich qualitative data and derive key ethical and practical considerations related to CGT towards an HIV cure.
Results
We interviewed 13 biomedical researchers, 5 community members, and 1 bioethicist. Informants generated considerations related to: perceived benefits of CGT towards an HIV cure, perceived risks, considerations necessary to ensure an acceptable benefit/risk balance, CGT strategies considered unacceptable, additional ethical considerations, and considerations for first-in-human CGT HIV cure trials. Informants also proposed important safeguards to developing CGT approaches towards an HIV cure, such as the importance of mitigating off-target effects, mitigating risks associated with long-term duration of CGT interventions, and mitigating risks of immune overreactions.
Conclusion
Our study identified preliminary considerations for CGT-based HIV cure across three key stakeholder groups. Respondents identified an ideal cure strategy as one which would durably control HIV infection, protect the individual from re-acquisition, and eliminate transmission to others. Known and unknown risks should be anticipated and perceived as learning opportunities to preserve and honor the altruism of participants. Preclinical studies should support these considerations and be transparently reviewed by regulatory experts and peers prior to first-in-human studies. To protect the public trust in CGT HIV cure research, ethical and practical considerations should be periodically revisited and updated as the science continues to evolve. Additional ethics studies are required to expand stakeholder participation to include traditionally marginalized groups and clinical care providers.
FDA – Human Gene Therapy Products Incorporating Human Genome Editing; Draft Guidance for Industry
FDA – Human Gene Therapy Products Incorporating Human Genome Editing; Draft Guidance for Industry
[Docket No. FDA-2021-D-0398];
In this guidance, we, FDA, are providing recommendations to sponsors developing human gene therapy products incorporating genome editing (GE) of human somatic cells. Specifically, this guidance provides recommendations regarding information that should be provided in an Investigational New Drug (IND) application in order to assess the safety and quality of the investigational GE product, as required in Title 21 of the Code of Federal Regulations 312.23 (21 CFR 312.23). This includes information on product design, product manufacturing, product testing, preclinical safety assessment, and clinical trial design.
Center for Genomic Medicine Governance, Ethics & Policy 