Wk 4.1 Genetic Research and Sovereignty in Indigenous Communities

Learning Objectives

● Describe some of the reasons why researchers have wanted to sample DNA from Indigenous communities, giving

examples from case studies (e.g., the Human Genome Diversity Project, research on the Havasupai Tribe, the Navajo

Nation, etc.). Refer back to Wk 3.1 for some of these examples.

● Explain why some Indigenous communities have elected to institute moratoriums on genetics research or have been

hesitant to engage with genomics research.

● Discuss the current level of representation of Indigenous people in genomics research, and brainstorm the

implications of this more broadly – why might under-representation matter from a variety of perspectives?

● Draw and explain the circular framework for conducting ethical research with Indigenous communities (this figure

was also in your assigned reading), being sure to label and define each component and describe the

inter-relationships between them (including bioethical considerations that were modeled on the Belmont Report

but have been amended to be more relevant to Indigenous communities).

● Describe the FAIR and CARE principles, and how they might conflict and/or be considered together in the context of

Indigenous sovereignty surrounding genetics research.

Key Terms

● MAOA in Māori community, forced sterilizations, data governance, cultural competency

Personal Introduction and Cultural Contextualization

Speaker Identity and Language: Speaker Nanibaa' Garrison introduced herself in Navajo (Diné) as a member of an indigenous community. She explained that a traditional Navajo introduction provides a summary of one's genetics by stating the lineage of four clans: * Mother’s lineage on her mother's side. * Father’s lineage on his mother's side. * Mother’s lineage on her father's side. * Father’s lineage on his father's side.
Clan Relationships: This system of four clans allows indigenous people to identify familial and clan relationships to determine how closely or distantly related they are. It illustrates that ancestors have followed patterns of relationship and genetic awareness for a long time.
Land Acknowledgment: The presentation took place at UCLA, which is situated on the traditional homelands of the Tongva (Topanga) people, the original land takers and residents of the Los Angeles area.

Review of Ethical Principles and Genetic Research

Belmont Report Principles: The lecture opened with a review of whether the three or four principles from the Belmont Report (Respect for Persons, Beneficence, Justice, and sometimes Non-maleficence) are sufficient to address concerns in indigenous communities regarding genetic research.
Inadequacy of Traditional Principles: * Community Aspects: Students noted that traditional principles do not fully cover the relationship and community engagement aspects (e.g., happiness and communal well-being). * Systemic Barriers: There are deep-seated systemic barriers, such as historical fear and mistrust, which 3 or 4 principles cannot easily overcome. * Justice Concerns: Historical neglect leads to inequities in access to participation and resources.

Historical Overview of Population-Scale Genetic Research

Early 1990s Research Objectives: Anthropology, genetics, and bioinformatics researchers aimed to catalog global genetic markers to examine human diversity and trace migration patterns.
Out of Africa Hypothesis: This theory posits that humans originated in a specific part of Africa and migrated out through Europe, Asia, and eventually the Americas.
Indigenous Objections: Many indigenous groups objected to migration data as it often challenged or conflicted with cultural origin stories and traditional beliefs about their ancestry.
Human Genome Diversity Project (HGDP): * Leadership: Led by Luca Cavalli-Sforza (Stanford geneticist) and Allan Wilson (UC Berkeley anthropologist). * Goals vs. Reality: They aimed to collect hundreds of thousands of samples but only managed samples from 51 populations, totaling 1,064 individuals. * Consent Issues: Researchers took samples from university freezers. While some researchers refused due to lack of proper informed consent, many samples were used regardless. * Lymphoblastic Cell Lines: Some samples were used to create "immortalized" cell lines using reagents to allow continuous division for future genetic material production. * Storage: These cell lines are stored in Paris at the Center for the Study of Human Polymorphism (CEPH).

Genetic Variants and Ancestry Informative Markers

Single Nucleotide Polymorphisms (SNPs): HGDP samples were used to look at global variations in SNPs, which inform ancestry databases.
Key Genetic Examples: * Kit Ligand: A gene with two variants (alleles). One version is common in European and Asian backgrounds (red on charts), while the other is found primarily in African backgrounds (blue). * $SLC24A5$ : A gene associated with skin color. One variant is linked to lighter skin color (common in Europe and parts of Asia), while the other is found in other parts of the world. * $MC1R$ : A gene with multiple variants; one rare variant is associated with red hair.
Indigenous Response to Ancestry Testing: Many viewed this information as meaningless, asserting, "We already know who we are," and felt the data offered no benefit to their communities.

The Genographic Project

Launch: Started by National Geographic in 2005.
Approach: Attempted to work with indigenous groups by offering free ancestry tests before companies like 23andMe existed.
Outcome: Fizzled out and was discontinued in 2019 due to lack of interest and the rise of commercial Direct-to-Consumer (DTC) companies like Ancestry.com and African Ancestry.

Indigenous Perspectives on DNA and Sovereignty

Sacredness of DNA: Dr. Frank Duke-Apu, one of the first Native American geneticists, advocated at NIH and Congress, stating that for indigenous people, DNA is not just a molecule; it is a sacred part of the essence of a person.
Fragmented Souls: A belief exists that if DNA is stored in freezers around the world, the person is "fragmented." Upon death, individuals want all pieces of themselves returned to leave the world "whole."
Tribal Diversity in the US: There are over 474 federally recognized tribes. Many were forcibly relocated (e.g., to Oklahoma) and have complex histories (e.g., the Gold Rush in California pushing tribes out).
Bio-informatics Tension: A current scientific tension exists regarding whether it is right to mathematically "parse out" a Native American component from genomes with historic admixture (multiple continental backgrounds).

Case Study: The Havasupai Tribe and Research Misconduct

Setting: A tribe living at the bottom of the Grand Canyon in Arizona.
Access: Only reachable via hiking, donkey, or helicopter. Lack of fresh food led to high rates of Type 2 Diabetes.
Research Misuse: * Researchers from Arizona State University (ASU) were invited to study diabetes genetics. * Therese Markow (a Drosophila/fly geneticist, not a human diabetes geneticist) used a very broad informed consent for "behavioral medical problems." * Unauthorized Studies: Collected 400 blood samples. When diabetes studies were inconclusive, she used samples for research on schizophrenia, inbreeding, and migration patterns—all without specific tribe consent. * Impact on Cultural Identity: The inbreeding studies were viewed as shameful/embarrassing given the tribe’s clan marriage systems. The migration studies contradicted their origin story that they emerged from the Grand Canyon.
Legal Outcome: The tribe sued ASU and won the right to the return of their samples. Since the case settled out of court, it set no legal precedent.
Outcome for Institutional Policy: The NIH subsequently revised the "Common Rule," but ultimately endorsed "broad consent" despite the Havasupai case, favoring bookkeeping ease over tiered/specific consent.

Case Study: The Navajo Nation (Diné) and Genetic Research

Demographics: The Navajo Nation is a sovereign nation with its own judicial system and IRB (Human Research Review Board).
Genetic Bottleneck: The population once dwindled to 8,000–10,000 during the "Long Walk" (forced migration to eastern New Mexico) before expanding to over 400,000 in 150 years. This bottleneck increased the prevalence of rare Mendelian and complex diseases.
Severe Combined Immunodeficiency (SCID): * Navajo people have a high rate of a specific variant ( $Artemis$ ). * Since 2002, the Navajo Nation has had a moratorium (ban) on genetic research. * UCSF researchers had to identify the condition via the byproduct of the gene rather than DNA sequencing to avoid violating the ban. * Gene Therapy: In 2018, a boy from the Navajo Nation was successfully treated with experimental gene therapy to correct the $Artemis$ variant in his bone marrow cells.

Other Global Indigenous Moratoria/Experiences

Native Hawaiians (2003): * University of Hawaii proposed sequencing and patenting a Native Hawaiian genome. * Proposed genetic modification of the sacred taro (kalo) plant raised "biopiracy" concerns. * A 5-year moratorium was passed (2003–2008), which effectively stopped the proposals.
Māori People (New Zealand): * MAOA Gene: Misinterpreted by media as the "warrior gene" to explain domestic violence after a researcher presented data on only 46 Māori men. * The Māori have since become proactive, with many obtaining genetics degrees to drive their own research agendas.

Diversity and Representation in Genetic Research (GWAS)

Historical Imbalance: * In 2009, 96% of Genome-Wide Association Studies (GWAS) individuals were of European ancestry. * By 2016, European ancestry fell to 81%, but the shift was mostly due to research in Asian countries, not increased diversity elsewhere. * Indigenous representation was roughly $0.06\%$ in 2009 and shrunk to $0.05\%$ in 2016 relative to global growth.

Frameworks for Ethical Indigenous Genetic Research

SING Program: The Summer internship for INdigenous peoples in Genomics (SING) was created to train indigenous scholars in lab work, bioinformatics, and ethics.
Research Ethics Framework Components: * Sovereignty/Regulation: Acknowledging tribal governments and IRBs. * Community Engagement: Must touch all aspects of the research process. * Cultural Competency: Bi-directional learning between researchers and community. * Transparency: No hidden agendas or records-checking after hours. * Capacity Building: Bringing students into the project to run analysis. * Dissemination: Sharing information in community-accessible formats, not just PDFs. * Reciprocity: A bidirectional relationship between the researcher and the tribe.
FAIR vs. CARE Principles: * FAIR: Findable, Accessible, Interoperable, Reusable (focused on data openness). * CARE: Collective benefit, Authority to control, Responsibility, and Ethics (focused on indigenous data governance). * Alignment: Scientific projects (like the Human Genome Reference Consortium) are now trying to align both sets of principles.

Questions & Discussion

Q: Does the Common Rule allow for an option or process to avoid broad consent? * A: The Common Rule focuses on broad consent. While tiered consent (where participants check boxes for specific uses) exists, it is becoming rare because it is difficult for biobanks and the NIH to track. Today, participants often have to opt-in to broad use, and tiered options are usually limited to whether results should be returned to the individual.

Context and Learning Foundations

Geographic and Cultural Location: UCLA is situated on the ancestral homelands of the Tongva peoples, recognized as the traditional land caretakers of Tovaangar (the Los Angeles basin and Southern Channel Islands).
Date of Presentation: April $21$ , $2026$ .
Learning Goals: * Identify and understand historical factors leading to distrust in genetic research within Indigenous communities. * Analyze and contrast Indigenous bioethical frameworks with the standards set by the Belmont Report.
Learning Outcomes: * Explain motivations for sampling DNA from Indigenous communities using specific case studies, including the Human Genome Diversity Project, the Havasupai Tribe, and the Navajo Nation. * Articulate reasons for Indigenous moratoriums on genetics research and general hesitancy toward genomics. * Analyze the current representation of Indigenous people in genomics data and discuss the implications of under-representation. * Describe and define the components of the circular framework for ethical research collaborations, including adaptations of the Belmont Report principles. * Identify the FAIR and CARE principles and evaluate how they conflict or harmonize in the context of Indigenous sovereignty.
Key Terms and Concepts: * MAOA in the Māori community. * Forced sterilizations. * Data governance. * Cultural competency.
Warm-up Inquiry (iClicker): * Question: "Today’s readings demonstrate that the $3$ (or $4$ ) principles from the Belmont Report are adequate to prevent or ameliorate concerns about genetics research in Indigenous communities. (True/False and Explain)." * Context: Based on "Promise & Peril, $2008$ ."

Indigenous Perspectives on Genetic Identity

Group Belonging: Genetic research impact extends beyond individuals; DNA is inherently linked to families, community members, and closely related groups.
Concerns: Risks include social, psychological, and cultural impacts, specifically regarding discrimination and stigmatization.
Frank Dukepoo, Ph.D. (Hopi Geneticist, $1943\text{-}1999$ ): * "To us, any part of ourselves is sacred. Scientists say it's just DNA. For an Indian, it is not just DNA, it's part of a person, it is sacred, with deep religious significance. It is part of the essence of a person."
Conflicting Paradigms: Human Migration Patterns: * Genetic markers are used to trace human diversity and migration, such as the theory that American Indians migrated across the Bering Strait. * Indigenous objection: These scientific conclusions often conflict with cultural identity and traditional origin stories, leading to the halting of projects.

Historical Studies of Human Ancestry and Migration

Human Genome Diversity Project (HGDP) - $1990\text{s}$ : * Leadership: Led by geneticist Luca Cavalli-Sforza and anthropologist Allan Wilson. * Scale: Collected samples from $51$ populations worldwide with an $n = 1064$ individuals. * Ethical Issues: Many samples were provided by external researchers; informed consent status for these samples remains uncertain. * Storage: Lymphoblastoid cell lines were established and housed at the Center for the Study of Human Polymorphism (CEPH) in Paris. * Global Variation Examples Investigated: * $KITLG$ : Stem cell factor. * $SLC24A5$ : Skin color. * $MC1R$ : Red hair.
HGDP Representation Gaps: Identified populations included Africans ( $1\text{-}7$ , e.g., Bantu, San, Mbuti pygmy), Europeans ( $8\text{-}15$ , e.g., Basque, Sardinian), Western Asians ( $16\text{-}18$ ), Central and Southern Asians ( $19\text{-}27$ ), Eastern Asians ( $28\text{-}45$ ), Oceanians ( $46\text{-}47$ ), and Native Americans ( $48\text{-}52$ : Karitiana, Surui, Colombian, Maya, Pima). Significant "blank parts" exist on the global map of representation.
National Genographic Project (NGP) - $2005\text{-}2019$ : * Described as "eerily similar" to the HGDP. * Aimed to answer questions of human origins through work with Indigenous communities and the public.

Case Studies in Misuse and Sovereignty

Havasupai Tribe Case ( $2010$ ): * Origin: A study on diabetes approved by the Arizona State University (ASU) Institutional Review Board (IRB). * Consent: Tribal members ( $\sim 400$ ) signed forms for "behavioral / medical problems." * Misuse: Diabetes results were inconclusive. Samples were shared without additional consent for studies on schizophrenia, inbreeding, and migration. * Resolution: The tribe sued ASU researchers. Settlements included the return of DNA samples, though no official legal precedent was set due to technicalities (timing/lawsuit specifics). * Impact: Influenced revisions to the Common Rule to endorse "broad consent."
Navajo Nation and Genetic Research: * Considered an "ideal" study population due to isolation and the genetic bottleneck effect resulting from the "Long Walk" forced relocation. * Navajo Nation Human Research Review Board (NNHRRB): Reviews all research; the Nation is sovereign with its own judicial system. * Artemis-SCID Case: * Severe Combined Immunodeficiency Disease (SCID) is more common in the Navajo population. * Timeline: $2002$ : Genetic variant identified ( $ART\text{-}SCID$ ). $2009$ : Research on screening. $2012$ : Indian Health Service (IHS) clinical screening implementation. * Gene Therapy Breakthrough ( $2018$ ): Clinical trial for a Navajo boy using "corrected" genes in bone marrow stem cells. * Navajo Moratorium ( $2002$ ): Imposed due to concerns over stigmatization, biased interpretation, and lack of direct benefit. SCIDs was viewed as a "special case" as it involved a byproduct of a gene rather than human DNA directly.
Native Hawaiian Genome Sovereignty: * $2003$ : University of Hawaii researchers proposed sequencing and patenting a Native Hawaiian genome for economic and health benefits. * Associated Conflict: Proposals to genetically modify the taro plant (kalo), which is sacred. * $2008$ : A $5\text{-year}$ moratorium on genetic research was passed, modeled after the Navajo Nation.

Socio-Cultural Impacts: The MAOA "Warrior Gene" Controversy

Scientific Background: Low MAOA (Monoamine oxidase A) activity combined with child maltreatment is associated with antisocial behavior.
Māori Case (Aotearoa/New Zealand): * Researchers presented unpublished work claiming $56\%$ of Māori men carried the variant. * Sample size: High-level conclusions were drawn from only $17$ (or $46$ ) samples. * Nicknamed the "warrior gene," suggesting an advantage for Māori during Polynesian colonization. * Media extension: Incorrectly used the gene to explain domestic violence, reinforcing negative stereotypes.
Scientific Rebuttal (Merriman and Cameron): * Genomic data indicates MAOA is not associated with aggression. * Macaque Study ( $n = 45$ ): Found no main effect of genotype on aggression; only some evidence of Gene-Environment ( $G \times E$ ) interaction in motherless monkeys. * Māori data was deemed non-representative and non-generalizable.
Variants and Associations: * $MAOA\text{-}L$ (Low activity): Linked to weapon use in fights ( $4\times$ increase) and gang culture, yet $1/3$ of white people possess it. Also linked to depression, anxiety, ADHD, and gambling. * $MAOA\text{-}H$ (High activity): Linked to risky financial choices. * Taiwanese Study: Linked the gene to gout (uric acid build-up), unrelated to behavior.

Indigenous Representation Statistics

Popejoy and Fullerton ( $2016$ ) Analysis: * $2009$ : $1.7$ million samples ( $373$ studies). $96\%$ European ancestry. Native Peoples represented only $0.06\%$ ( $3\%$ of the non-European total). * $2016$ : $35$ million samples ( $2,511$ studies). $81\%$ European ancestry. Native Peoples dropped to $0.05\%$ .
Reasons for Low Representation: * Historical distrust (medical abuses, broken promises). * Perceived lack of individual/community benefit. * Conflict with personal/cultural norms. * Lack of control over secondary data use and biospecimen management after death.

Bioethical Frameworks and Data Governance

iClicker Comparison: Frameworks for Indigenous research and CARE principles differ from the Belmont Report because they emphasize community-level autonomy and benefit, whereas the Belmont principles are primarily individualistic.
Circular Framework for Ethical Research (Claw et al., $2018$ ): 1. Understand tribal sovereignty and research regulation. 2. Engage and collaborate with tribal community. 3. Build cultural competency. 4. Improve transparency of research practices. 5. Build tribal research capacity. 6. Disseminate findings in community-accessible formats.
Data Governance Principles: * FAIR: Findable, Accessible, Interoperable, Reusable (Wilkinson et al., $2016$ ). * CARE: Collective Benefit, Authority to Control, Responsibility, Ethics (Carroll et al., $2020$ ).
Comparison of FAIR vs. CARE: * FAIR focuses on data accessibility and management. * CARE focuses on Indigenous rights, interests, and authority over data.
Indigenous Expectations for Genomic Data: * Early consultation and exercising data governance. * Formalizing benefit-sharing and data access agreements. * Protecting personal and community identifiers. * Improving publication standards and preventing data misuse.

Professional and Community Initiatives

Summer Internship for INdigenous peoples in Genomics (SING): * Established in: USA ( $2010$ ), Aotearoa ( $2016$ ), Canada ( $2018$ ), Australia ( $2019$ ). * Participants: >150 Indigenous participants from >44 tribes, including students, professors, and industry scientists. * Curriculum: Wet-lab (mtDNA extraction), Bioinformatics (mtDNA analysis), ELSI (Ethics, Policy, Consent), Equity/Decolonizing science.
Indigenous Land Stewards Lab: Research supported by NSF Award (SMA/SBE $1911673$ ).
Policy Development: Collaboration involves radio forums, DNA extraction workshops, and incorporating interview/survey findings into tribal policy recommendations to lift moratoriums.

Conclusions

Tribes remain cautious but are fundamentally interested in genetic research.
Studies can be used to inform the development of data-driven policies that protect cultural norms.
Mutually beneficial outcomes arise from collaborations between researchers and interest holders.