“The new pangenome reference shows many possible routes for a sequence to take, represented by different colors: Yellow is a duplication variant; pink is an inversion variant; green and blue represent a deletion variant, and light blue is an insertion variant”

Scientists Unveil a More Diverse Human Genome
by Elie Dolgin  /  May 10, 2023

“More than 20 years after scientists first released a draft sequence of the human genome, the book of life has been given a long-overdue rewrite. A more accurate and inclusive edition of our genetic code was published on Wednesday, marking a major step toward a deeper understanding of human biology and personalized medicine for people from a wide range of racial and ethnic backgrounds. Unlike the previous reference — which was largely based on the DNA of one mixed-race man from Buffalo, with inputs from a few dozen other individuals, mostly of European descent — the new “pangenome” incorporates near-complete genetic sequences from 47 men and women of diverse origins, including African Americans, Caribbean Islanders, East Asians, West Africans and South Americans. The revamped genome map represents a crucial tool for scientists and clinicians hoping to identify genetic variations associated with disease.

“The new pangenome reference resembles a corn maze … that allows scientists to explore a broader range of the genetic diversity found in people the world over”

It also promises to deliver treatments that can benefit all people, regardless of their race, ethnicity or ancestry, researchers said. “It’s been long needed — and they’ve done a very good job,” said Ewan Birney, a geneticist and deputy director general of the European Molecular Biology Laboratory, who was not involved in the effort. “This will improve our fine-grained understanding of variation, and then that research will open new opportunities toward clinical applications.” Powered by the latest in DNA sequencing technology, the pangenome collates all 47 unique genomes into a single resource, providing the most detailed picture yet of the code that powers our cells.

“47 accurate and near-complete diverse diploid human genome assemblies”

Gaps in the earlier reference are now filled, with nearly 120 million previously missing DNA letters added to the three-billion-letter-long code. Gone is the idea of a totemic strand of DNA that extends six feet when uncoiled and stretched out in a straight line. Now, the rebooted reference resembles a corn maze, with alternative paths and side trails that allow scientists to explore a broader range of the genetic diversity found in people the world over. Dr. Eric Green, director of the National Human Genome Research Institute, the government agency that funded the work, likens the pangenome to a new kind of bodywork manual for automotive repair shops. Whereas before, every mechanic only had the design specs for one kind of car, now there is a master plan that covers different makes and models. “We’ve gone from having one really nice blueprint of the Chevy to now having blueprints of 47 representative cars from each of 47 different manufacturers,” he said.

Knowing what to do with this Kelley Blue Book of genomics will involve a steep learning curve. New analytical tools are needed. Coordinate systems must be redefined. Widespread adoption will take time. “Making this easy to be used by the community is work to be done,” said Heidi Rehm, chief genomics officer at Massachusetts General Hospital in Boston, who was not involved in the project. But in due course, experts said, the pangenome will revolutionize the field of genomic medicine. “We’re going to have the benefit of actually understanding ourselves as a species much, much better,” said Evan Eichler, a genome scientist at the University of Washington. Dr. Eichler was among more than 100 scientists and bioethicists who described the new pangenome reference in the journal Nature.

The architects of the project are continuing to add more population groups, with the goal of including at least 350 high-quality genomes that encompass the bulk of global human diversity. “We want to represent all the branches of the human tree,” said Ira Hall, a geneticist who leads the Yale Center for Genomic Health. Some of the new genomes will come from New Yorkers who previously participated in a research program at the Mount Sinai Health System. If their preliminary DNA data seems to reflect certain underrepresented genetic backgrounds, those individuals will be invited to participate in the pangenome project. Some gaps might never get plugged in the publicly available reference, though — by design.

Previous attempts to capture human genetic diversity often extracted sequence data from marginalized populations without regard for their needs and preferences. Informed by those ethical missteps, pangenome coordinators are now collaborating with Indigenous groups to develop formal policies around data ownership. “We are still grappling with the issue of native and tribal sovereignty,” said Barbara Koenig, a bioethicist at the University of California, San Francisco, who was involved in the project. In Australia, researchers are incorporating DNA sequences from various Aboriginal peoples into a similar depository that will be combined with the open-source pangenome, but then kept behind a firewall.

According to Hardip Patel of Australia’s National Centre for Indigenous Genomics in Canberra, the scientists next plan to consult with community leaders about if or how to make the data accessible through request. Some Indigenous advocates want to see the pangenome project go further. Keolu Fox, a genomics scientist at the University of California, San Diego, who is Native Hawaiian has suggested training the next generation of Indigenous scientists to have greater agency over the genomic data. “It’s finally time that we decentralize power and control and redistribute that among the communities themselves,” Dr. Fox said.”

“Paleogenomic approaches to study the demographic history of pre-Hispanic Mexico involve analysis of ancient human DNA collected from archaeological sites like the ruins in Toluquilla”

Paleogenomic study of the Mexican past
by Bastien Llamas, Xavier Roca-Rada  /  11 May 2023

“The discovery that DNA survives in archaeological remains revolutionized archaeology, anthropology, and evolutionary biology, leading to the establishment of paleogenomics as a bona fide field of research (1). In the context of the Americas, paleogenomic researchers have used ancestral genomic information to reconstruct human history with exquisite detail. However, ethical concerns surrounding practices perceived as extractive and colonizing have sometimes overshadowed this endeavor (2). On page 598 of this issue, Villa-Islas et al. (3) set a standard for how paleogenomics can be conducted in an ethical and sustainable manner. They analyzed ancient DNA retrieved from 27 ancestral humans from eight archaeological sites in Mexico, providing insights into the demographic history of Indigenous populations in Central and North Mexico.

“Map of archeological sites and modern populations”

Although Mexico has a rich cultural heritage, paleogenomic studies have primarily considered it as a bridge between North and South America, acting as an obligate transit for early southward human migrations (4-6). Limited paleogenomic studies applying high-throughput sequencing have addressed Mexican-specific demographic questions, finding that ancient northwest Mexico shared genetic affinities with neighboring populations further north, and that Central Mexican cities between 900 and 1500 CE were highly multi-ethnic (7,8). The study of Villa-Islas et al. not only fills a gap in terms of paleogenomic resources in the Americas, but also demonstrates how combining multidisciplinary evidence, including archaeology, anthropology, paleoclimatology, and paleogenomics, can advance our understanding of past human demography. The archaeological record had hinted at an expansion of Aridoamerican cultures (in northern Mexico, inhabited by hunter-gatherers) into Mesoamerican territory (in central and southern Mexico, home to some of the largest pre-Hispanic agriculture-based civilizations in the Americas) around 1100 CE, coinciding with a period of severe droughts. Genomic information can capture the genetic history and diversity of its population, providing insights into population-size changes, migrations, and interactions with other groups.

“Population continuity and ghost genetic ancestries in pre-Hispanic Mexico”

Leveraging the information contained in the ancient genomes, Villa-Islas et al. found that droughts likely triggered large-scale migrations, leading to population replacement in the shifting border region of Aridoamerica and Mesoamerica. Interestingly, some Mesoamerican people stayed behind in the Sierra Gorda area, prompting questions about how these ancient cultures adapted to climate change. The results also echo the coincidence of climatic and demographic events in pre-Hispanic Central Andes (9) and call for in-depth paleoecological modeling to test causality. One major challenge in paleogenomic studies is the scarcity of temporal and geographical data points that would enable a detailed reconstruction of the past. For instance, the archaeological record may lack entire regions or time periods, or cultural practices—such as cremation, and the use of cinnabar (mercury mineral ore used for red pigments)—or adverse environmental conditions may hinder DNA preservation. Moreover, in some cases, there may be no data available from relevant present-day populations for comparison. These issues are magnified in regions of the world such as Mexico, where the cultural heritage is incredibly diverse but conditions for ancient DNA preservation are suboptimal, the demographic history is potentially highly complex, and the recent colonial past has substantially altered the genetic makeup of some regions. Consequently, paleogenomicists use modeling to compensate for missing data and may resort to including unsampled “ghost” populations in their statistical inferences.

“Ghost ancestries in pre-Hispanic individuals from Mexico”

In this regard, Villa-Islas et al. not only confirmed the existence of a previously reported ghost population ancestral to present-day Central Mexicans (e.g., Mixe) (10), but they also uncovered a second ghost population whose ancestry was last detected in an individual from Cañada de la Virgen, a Mesoamerican site occupied between 540 and 1050 CE. Recently, scholars from the Global South argued that sustainable paleogenomic research should be based on principles of “knowledge sharing, capacity building, mutual respect, and equitable participation” (11). The study of Villa-Islas et al. is a remarkable example of this approach because it targets a Global South region and is led and conducted by (predominantly) local researchers. This is a considerable departure from collaboration between local scholars and laboratories from the Global North, which requires the export of samples and often leads to the relocation of local students and early-career researchers to the Global North for training. Although such collaborations can promote a two-way transfer of knowledge and expertise, they may not foster local development of paleogenomic research owing to economic constraints. This perpetuates global power and wealth imbalances and invariably results in a loss of both control of the traditional narrative and sovereignty over cultural material and data (12). Therefore, developing capacity and capability in paleogenomic research in the countries where studies are conducted is crucial to empower researchers and participating communities. This approach promotes engagement with and involvement of local populations.

“Genetic structure of Indigenous and pre-Hispanic individuals”

The study by Villa-Islas et al. is an excellent example of high-quality and ethical paleogenomic research. Indeed, assigning a contemporary population as the sole direct descendant of ancestral remains is highly complex in Mexico owing to the sociopolitical and historical context, including the institutionalized imposition of the “mestizaje” rhetoric (which supports that all Mexicans have mixed European and Indigenous ancestry) that undermines the voice of Indigenous peoples, especially in genomic research (13). In this context, only Mexican researchers who are sensitive to the social reality of their country can implement best practices when engaging with the communities closest to the archaeological sites, especially given the challenges involved in consulting with Indigenous populations regarding the destructive analysis of ancestral humans in Mexico.”

References and Notes
1 A. Curry, Science 378, 12 (2022). DOI PubMed
2 A. D. Cortez, D. A. Bolnick, G. Nicholas, J. Bardill, C. Colwell, J. Soc. Archaeol. 21, 157 (2021). DOI
3 V. Villa-Islas et al., Science 380, eadd6142 (2023). DOI
4 C. L. Scheib et al., Science 360, 1024 (2018). DOI PubMed
5 M. Raghavan et al., Science 349, aab3884 (2015). DOI PubMed
6 J. C. Chatters et al., Science 344, 750 (2014). DOI PubMed
7 A. Y. Morales-Arce et al., Archaeol. Anthropol. Sci. 11, 3459 (2019). DOI
8 A. Y. Morales-Arce et al., Sci. Rep. 7, 18100 (2017). DOI PubMed
9 L. Fehren-Schmitz et al., Proc. Natl. Acad. Sci. U.S.A. 111, 9443 (2014). DOI PubMed
10 J. V. Moreno-Mayar et al., Science 362, eaav2621 (2018). PubMed
11 M. C. Ávila-Arcos et al., Front. Genet. (2022). DOI
12 B. Yáñez et al., Am. J. Biol. Anthropol. 180, 417 (2022). DOI
13 P. Wade, C. López Beltrán, E. Restrepo, R. Ventura Santos, Mestizo Genomics: Race Mixture, Nation, and Science in Latin America (Duke Univ. Press, 2014). PDF



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