Published On August 11, 2022
The Human Genome Project completed the first draft human reference genome in 2001. That started a new epoch in medicine, one that could better trace genetic differences and the roots of diseases. Yet the map established by the Human Genome Project still has its limitations, not least of which is that some 70% of the genome sequence came from a single man.
The Human Pangenome Reference Consortium, born in 2019, aims for an updated reference genome—one that is at once more complete and more representative of human diversity. Ting Wang, a geneticist at Washington University in St. Louis, leads the center coordinating the effort. When the project finishes up five years from now, he hopes the new pangenome materials will give a boost to diagnostics and therapies, as well as a more complete picture of who awe are.
Q: Your plan is to sequence 350 people from diverse backgrounds. How did you choose that number?
A: It was a calculation that required us to balance the limiting factor of funding with how to maximize the number of genetic variants represented. This is a rough estimate, but with 350 diverse genomes, we can cover the majority of genetic variants having at least a 1% allele frequency in the global population.
Q: Where will these samples come from?
A: During the first two years of the project, we took advantage of existing samples from the 1000 Genomes Project. This is an international effort that launched in 2008 and that has samples from individuals from diverse genomic and biogeographical backgrounds. Currently, we are recruiting participants through the Mount Sinai
BioMe Biobank along with a cohort of African American individuals who were recruited by Washington University.
Q: Past projects ran into opposition from Indigenous groups. They felt autonomy over their own genetic data wasn’t respected. What’s different this time?
A: When the project launched, we formed a team of scholars devoted to the ethical, legal and social implications of our efforts to ensure that we do not repeat past mistakes. This team is made up of leaders at the intersections of genomics, biomedical ethics, law, social science and community engagement. The team is embedded in all aspects of the project, including very technical aspects, to ensure that the scientists working on this project understand and appreciate what is at stake. We are actively engaging with Indigenous geneticists, leaders and community members to collaboratively develop a truly inclusive pangenome.
Q: What are the biggest technical challenges the project faces?
A: The current human reference genome is roughly 90% complete. The remaining 10% is missing. The missing parts are made of highly repetitive sequences, which are very important to the genome but very difficult to read with traditional short-read sequencing. So the T2T, or Telomere-to-Telomere, consortium, which is a partner in the project, is actually using long-read sequencing technology to try to decode the missing parts.
Another challenge, which is very dear to my heart, is to functionally understand the genome. We want to annotate the genome and understand how genomic variation leads to phenotypic variation. We want to understand what forces shaped our species evolution and what genomic signatures these forces made. We want to understand how genetic variants affect how cells behave. The current reference genome is a composite, so there is no single naturally living cell on this planet with the reference genome. Functionally annotating the pangenome presents many unique technical challenges, but the opportunity to address these challenges is exciting.
Q: So this project will wrap up in five years. What then?
A: Ultimately, we want this project to continue long after we have collected our 350 genomes and the funding from the NIH has run out. We are working to establish a global alliance of genomics partners. The United States can be a founding member and pave the way for developing the technology and tools, but we believe that the effort to create a resource to better serve humanity should be a global one. It should continue for as long as there are discoveries to be made.
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