Beyond Everyman - mapping the human pangenome
From a single reference genome to appreciating the genetic diversity of humankind.
Cast your mind back to the year 2000, and the grand announcement from a US-led global research consortium that they had successfully mapped the human genome. This was Big Science at its most theatrical, with then-president Bill Clinton basking in the limelight of a massive breakthrough in human biology.
Being the first mapping of an entire human genetic code, the reference genome was a big deal, and since then has formed the backbone of human genomics. As a technical accomplishment it was huge, given the tools available and costs involved. But the development was limited to the genome of a single person of mixed European and African heritage. Think of it as biological Everyman, and thus a poor representation of the genetic diversity of humankind.
Step forward 20+ years, and the technology for mapping genes has progressed from the short-read sequencing which breaks DNA into millions of small fragments that are copied and sequenced to build a full picture of the genome. Today’s long-read sequencing allows for gene segments to be assembled together with less ambiguity, and it can be used to directly sequence single molecules of DNA in real time, without the need for amplification through copying.
In a series of papers1234 published today in Nature, the Human Pangenome Reference Consortium - another US-led effort - presents the first draft of a human pangenome reference developed from a cohort of 47 ancestrally diverse individuals. This publication blitz is the interim stage of a project that aims to characterise the genetic structural diversity of 350 human beings.
At a press briefing held yesterday, the research leaders presented their results and took questions from journalists keen to understand the social as well as scientific significance of this much-trumpeted development. So what does the mapping of the human pangenome mean in practice?
Genetic diversity is what makes organisms unique. Variations in genes, defects and mutations give rise to physical differences, strengths, weaknesses, disease and organ malfunction. Understanding genetic diversity is critical in appreciating the richness of the human species and overcoming its myriad points of biological failure.
For example, lipoprotein(a) levels are associated with coronary heart disease, and variations in its gene correlate with the risk of arterial problems. Drug discovery and effectiveness are tied in with genetic variation, as are immune response and disorders such as schizophrenia. Mapping the human pangenome should promote the development of precision medicine.
Ethical concerns around the use of the human pangenome came up in the media briefing, and the researchers made some effort to address the matter, focusing on personal sovereignty, genetic sample security, subject recruitment, and the potential impact of genetic surveillance. There is a danger that science could outpace the development of regulatory frameworks, as appears to be happening now with machine learning and large language models, aka artificial intelligence.
When it comes to the science, the researchers are struck by the remarkable and greater than expected patterns of genetic variations in human beings.
Liao et al., “A draft human pangenome reference”, Nature (2023); doi:10.1038/s41586-023-05896-x.
Vollger et al., “Increased mutation and gene conversion within human segmental duplications”, Nature (2023); doi:10.1038/s41586-023-05895-y.
Guarracino et al., “Recombination between heterologous human acrocentric chromosomes”, Nature (2023); doi:10.1038/s41586-023-05976-y.
Hickey et al., “Pangenome graph construction from genome alignments with Minigraph-Cactus”, Nature Biotechnology (2023); doi:10.1038/s41587-023-01793-w.