An international team of scientists has decoded some of the most stubborn, overlooked regions of the human genome using complete sequences from 65 individuals across diverse ancestries. The study, published online today in Nature and co-led by The Jackson Laboratory (JAX), reveals how hidden DNA variations that influence everything from digestion and immune response to muscle control—and could explain why certain diseases strike some populations harder than others.
This milestone builds on two foundational studies that reshaped the field of genomics. In 2022, researchers achieved the first-ever complete sequence of a single human genome, filling in major gaps left by the original Human Genome Project. In 2023, scientists released a draft pangenome constructed from 47 individuals—a critical step toward representing global genetic diversity. The new study significantly expands on both efforts, closing 92% of the remaining data gaps and mapping genomic variation across ancestries with a breadth and resolution never before achieved.
"For too long, our genetic references have excluded much of the world's population," said Christine Beck, a geneticist at JAX and the University of Connecticut Health Center who co-led the work. "This work captures essential variation that helps explain why disease risk isn't the same for everyone. Our genomes are not static, and neither is our understanding of them."
By decoding DNA segments once thought too complex or variable to analyze, the study sets a new gold standard for genome sequencing and propels the field toward a more complete and inclusive vision of human biology. The findings clear a critical path for advancing precision medicine and ensuring that future discoveries benefit all populations—not just those historically overrepresented in research.
Hiding within our DNA
Scientists decode DNA by reading the order of its building blocks, called nucleotides, which act like letters in an instruction manual to direct all body functions. Current technologies can read most of that text but often miss or misread long, complex, and highly repetitive segments that span millions of letters that influence how genes work. These long stretches are called structural variants, and they can increase disease risk, protect the body, or offer no apparent effect at all.
Structural variants mainly arise when cells replicate and repair DNA, especially in sections with extremely long and repetitive sequences prone to errors. Unlike many other types of genetic variation, there are different types of structural variants, and they can span large regions of DNA. These structural variants include deletions, duplications, insertions, inversions, and translocations of genome segments. More complex variations, where large DNA chunks rearrange and fuse in unpredictable ways, were a primary focus of the new study.
Complex rearrangements of genomes can also drive evolutionary changes that shape our biology, like how the human brain became larger and more sophisticated over time. But mapping these changes contiguously is remarkably difficult because they scramble the genome in ways that defy decoding — like trying to make sense of pages from a book that's been torn up, rearranged, and reassembled without seeing the original version.
"It's only been in the last three years that finally technology got to the point where we can sequence complete genomes," said Charles Lee, the Robert Alvine Family Endowed Chair and a JAX geneticist who in 2004 discovered the widespread presence of structural DNA variation in people's genomes. "Now, we've captured probably 95% or more of all these structural variants in each genome sequenced and analyzed. Having done this for not five, not 10, not 20—but 65 genomes—is an incredible feat."
Turning on the light
Until now, geneticists could only chart the "easiest" of structural variations in our DNA, leaving in the dark not only the most tangled, repetitive regions, but also their connection to rare genetic diseases. The new research has now broken that logjam, untangling 1,852 previously intractable complex structural variants and sharing an open-source playbook that any scientists sequencing genomes to this level can use in their laboratories.
Resolving these previously "hidden" regions across a wide range of ancestries turns areas that were once genetic blind spots into valuable sources of insight.
The work completely resolved the Y chromosome from 30 male genomes, shedding light on a chromosome that has been particularly challenging to resolve due to its highly repetitive sequences, and which JAX scientists fully sequenced from telomere to telomere just 18 months ago. In addition, the team fully resolved an intricate region of human genomes associated with the immune system called the Major Histocompatibility Complex, which is linked to cancer, autoimmune syndromes, and more than 100 other diseases.
The work also provides full sequences for the notoriously repetitive SMN1 and SMN2 region, the target of life-saving antisense therapies for spinal muscular atrophy, as well as a gene called NBPF8 involved in developmental and neurogenetic disease. The amylase gene cluster, which helps humans digest starchy foods according to a recent JAX study , was also fully sequenced.
The study additionally mapped transposable DNA elements in unprecedented detail, cataloguing 12,919 of these mobile element insertions across the 65 individuals. These elements, which can "jump" around the genome and change how genes work, accounted for almost 10% of all structural variants. In 1983, Barbara McClintock, a Hartford, Conn. native, received the Nobel Prize in Physiology and Medicine for her discovery of similar "jumping genes", also known as transposable elements, in corn.
Some of these jumping genes in this study were even found in centromeres—regions of the chromosome that are essential for cell division and extremely difficult to sequence due to their repetitive DNA. Overall, the work accurately resolved and validated 1,246 human centromeres, shedding light on the extreme variability at their cores.
"With our health, anything that deals with susceptibility to diseases is a combination of what genes we have and the environment we're interacting with," Lee said. "If you don't have your complete genetic information, how are you going to get a complete picture of your health and your susceptibility to disease?"
The work was made possible by genome sequencing techniques that combine highly accurate medium-length DNA reads with longer, lower-accuracy ones. The interpretation of variation in the genomes was driven by software from JAX that accurately catalogues variants between two human sequences. This software has now pushed forward to identifying structural variation within the most complex regions of human DNA.
"Just because we have a long, complete sequence doesn't mean we actually know what's in it. It's like having a really good book, but there are still some pages we can't read, and these tools are finally allowing us to interpret those missing parts of the genome," said Peter Audano, a JAX computational biologist in the Beck lab who developed and implemented the variant-finding software. "Now we can say, 'Here's a mutation, it starts here, ends there, and this is what it looks like.' That's a huge step forward. Now, scientists studying autism, rare diseases, and cancers will have the tools to see everything we've been missing for decades."
This work was conducted in collaboration with more than 20 institutions, including the University of Washington, the European Molecular Biology Laboratory, Heinrich Heine University, University of Pennsylvania, Clemson University, Yale University and the University of Colorado under the auspices of the Human Genome Structural Variation Consortium .
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