An international team of scientists has achieved a groundbreaking milestone by decoding some of the most stubborn and overlooked regions of the human genome. Utilizing complete sequences from 65 individuals across diverse ancestries, the study, published today in Nature and co-led by The Jackson Laboratory (JAX), unveils hidden DNA variations that influence everything from digestion and immune response to muscle control. This could potentially explain why certain diseases impact some populations more severely than others.
The announcement comes as a significant expansion on previous efforts in genomics. In 2022, researchers completed the first-ever full sequence of a single human genome, addressing major gaps left by the original Human Genome Project. Following this, a draft pangenome constructed from 47 individuals was released in 2023, marking a critical step toward representing global genetic diversity. The new study closes 92% of the remaining data gaps, mapping genomic variation across ancestries with unprecedented breadth and resolution.
Unveiling Hidden DNA Variations
Christine Beck, a geneticist at JAX and the University of Connecticut Health Center, emphasized the importance of this work. “For too long, our genetic references have excluded much of the world’s population,” she stated. “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. It propels the field toward a more complete and inclusive vision of human biology, paving the way for advances in precision medicine that benefit all populations—not just those historically overrepresented in research.
The Complexity of Structural Variants
Scientists decode DNA by reading the order of its building blocks, called nucleotides, which function like letters in an instruction manual directing all body functions. Current technologies can read most of that text but often miss or misread long, complex, and highly repetitive segments. These segments, known as structural variants, influence how genes work and can increase disease risk, protect the body, or have no apparent effect.
Structural variants mainly arise during DNA replication and repair, especially in sections with extremely long and repetitive sequences prone to errors. These include deletions, duplications, insertions, inversions, and translocations of genome segments. More complex variations, where large DNA chunks rearrange and fuse unpredictably, were a primary focus of the new study.
“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.
Turning on the Light
Until now, geneticists could only chart the “easiest” structural variations, leaving the most tangled, repetitive regions and their connection to rare genetic diseases in the dark. The new research has broken that logjam, untangling 1,852 previously intractable complex structural variants and sharing an open-source playbook for other scientists.
This achievement has resolved the Y chromosome from 30 male genomes, shedding light on a chromosome particularly challenging to decode due to its highly repetitive sequences. Additionally, the team fully resolved a region associated with the immune system, the Major Histocompatibility Complex, linked to cancer, autoimmune syndromes, and over 100 other diseases.
The study also provides full sequences for the SMN1 and SMN2 regions, targets of life-saving therapies for spinal muscular atrophy, and the NBPF8 gene involved in developmental and neurogenetic diseases. Moreover, the amylase gene cluster, crucial for digesting starchy foods, was fully sequenced.
Mapping the Unseen
The research mapped transposable DNA elements in unprecedented detail, cataloguing 12,919 mobile element insertions across the 65 individuals. These elements, which can “jump” around the genome and alter gene function, accounted for almost 10% of all structural variants. Some were even found in centromeres—regions essential for cell division and difficult to sequence due to their repetitive DNA.
“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.
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 was driven by JAX software that accurately catalogues variants between human sequences, now identifying structural variation within the most complex regions of human DNA.
Implications for Future Research
The study’s findings represent a significant leap forward in genomics, offering tools to scientists studying autism, rare diseases, and cancers to see what has 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, and Yale University, under the Human Genome Structural Variation Consortium.
As genomic science continues to evolve, the implications of this research are profound. It not only enhances our understanding of human biology but also ensures that future discoveries in precision medicine are more inclusive and representative of global diversity. The path forward is now clearer, promising a future where genetic insights can be applied universally to improve health outcomes worldwide.
