A new study has produced the most complete and ancestrally diverse reference of the human genome to date, capturing elusive structural variants that standard approaches have long failed to characterize. The work, published in Nature, analyzed complete genomes from 65 individuals representing global populations and closed 92% of previously unresolved regions.
Led by researchers from The Jackson Laboratory and collaborators across 20 institutions, the study advances efforts to build a representative human pangenome. It includes fully resolved sequences for regions that have resisted decoding due to their repetitive or complex structure, such as the SMN1/SMN2 locus, NBPF8, the amylase gene cluster, and all 1,246 centromeres.
“Now, we’ve captured probably 95% or more of all these structural variants in each genome sequenced and analyzed,” said Charles Lee, a geneticist at The Jackson Laboratory. Having done this for not five, not 10, not 20, but 65 genomes is an incredible feat.”
The researchers also provided complete Y chromosome sequences from 30 males and fully mapped the Major Histocompatibility Complex, an area linked to cancer and autoimmune conditions. They cataloged 12,919 transposable element insertions, accounting for nearly 10% of all identified structural variants. Some of these mobile elements were even detected in centromeres.
New software developed at JAX enabled accurate annotation of complex structural variation within these regions. “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, who built the variant-finding tool. “Now we can say, ‘Here’s a mutation, it starts here, ends there, and this is what it looks like.’”
The team’s open-source methods are intended to support broad adoption of long-read sequencing in diverse populations. “This work captures essential variation that helps explain why disease risk isn’t the same for everyone,” said co-lead Christine Beck. “Our genomes are not static, and neither is our understanding of them.”
Publication Details
Logsdon, G.A., Ebert, P., Audano, P.A. et al. Complex genetic variation in nearly complete human genomes. Nature (2025). https://doi.org/10.1038/s41586-025-09140-6
Led by researchers from The Jackson Laboratory and collaborators across 20 institutions, the study advances efforts to build a representative human pangenome. It includes fully resolved sequences for regions that have resisted decoding due to their repetitive or complex structure, such as the SMN1/SMN2 locus, NBPF8, the amylase gene cluster, and all 1,246 centromeres.
“Now, we’ve captured probably 95% or more of all these structural variants in each genome sequenced and analyzed,” said Charles Lee, a geneticist at The Jackson Laboratory. Having done this for not five, not 10, not 20, but 65 genomes is an incredible feat.”
The researchers also provided complete Y chromosome sequences from 30 males and fully mapped the Major Histocompatibility Complex, an area linked to cancer and autoimmune conditions. They cataloged 12,919 transposable element insertions, accounting for nearly 10% of all identified structural variants. Some of these mobile elements were even detected in centromeres.
New software developed at JAX enabled accurate annotation of complex structural variation within these regions. “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, who built the variant-finding tool. “Now we can say, ‘Here’s a mutation, it starts here, ends there, and this is what it looks like.’”
The team’s open-source methods are intended to support broad adoption of long-read sequencing in diverse populations. “This work captures essential variation that helps explain why disease risk isn’t the same for everyone,” said co-lead Christine Beck. “Our genomes are not static, and neither is our understanding of them.”
Publication Details
Logsdon, G.A., Ebert, P., Audano, P.A. et al. Complex genetic variation in nearly complete human genomes. Nature (2025). https://doi.org/10.1038/s41586-025-09140-6
Comment