Human genome benchmark maps both sets of chromosomes to fill gaps in genetic data

Scientists have obtained the most complete and accurate sequence of a human diploid reference genome to date, paving the way for advancements in personalised medicine.

Human somatic cells are typically diploid, meaning they carry two slightly different copies of each chromosome – one from each parent. Previous attempts to sequence the human genome have relied on haploid cell lines with only a single copy of each chromosome. Now, US researchers have published the most complete sequenced genome to date, mapping 99.4 percent of a diploid reference genome. This study builds on the work of the Telomere to Telomere (T2T) consortium, which had previously finished mapping the full sequence of a human haploid genome.

'The first T2T project was like assembling a huge jigsaw puzzle. This time, we had pieces from two similar puzzles, one from mom and one from dad, all thrown into the same box,' said Professor Adam Phillippy, researcher in computer science, biomedical engineering and genetic medicine at Johns Hopkins University and senior author of the study published in Cell. 'So, it's a harder computational challenge, but we've figured it out.'

The final draft of the Human Genome Project, published in 2003, mapped around 92 percent of the haploid human genome (see BioNews 204). In 2022, the T2T consortium sequenced the remaining eight percent, working on a widely used reference sample from a living male donor known as the HG002 genome (see BioNews 1098 and 1140). The new study expands on these results, this time sequencing a full, diploid version of the HG002 genome, including the sex chromosomes.

The team used high-coverage and ultra-long-range sequencing approaches, allowing them to reconstruct repetitive and highly variable portions of the genome that other methods struggle to resolve. Their work adds an extra 900 million DNA bases that were missing from existing reference genomes, revealing 15 percent more of the genome that was previously inaccessible, including regions known to affect disease risk.

Since the publication of the Human Genome Project, the cost of sequencing the human genome has fallen dramatically. The sequencing and analysis pipelines the team developed for their work would now make it easier to reconstruct a person's own diploid genome. This 'genomic benchmarking' could prove useful for genetic testing, as current methods typically rely on comparing short DNA sequences from a patient against a haploid reference genome.

'This represents a paradigm shift from trying to find the differences between your genome and a reference to actually reconstructing your complete, unique genome,' said Professor Phillippy. 'This ensures that no regions of the genome are missed, and that the quality of the analysis does not depend on how similar you are to the reference genome.'

Such approaches could open new diagnostic possibilities for people with rare genetic diseases, particularly when these conditions are caused by variants in highly complex, repetitive regions of the genome. 'We hope that these complete genomes will close the gap in rare disease diagnostics and give families the answers they need,' Professor Phillippy said.