The first complete sequence of a human genome

T2T Consortium publish the first complete sequence of a human genome, along with epigenetic patterns.

The human genome project was launched in 1990, and more than 30 years later, it is still not complete. Today, a team of researchers that make up the T2T Consortium released a paper describing the first complete human genome, addressing the gaps in a haploid human genome, and using nanopore sequencing to address these gaps.

The current human reference genome contains 151 Mbp of unknown sequence throughout the genome, primarily highly-repetitive regions that have been impossible to resolve with traditional sequencing technology. In recent years, researchers have been using nanopore technology to overcome some of these challenges, uncovering new information about the genetics of human health and disease.

This week, a significant milestone has been reached in the race for the complete assembly of a human genome. A team of scientists have published a new reference genome (T2T-CHM13), which includes five entirely new chromosome arms and is the single largest addition of new content to the human genome in the past 20 years.

The authors comment: “The resulting T2T-CHM13 reference assembly removes a 20-year-old barrier that has hidden 8% of the genome from sequence-based analysis, including all centromeric regions and the entire short arms of five human chromosomes.”

This 8% of the genome has not been overlooked due to its lack of importance, but rather due to technological limitations. High accuracy, and ultra-long read sequencing has finally removed this technological barrier, enabling comprehensive studies of genomic variation across the entire human genome. Nanopore technology is the only sequencing technology able to span some of the most complex regions of the human genome, which to date have been unresolved. “The complete, telomere-to-telomere assembly of a human genome marks a new era of genomics where no region of the genome is beyond reach.”

In addition to spanning these complex regions, nanopore technology also provides information about base modifications, which are commonly being linked to disease — for example, methylation changes have previously been linked to normal aging and neurogenerative diseases, something an NIH team are exploring using nanopore technology. Nanopore sequencing is the only approach to enable direct, conversion-free detection of methylation changes across the whole genome, and the generation of long reads makes phasing of modifications simpler.

The T2T Consortium also published their work profiling the epigenetic landscape of the entire genome as part of this project and uncovered novel methylation patterns, including a hypomethylated and highly dense chromatin region within the centromere.

The team won’t be stopping here, stating that: “complete assembly of the CHM13 genome and our companion analyses have given only a small glimpse of the extensive structural variation that lies within the complete genome.”