Complete Reference Genomes Set New Genomics Milestones

The genomic revolution that began at the end of the 20^th century has given researchers increasingly detailed insights into the organization of DNA and the role of genes in diseases. However, due to the complexity of the genome, many initial reference genomes for different organisms were incomplete.

Now, with advances in sequencing and analysis technologies, researchers are expanding the potential for genomic studies. In 12 papers published in Cell and Cell Genome, researchers across institutions published multiple completed reference genomes, reaching a new milestone in genomic research that could improve personalized medicine, disease modeling, and evolutionary research.

A Complete, Diploid Human Genome Reference Lends Greater Accuracy

In 2022, the Telomere-to-Telomere (T2T) consortium published the most complete human genome to date from a haploid human cell line with the help of long-read sequencing technology.¹ While this resolved many of the remaining gaps in the human DNA reference genome, this sequence and others have continued to rely on incomplete references as benchmarks, complicating researchers’ ability to identify genomic variants.^2,3

To overcome these limitations, T2T consortium researchers developed a new approach to assemble genome sequences that does not rely upon aligning sample reads to potentially incomplete references. Instead, in one study published in Cell, researchers generated a diploid human genome reference with the highest coverage to date by combining the long-read sequences of the human genome completed by previous consortium studies.⁴ The authors propose using such diploid genome sequences as a sample reference, called “genome benchmarking,” as opposed to aligning sample sequences and variants to reference genomes.

“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 Adam Phillippy, a bioinformatician at Johns Hopkins University and study coauthor in a press release. “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.”

The findings expand researchers’ ability to sequence difficult genome regions, such as those with highly repetitive sequences, more easily. In a companion study published in Cell Genomics, researchers used the diploid human genome reference from Phillippy’s group to improve characterization of the centromere, the point where the sister chromatids meet before getting segregated into daughter cells during cell division.⁵ The researchers mapped the complicated pattern of histone proteins and methylation sites of this chromosomal region, providing a genomic resource for a crucial point in cell division.

T2T Approaches Improve Animal Genomic Studies

Beyond humans, the reference genomes for many animal models have also remained incomplete due to technical limitations. Another T2T consortium team from the University of California, Santa Cruz (UC Santa Cruz) Genomics Institute used the consortium’s methods to create a complete reference genome for the marmoset, a small primate increasingly used to study neurodegenerative diseases.⁶

In addition to resolving sequences at the centromeres and other challenging genomic locations, the researchers also identified several gene variations, many of them related to Alzheimer’s disease in humans. “We see variation in these marmosets in the same genes that we do in humans, further reinforcing the idea that the marmoset is a good model for studying Alzheimer’s disease in humans,” said UC Santa Cruz PhD student and study coauthor Prajna Hebbar in a press release. “Now, we have this really complete, high-quality resource that people can take advantage of.”

Researchers also used the T2T genome sequencing approach to investigate the diploid DNA blueprint of non-mammalian animals. A team at Rockefeller University identified more than 2,000 new genes in the zebra finch, a songbird often used to study vocalization.⁷ Traditionally, bird genomes have been challenging to study because of their repetitive sequences and complicated chromosomal architecture, leading to questions about whether genes are lost through evolution or just missing from the reference genome.

In addition to the new genes, the songbird scientists also demonstrated how the centromeres in bird genomes are highly similar to those of humans. “This is a turning point in the field,” said neuroscientist and study author Erich Jarvis in a press statement.

Researchers also demonstrated new sequencing milestones in the genomes of rats, rhesus macaques, voles, equids, and giraffes.^8-12 These references can help improve research involving animals for modeling human disease as well as studying biodiversity and evolution.

New Genomic Insights Expand Personalized Medicine

As Phillippy and other T2T consortium members wrote in an accompanying perspective, the advancement of genomic sequencing paves the way for personalized medicine to more precisely diagnose and guide medical care.¹³

“It will soon become commonplace to sequence an individual’s entire genome. What will that enable? And what does the future of medicine look like when you can generate someone’s complete genome at birth, attach it to their medical record, and then use that to inform precision medicine throughout their life,” Phillippy said.

These insights also continue to impress the T2T researchers themselves. “It’s pretty crazy that I'm doing this research in what is one of the best times to be doing your Ph.D. in genomics,” Hebbar said. “It’s cool to be part of this era where you can actually study all of these complex regions.”

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