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Completing the sequence

Stowers Institute researchers help assemble the complete human genome

31 March 2022

During the COVID-19 pandemic, Stowers Institute researchers played several roles within a scientific consortium to fully assemble the human genome sequence

By Melissa Fryman  

Since the Human Genome Project published almost two decades ago, the field of genomics has exploded, raising questions we didn’t even know to ask at the start of this millennium.

A little-known fact—outside of the biomedical research community—is that the original reference human genome was incomplete. Roughly 8% of it was unknown, and until just last year, there were still around 100 gaps in the sequence.

Many of the gaps were located at specialized points of attachment between chromosomes, called centromeres. Additional gaps were located at the short ends of acrocentric chromosomes, where one of the chromosomes arms is substantially shorter than the other, of which humans normally have five pairs. Replete with repetitive DNA elements, these gaps were notoriously difficult to assemble with standard methods.

Proper centromere function is essential for faithful cell division and chromosome segregation; problems with centromere function can lead to cancer, or chromosomal disorders such as Down syndrome and Fragile X syndrome.

In acrocentric chromosomes, the centromere is located near the end, or telomere, of the chromosome. The short arms of acrocentric chromosomes house ribosomal DNA, an array of nearly identical genes that support protein-producing ribosomes, in addition to other DNA sequences that are just now starting to be elucidated.

Assembling the complete human genome was an international, multi-institutional feat of creativity and technology by the Telomere-to-Telomere (T2T) consortium, which is headed by Karen Miga, PhD, from the University of California, Santa Cruz, and Adam Phillippy, PhD, from the National Human Genome Research Institute of the National Institutes of Health. Also part of the consortium are several Stowers researchers including Investigator Jennifer Gerton, PhD.

Jennifer Gerton, PhD

The findings thus far from the T2T consortium confirmed that the gaps in the human genome comprise some of the most functionally significant regions, and offer a tantalizing hint that sequences in the centromere and short arm of acrocentric chromosomes may account for much of our individual biological variation, from human to human.

Gerton joked that the ends of acrocentric chromosomes are like “Spring Break Daytona Beach” for repetitive DNA. Perhaps because of a permissible environment due to the existence of ribosomal DNA, “they are full of repetitive DNA. Everything kind of goes crazy out there.”

“The T2T consortium suspects these regions are different in every single human,” added Gerton. “I might have 1000 copies of a particular repeat, but you may have 200 copies. And for me, they may be spread over three of my acrocentric chromosomes, and for you, spread over all five. There is this amazing variation and diversity that we didn’t fully appreciate before.”

Ultimately, researchers from the Stowers Institute made substantial contributions to the effort of completing the human genome, described in three articles from a group of six published April 1, 2022, in Science.

Read more about these efforts in the following three-part series:

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