UW scientists help complete sequencing of human genome

Twenty years ago, as a youngster with an interest in science, Mitchell Vollger saw the headlines heralding the cracking of the human genetic code. He was struck with a sense of melancholy.

“I remember very clearly seeing the covers of National Geographic and Science and Nature in the early 2000s and truly thinking, ‘Oh, that’s so cool,’ ” Vollger says. “ ‘Too bad it’s over.’ ”

But it wasn’t over. There were gaps in the sequence, and about 8% of the genome was still missing.

Now a postdoctoral fellow in Professor Evan Eichler’s genome sciences research lab, Vollger, ’21, is part of an international team building on the groundbreaking work of the Human Genome Project by producing the first gapless sequence of the human genome.

Vollger came to the UW with experience helping complete a reference genome for a yeast strain. Upon joining the Eichler lab, “I learned that it wasn’t complete in humans, either. There was still work to be done completing the human genome. And so I think that’s been the ambition from sort of almost day one in Evan’s lab. My thesis proposal, written four or five years ago, was to finish a human genome. And it’s exciting that the technologies all came together at exactly the right time to do that.”

In 2001, when researchers announced to great fanfare that they’d mapped the human genome, they were able to do so because they determined there were parts of the genome that were too hard to decipher. And, frankly, those parts didn’t look all that promising; just a jumble of incomplete and repetitive information.

Eichler, then in his early 30s and among the youngest scientists in the group of 3,000 on the project, wasn’t convinced that the missing 8% was unimportant. “There was a lot of celebration,” Eichler says. “I remember there being huge parties, actually, about this.” But like we all learned in the movie “Jurassic Park,” filling in the gaps of a genome is a tricky business and genetics requires precision. “When the job isn’t complete, it comes back to haunt you,” Eichler says.

Eichler became convinced these mysterious regions of  DNA—called segmental duplications—were really important. While some folks agreed, the easiest thing for most scientists on the project to do was decide “these are really difficult bits” and set them aside, he says.  “They realized that the technologies just weren’t ready and it would just take hard slogging to get through some of this. So when I set up my lab, I designed it to basically focus on the hard slogging, to go through these difficult regions, and that’s the way it was for 15 years. I would say it was really hard slogging.”

Eichler, Vollger and their 100 or so colleagues in the Telomere-to-Telomere consortium set out to obtain complete sequences of all 23 human chromosomes end to end. Their research slowly revealed Eichler’s early suspicions were correct as technology allowed them to examine longer and longer strands of DNA, among other advances. The areas were indeed key, governing aspects important to human evolution and development like cell division, protein production in living cells and brain size. “I think that’s pretty fundamental stuff,” says Eichler.

They determined that about 950 of the 20,000 genes in our genome originate in the segmental duplications. The work was highlighted in a paper called “The Complete Sequence of the Human Genome,” published in the journal Science on April 1. Vollger was lead author on a companion paper, “Segmental Duplications and Their Variation in a Complete Human Genome,” based on research done with fellow graduate student Phil Dishuck.

Though the human genome is now fully mapped, it won’t be the last paper Vollger helps produce on the topic, says Eichler. “This is not the end of anything, right? It’s only the beginning.”

Next, Eichler is convinced, many more discoveries will come. They may revolutionize health care, and help us understand both where we came from evolutionarily and where we’re going.

“Ultimately, if we could fast forward 20 years, this will be part of the way your genetic record is reported,” Eichler says. “You will actually have a complete sequence of your mom’s and your dad’s contributions sitting in your medical record and people will be mapping predispositions and protections against disease based on that complete map.”