By
Evan
BushNBC
News
Mission accomplished or nearly accomplished.
That was the message scientists sent to the world in 2003 when they announced that the human genome had been sequenced, assembled, and essentially complete, with a few seemingly minor gaps.
In reality, the effort to quantify and identify the genetic code that makes us all human, which cost the United States Government billions of dollars, remained in a draft
and was at least 8% missing.
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However, some of the largest, most repetitive and complex pieces of the DNA puzzle have remained in the dark, until now.
Researcher Kevin Bishop looks at a sample of zebrafish at the National Institutes for Health. National Institutes for Health
Thanks to a powerful new sequencing technology, a group of some 100 scientists collaborating on the same project announced Thursday that they had managed to fill in the remaining gaps:
completing a single human genome from one end to the other and opening up promising new lines of research
in areas where scientists had been in the dark.
Genome sequencing was first shared publicly more than a year ago, but the results of a comprehensive review, vetted by scientists around the world who are already using it, were first published Thursday in a peer-reviewed scientific journal.
Six new articles in the journal Science describe the full sequencing and discuss its impacts.
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"It's completed, it's correct, and it's gone through all those levels of research," said Adam Phillippy, a computational biologist at the National Human Genome Research Institute and leader of that project.
"We are optimistic that there could be clues to human evolution and what makes us unique human beings
. "
This groundwork could one day help researchers identify the genetic causes of mental disorders, unravel the mysteries of what drives some cells to become cancerous, and help explain how different groups of people developed different traits over time, such as the ability to live at high altitude.
"It's a milestone," said Steve Henikoff, a molecular biologist and professor at the Fred Hutchinson Cancer Research Center and the University of Washington, who was not involved in the project.
From lines to pages
Assembling a genome is akin to “taking a book, ripping it into little pieces and putting them back together again,” said Megan Dennis, an assistant professor who studies human genetics and genomics at UC Davis Health, who contributed to the sequencing effort.
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First, the researchers must cut the DNA into short pieces.
Then, it is processed and read little by little.
Chopped up into pieces, it's hard to tell where each strand came from, so scientists must "put that DNA together computationally," Dennis said.
During the 2000s, DNA sequencing technology could only produce short snippets of genetic code, about 500 base pairs or letters at a time.
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But some regions of the human genome are extremely repetitive, almost like a page in a book with words repeated many times.
“Repetitive elements exist in many different places.
It's hard to know where they belong,” said Dennis.
For years, scientists simply had to leave those pages, and their understanding of the genome, blank.
In recent years,
new technology that creates longer reads of DNA has changed things completely
.
The new machines can produce hundreds of thousands of base pairs in a single chunk.
And these advances have allowed researchers to fill in the missing pieces of the genome.
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“It would have been unthinkable 20 years ago to have this technology,” Phillippy said.
Suddenly, researchers were able to order and put these repetitive parts of the genome in context.
"Those sequences have genes ... there are very important functions contained within those regions," he added.
a pandemic project
The idea of finishing the genome was a natural one.
A born perfectionist, Phillippy had always resented that the human genome remained incomplete.
About five years ago, he teamed up with Karen Miga, an assistant professor in the biomolecular engineering department at the University of California, Santa Cruz, to finish the job.
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When they got stuck, they sought help.
The project began to snowball, amassing a few hundred scientific collaborators and growing into what is now called the Telomere-to-Telomere project, using a term that describes the ends of chromosomes.
When the pandemic hit, the pace of research only quickened, with investigators communicating from dingy basements on the communication platform Slack and through Zoom calls.
“2020 was a crazy year for many reasons. It gave us something to focus on
,” Phillippy said.
Ultimately, the researchers put together the entire genetic code for a single version of a genome.
That genome, which was derived decades ago from the cellular tissue that contains the genetic information of a single sperm, does not represent any human who has ever lived because it only contains one set of paternal chromosomes.
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The complete code will now form the backbone of new genomics research and become a new and finished reference for comparison.
Theory and practice
The complete genome opens new avenues for scientific research.
For decades, scientists have pored over the 92% of the available genome, testing it for genetic variations that could be causing disease.
"We have a good understanding of what variation looks like in those regions, but we have no idea about the other 8%," Phillippy said.
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Now, the researchers are starting to check their old data against the new reference genome, trying to uncover new clues to what they've been missing.
"We identified many more, tens of thousands if not hundreds of thousands of new variants," said Dennis.
"Some of them fall under genes that code for proteins and some of those genes are medically important, clinically important and contribute to disease."
The new genome reference also allows further study of how centromeres work.
Centromeres are structures in the middle of chromosomes that are filled with repetitive sequences of code and are an integral part of the cell division process.
Historically, they are among the least understood parts of the genome because they contain so much tedious and dense coding.
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"We don't understand the underlying mechanism of centromere evolution," said Henikoff.
"All of a sudden, in the last year, as the data came out, we learned a lot more about centromeres."
Using the new genome, researchers can better study how centromere proteins are assembled and what happens when they change or lose their function.
"Centromere dysfunction may be an important factor in cancer
," said Henikoff.
Until now, "we've been hampered because we haven't had a reference sequence."
Further study of newly sequenced portions of the genome could also help scientists better understand how humans developed particular traits, such as larger brains that sent them down a genetically distinct path than their ancestors, the great apes. .
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"The things that make our frontal cortex larger come from the genes that map to these repetitive regions," said Evan Eichler, a professor in the department of genome sciences at the University of Washington School of Medicine and also part of research collaboration.
Advances in genome sequencing technology could fuel a renaissance in medical advances, according to the researchers.
"I'm most excited about what we don't know and the opportunities for discovery," Miga said.
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Phillippy said his next goal is to optimize the sequencing process to make it cheaper, more efficient and widely available.
He also plans to sequence the genetic code with the paternal and maternal chromosomes.
Broad sequencing among people of many origins will help describe the world's genetic diversity and identify important genetic variations, she said.
He envisions a world in which everyone has access to their genetic data
, which could help provide individualized information about which diseases doctors should watch for or which drugs to prescribe.
"Within 10 years, obtaining a perfectly accurate, complete human genome will be a routine part of health care and cheap enough not to think twice: a lab test will cost less than $1,000," Phillippy said. .
“You will have the complete genome in your pocket.”