That was the message scientists sent to the world in 2003 when they announced that the human genome had been sequenced, assembled, and was nearly complete- save for 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 a rough draught that was at least 8% incomplete.
Until now, some of the largest, most repetitive, and complex pieces of the DNA puzzle remained unknown.
Findings of Research
With the help of powerful new sequencing technology, a loose collaboration of about 100 scientists announced Thursday that they'd filled in the gaps, completing a single human genome from beginning to end and opening up new, promising lines of research in areas where scientists had been stumbling.
The genome's sequencing was first made public more than a year ago, but the results of a full accounting, which is now vetted and used by researchers worldwide, were published for the first time Thursday in a peer-reviewed journal. In the journal Science, six new articles describe the entire sequencing effort as well as additional analysis of its implications.
"It's done, it's correct, and it's gone through all those levels of vetting," said Adam Phillippy, a computational biologist at the National Human Genome Research Institute and the project's leader. "We're hopeful that there may be clues to human evolution and what distinguishes us as humans."
This research could one day help researchers identify the genetic causes of disorders, unravel the mysteries of what causes some cells to become cancerous, and explain how different groups of people evolved different traits over time, such as the ability to thrive at high altitude.
"It's a watershed moment," said Steve Henikoff, a molecular biologist at the Fred Hutchinson Cancer Research Center and the University of Washington who was not involved in the project.
"It's like taking a book, ripping it up into tiny pieces, and putting it back together again," said Megan Dennis, an assistant professor who studies human genetics and genomics at UC Davis Health and contributed to the sequencing effort.
First, the DNA must be cut into short fragments by the researchers. The data is then processed and read bit by bit. Because it's difficult to tell where each strand came from when it's cut up, scientists must "stitch that DNA together in a computational way," according to dennis.
Until the early 2000s, DNA sequencing technology could only generate short snippets of genetic code- about 500 base pairs, or letters- at a time. However, some parts of the human genome are extremely repetitive, almost like a book page with many words repeated.
"Repetitive elements can be found in a variety of places." "I'm not sure where they belong," Dennis said. For years, scientists had no choice but to leave those pages blank, as well as their understanding of the genome.
In recent years, a new technology that generates longer reads of DNA has completely changed the game. In a single chunk, new machines can generate hundreds of thousands of base pairs. Researchers have been able to fill in the gaps in the genome as a result of these advancements.
"Having this technology would have been unthinkable 20 years ago," Phillippy said. Researchers were able to order and contextualize those repetitive parts of the genome for the first time. "Those sequences contain genes..There are critical functions contained within those regions."
Theory & Practice
The completed genome opens up new research opportunities. For decades, scientists have been poring over the genome's 92 percent, probing it for genetic variations that could be causing diseases.
"We have a good idea of what variation looks like in those regions, but we don't know about the other 8%," Phillippy said. Researchers are now re-analyzing their old data against the new reference genome, hoping to glean new insights from what had previously gone unnoticed.
"We found tens of thousands, if not hundreds of thousands, of new variants," Dennis explained. "Some of them fall within genes that encode proteins, and some of those genes are medically and clinically important, and some of those genes contribute to disease
The new genome reference also allows for more research into how centromeres function.
Centromeres are structures in the middle of chromosomes that contain repeating code sequences and are essential for cell division. Because they contain so much tedious, dense coding, they have historically been among the least understood parts of the genome.
"We don't understand the underlying mechanism of centromere evolution," Henikoff said. "All of a sudden, we've learned a lot more about centromeres in the last year as the data has been coming out."
Researchers will be able to better understand how centromere proteins assemble and what happens when they change or lose function thanks to the new genome.
"Centromere dysfunction can be a significant driver in cancer," Henikoff explained. Until now, "we've been hampered by the lack of a reference sequence."
Further research into newly sequenced portions of the genome may also help scientists better understand how humans evolved specific traits, such as larger brains that led them down a genetically distinct path from their great ape ancestors.
"The genes that map in these repetitive regions are what make our frontal cortex bigger," said Evan Eichler, a professor in the department of genome sciences at the University of Washington School of Medicine and a member of the research collaborative.
According to the researchers, advances in genomic sequencing technology could spark a renaissance of medical breakthroughs.
Phillippy's next goal is to simplify the sequencing process so that it is less expensive, more efficient, and widely available. In addition, he intends to sequence genetic code from both the paternal and maternal chromosomes. According to him, broad sequencing among people from various backgrounds will help describe the world's genetic diversity and zero in on important genetic variations.
He imagines a world in which everyone has access to their genetic data, which could help doctors provide more personalized information about which diseases to watch for and which drugs to prescribe.
"Within the next ten years, getting a complete, perfectly accurate human genome will be a routine part of health care, and it will be cheap enough that it won't be a second thought- an under $1,000 lab test," Phillippy predicted. "You'll carry the entire genome in your pocket."
(Source: The Atlantic)
