Scientists Finally Finished The Human Genome


Twenty years after the draft sequencing of the human genome open A team of 99 scientists finally deciphered it all. They filled in the big gaps and gave us a new view of our DNA, correcting a long list of bugs in previous versions.

The consortium has published six papers online in recent weeks where they described the complete genome. These challenging data, currently under review by scientific journals, will provide scientists with a deeper understanding of how DNA influences disease risks and how cells keep cells in properly organized chromosomes rather than molecular tangles.

For example, researchers have discovered more than 100 new genes that may be functional and have identified millions of genetic variations among humans. Some of these differences likely play a role in diseases.

For Nicolas Altemose, a postdoctoral researcher at the University of California, Berkeley, who worked on the team, the view of the entire human genome is similar to close-up pictures of Pluto taken from the New Horizons space probe.

“You could see every crater, you could see every color, from something we’ve only ever understood before in the most fuzzy way,” he said. “It was just an absolute dream come true.”

Experts not involved in the project said it will enable scientists to explore the human genome in much greater detail. Large chunks of the simply empty genome are now being deciphered so clearly that scientists can begin to study them in earnest.

“The fruition of this sequencing effort is amazing,” said Yukiko Yamashita, a developmental biologist at the Whitehead Biomedical Research Institute at the Massachusetts Institute of Technology.

A century ago, scientists knew that genes spanned 23 pairs of chromosomes, but these strange, worm-like microscopic structures remained largely a mystery.

By the late 1970s, scientists had gained the ability to detect and sequence several individual human genes. But their tools were so rough that hunting a single gene could take up an entire career.

Towards the end of the 20th century, an international network of geneticists decided to sequence all the DNA in our chromosomes. The Human Genome Project was a daring undertaking, given how much remains to be sequenced. Scientists knew that the twin strands of DNA in our cells contain roughly three billion pairs of letters – a text long enough to fill hundreds of books.

When this team got to work, the best technology available to scientists was bits of DNA lined up just a few dozen letters or bases long. The researchers were left to put them together like pieces of a big puzzle. To piece the puzzle together, they looked for pieces with the same ends, meaning they came from overlapping parts of the genome. It took years for them to gradually assemble the sorted pieces into larger strips.

The White House announced in 2000 that scientists had finished the first draft of the human genome, and details of the project were published the following year. But as scientists struggled to find where the millions of other bases belonged, long sections of the genome remained unknown.

Putting the genome together from small pieces turned out to be a very difficult puzzle. Most of our genes exist in multiple copies that are nearly identical to each other. Sometimes different copies perform different jobs. Other copies, known as pseudogenes, are disabled by mutations. A short piece of DNA from one gene can fit into the others in the same way.

And genes make up only a small percentage of the genome. The rest can be even more surprising. Most of the genome consists largely of virus-like stretches of DNA that exist only to insert new copies of themselves back into the genome.

In the early 2000s, scientists got a little better at putting together the genome puzzle from its little pieces. They made more parts, read them more accurately, and developed new computer programs to assemble them into larger parts of the genome.

Researchers would periodically reveal the latest and greatest draft of the human genome, known as the reference genome. The scientists used the reference genome as a guide for their sequencing efforts. For example, clinical geneticists will catalog disease-causing mutations by comparing genes from patients to the reference genome.

The most recent reference genome was released in 2013. It was much better than the first draft, but far from complete. Eight percent was empty.

“It’s basically an entire human chromosome that is lost,” said Michael Schatz, a computational biologist at Johns Hopkins University.

In 2019, two scientists—Adam Phillippy, a computational biologist at the National Human Genome Research Institute, and Karen Miga, a geneticist at the University of California, Santa Cruz—founded it. Telomere to Telomere Consortium to complete the genome.

Dr. Phillippy admitted that part of his motivation for such a daring project was that the missing gaps bothered him. “They were really bothering me,” he said. “You take a beautiful landscape puzzle and pull out a hundred pieces and you look at it – it’s very annoying for a perfectionist.”

Dr. Phillippy and Dr. Miga urged scientists to join them in finishing the puzzle. 99 scientists working directly to sequence the human genome and dozens more to make sense of the data. Researchers have worked remotely throughout the pandemic, coordinating their efforts through the messaging app Slack.

Dr. “It was an astonishingly beautiful ant colony,” Miga said.

The consortium took advantage of new machines that can read stretches of DNA reaching tens of thousands of bases in length. Researchers have also invented techniques to find where in a genome specifically mysterious repeating sequences belong.

Altogether, the scientists added or fixed more than 200 million base pairs to the reference genome. They can now say with confidence that the human genome is 3.05 billion base pairs long.

Scientists have discovered more than 2,000 new genes within these new DNA sequences. Most seem to have been disabled by mutations, but 115 appear to be able to produce proteins—a function that scientists have had to understand for years. The consortium now estimates that the human genome contains 19,969 protein-coding genes.

With a complete genome eventually put together, researchers can better look at variation in DNA from one person to another. They discovered more than two million new spots in the genome where humans differ. Using the new genome also helped them avoid detecting disease-associated mutations where none actually existed.

B.C. D., director of molecular oncology at Children’s Mercy, a hospital in Kansas City, who was not involved in the project. “This is a huge advance for the field,” said Midhat Farooqui.

Dr. Farooqi began using the genome for his research on rare childhood diseases and aligned DNA from his patients against newly filled gaps to look for mutations.

However, transitioning to the new genome can be challenging for many clinical laboratories. They will need to shift all their knowledge of the links between genes and diseases to a new genome map. D., a medical geneticist at Baylor College of Medicine in Houston. “It will be a huge effort, but it will take several years,” said Sharon Plon.

Dr. Altemose plans to use the entire genome to discover a particularly mysterious region on each chromosome known as the centromere. Instead of storing genes, centromeres anchor proteins that move chromosomes around the cell as they divide. The centromere region contains thousands of repeating DNA segments.

Dr. At first glance, Altemose and colleagues were surprised at how different the centromere regions could be from one person to another. This observation suggests that centromeres evolve rapidly as mutations add new DNA segments to regions or cut other segments.

While some of this repetitive DNA may play a role in separating chromosomes from each other, the researchers also found new segments, some of which were millions of bases long and were not visible. Dr. “We don’t know what they’re doing,” said Altemose.

But now that the empty regions of the genome have been filled, Dr. Altemose and colleagues can examine them closely. “I’m really excited to move forward to see all we can discover,” he said.


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