Researchers have finally deciphered a complete human genetic instruction book from start to finish.
The completion of the human genome has been announced several times in the past, but these are actually incomplete drafts. “This time we’re serious,” said human geneticist Evan Eichler, a Howard Hughes Medical Institute investigator at the University of Washington in Seattle.
Complete genome published in a series of papers published online March 31 science and natural method.
An international team of researchers including Eichler used new DNA sequencing techniques to unravel repetitive DNA segments edited from earlier versions of the genome, widely used as a reference to guide biomedical research.
Deciphering those tricky extensions Added about 200 million DNA bases, about 8% of the genomein the specification, the researchers science. This is basically a whole chapter. It’s a succulent, containing the first look at the short arms of some chromosomes, long-lost genes and important parts of chromosomes called centromeres — the machines responsible for dividing DNA that grab onto chromosomes.
“Some of the missing regions are actually the most interesting,” says human geneticist Rajiv McCoy of Johns Hopkins University, a member of the so-called telomere-to-telomere (T2T) consortium. complete genome. “It’s exciting because we can get a first look at these regions and see what we can find.” Telomeres are repetitive pieces of DNA found at the ends of chromosomes. Like the straps on a shoelace, they may help keep chromosomes from unraveling.
Data from this work is already available for other researchers to explore. Still others, such as geneticist Ting Wang of Washington University School of Medicine in St. Louis, have taken a deep dive. “Having a complete genome reference would definitely improve biomedical research…it’s a very useful resource,” he said. “There is no doubt that this is an important achievement.”
But, Wang said, “the human genome is not quite complete yet.”
To understand why and what this new encyclopedia of human genes tells us, take a closer look at this milestone.
What did the researchers do?
Eichler is careful to point out, “This is done A sort of human genome.no such thing This human genome. Any two people will have a large part of their genome, ranging from very similar to nearly identical to “small part completely different.” Reference genomes can help researchers understand how people are different, which can point to genes that may be involved in disease Understanding the entire genome, with no gaps or hidden DNA, allows scientists to better understand human health, disease and evolution.
The new complete genome has no gaps like the previous human reference genome. But it still has limitations, Wang said.The old reference genome is Group of 60+ DNA (SN: 3/4/21). “No individual or single cell on this planet has such a genome.” This also applies to new, complete genomes. “This is a citing-not-citing pseudogenome,” said Wang, who was not involved in the project.
Nor did the new genome come from a single person. This is the genome of a complete mole, a tumor that arises when sperm fertilizes an empty egg and the father’s chromosomes are duplicated. The researchers chose to decipher the complete genome from a cell line called CHM13, which is made from one of these unusual tumors.
The decision was made for technical reasons, says geneticist Karen Miga of the University of California, Santa Cruz. Usually, people get one set of chromosomes from their mother and another set from their father. So “we have two genomes in each cell.”
If putting the genome together is like a puzzle, “you actually have two very similar looking puzzles in the same box,” Miga said, borrowing an analogy from a colleague. The researchers had to sort the two puzzles before putting them together. “Genomes from moles don’t present the same challenges. It’s just a puzzle in a box.”
The researchers did have to add another person’s Y chromosome because the sperm that produced the mole had an X chromosome.
Even putting together a puzzle can be a daunting task. But new techniques that allow researchers to sequence DNA bases (represented by the letters A, T, C, and G) can spit out lengths of up to 100,000-plus bases. Just as children’s puzzles are easier to solve due to larger and larger fragments, these “long reads” make it easier to assemble fragments of the genome, especially in repeating parts, where only a few bases can distinguish one copy from another copy. The larger fragments also allowed the researchers to correct some errors in the old reference genome.
What did they find?
First, the newly deciphered DNA contains the short arms of chromosomes 13, 14, 15, 21 and 22. These “apoccentric chromosomes” are not as pretty and neat as other chromosomes. Instead, they have one set of long arms and one stubby arm.
The length of the short arms belies their importance. These arms are home to rDNA genes, which encode rRNA, key components of complex molecular machines called ribosomes. Ribosomes read genetic instructions and build all the proteins needed to make cells and bodies work. There are hundreds of copies of these rDNA regions in each person’s genome, an average of 315, but some people have more and some have fewer. They are important for making sure cells are ready to build protein factories.
“We don’t know what’s going to happen in these areas,” Miga said. “We found that every acrocentric chromosome, and every rDNA on that acrocentric chromosome, has a variation that alters the repeat unit that is exclusive to that particular chromosome.”
Using fluorescent tags, Eichler and colleagues found repeating DNA—and perhaps rDNA—next to regions of rDNA that sometimes Switch positions to land on another chromosometeam in science. “It’s like a musical chair,” he said. Why and how this happens remains a mystery.
The complete genome also contained 3,604 genes, including 104 that code for proteins, that were not present in the old, incomplete genome. Many of these genes are slightly different copies of previously known genes, including some involved in brain evolution and development, autism, immune response, cancer and cardiovascular disease. Having a map of where all these genes are located could lead to a better understanding of what they do, and possibly even what makes humans human.
One of the biggest discoveries may be the structure of all human centromeres. The centromere, the constricted part that gives most chromosomes their characteristic X shape, is the assembly point of the kinetochore, the cellular machinery that divides DNA during cell division. This is one of the most important jobs in the cell. When it goes wrong, it can lead to birth defects, cancer or death.Researchers have deciphered Drosophila centromere and human chromosomes 8, X, and Y (SN: May 17, 2019), but this is the first time the researchers have seen the rest of the human centromere.
These structures are primarily head-to-tail repeats of about 171 base pairs of DNA called alpha satellites.But these repeats are tightly linked with other repeats, forming complex patterns that distinguish the individual centromeres of each chromosome, Miga and colleagues found in scienceKnowing these structures will help researchers learn more about how chromosomes are divided and the problems that sometimes cause this process.
Researchers also now have a more complete map of epigenetic marks — chemical tags on DNA or related proteins that may alter how genes are regulated.One type of epigenetic mark, called DNA methylation, is fairly abundant in centromeres, except for a spot on each chromosome called centromere inclination zonebiomedical engineer Winston Timp and colleagues at Johns Hopkins University science.
These dips are where the kinetochore grabs DNA, the researchers found. But it’s not clear whether the drop in methylation causes the cellular machinery to assemble at that location, or whether the assembly of the machinery results in lower methylation levels.
Examining DNA methylation patterns in the DNA of multiple people and comparing them to a new reference, it was found that the drop occurred at a different location in each individual’s centromere, although the consequences were unclear.
About half of the genes are associated with The evolution of the large, wrinkled human brain Found in multiple copies of the newly discovered repetitive part of the genome (SN: 2/26/15). Overlaying epigenetic maps on a reference allows researchers to determine which of the multiple copies of these genes are turned on and off, says geneticist Ariel Gershman of the Johns Hopkins University School of Medicine.
“This gives us a deeper understanding of which of them are actually important and play a functional role in the development of the human brain,” Gershman said. “This is exciting for us because there has never been a sufficiently accurate reference in the literature [repetitive] regions to tell which gene is which gene and which genes are turned on or off. “
One criticism of genetics research is that it relies too heavily on the DNA of people of European descent. CHM13 also has a European heritage. But researchers have used the new reference to discover new patterns of genetic diversity.Using DNA data collected from thousands of people of different backgrounds who participated in an earlier research project compared to a T2T reference, researchers Easier and more accurate to find where people differMcCoy and colleagues in science.
The Telomere-to-Telomere Consortium has now partnered with Wang and his colleagues to Complete genomes of 350 people from a different background (Serial Number: 2/22/21). The effort, known as the Pan-Genome Project, is expected to announce some of its initial findings later this year, Wang said.
McCoy and Timp say it may take some time, but eventually, researchers may move away from using older reference genomes to more complete and accurate T2T references. “It’s like upgrading to a new version of the software,” Timp said. “Not everyone wants to do it right away.”
The full human genome will also be useful to researchers studying other organisms, says Amanda Larracuente, an evolutionary geneticist at the University of Rochester in New York who was not involved in the project. “What excites me is the techniques and tools this team has developed and the ability to apply them to study other species.”
Eichler and others already plan to make the complete genomes of chimpanzees, bonobos and other great apes to learn more about how humans evolved differently than apes. “No one should see this as the end,” Eichler said, “but a shift, not just in genomics, but in clinical medicine, even though it will take years to achieve.”