It’s been 20 years since scientists pieced together the first draft of the human genome, the three billion genetic letters of DNA tightly coiled inside most of our cells. Today, scientists are still struggling to decipher it.
But a series of studies published in Science on Thursday shed a bright light into the dark recesses of the human genome by comparing it to those of 239 other mammals, including narwhals, cheetahs and screaming furry armadillos.
By tracing this genomic evolution over the past 100 million years, the so-called Zoonomia Project has revealed millions of stretches of human DNA that have changed little since our shrew-like ancestors scuttled into the shadows of the dinosaurs. These ancient genetic elements most likely perform essential functions in our bodies today, the project found, and mutations within them can put us at risk for a range of diseases.
The strength of the project lies in the huge amount of data analyzed not just about genomes, but experiments on thousands of pieces of DNA and information from medical studies, said Alexander Palazzo, a geneticist at the University of Toronto who was not involved in work. This is the way it has to be done.
Mammalian genomes have also allowed the Zoonomia team to identify pieces of human DNA with radical mutations that distinguish them from other mammals. Some of these genetic adaptations may have played a role in the evolution of our large and complex brains.
The researchers have only scratched the surface of potential revelations in their database. Other researchers say it will serve as a treasure map to guide further exploration of the human genome.
The melting pot of evolutions sees everything, said Jay Shendure, a geneticist at the University of Washington who was not involved in the project.
Scientists have long known that only a tiny fraction of our DNA contains so-called protein-coding genes, which make such crucial proteins as the digestive enzymes in our stomachs, the collagen in our skin, and the hemoglobin in our blood. All of our 20,000 protein-coding genes make up just 1.5% of our genome. The other 98.5% are much more mysterious.
Scientists have found that a few bits of that inscrutable DNA help determine which proteins are being made in which places and at which times. Other pieces of DNA act as switches, turning on nearby genes. And still others can amplify the production of those genes. And still others act like switches that are turned off.
Through painstaking experiments, scientists have discovered thousands of these switches nestled in long stretches of DNA that appear to do nothing for us—what some biologists call junk DNA. Our genome contains thousands of broken copies of genes that no longer work, for example, and vestiges of viruses that invaded the genomes of our distant ancestors.
But it’s still not possible for scientists to look directly at the human genome and identify all the switches. We don’t understand the language that makes these things work, said Steven Reilly, a geneticist at the Yale School of Medicine and one of more than 100 Zoonomia team members.
When the project started over a decade ago, the researchers acknowledged that evolution could help them decipher this language. They reasoned that switches that last for millions of years are probably essential to our survival.
In each generation, mutations randomly affect the DNA of each species. If they hit a piece of DNA that isn’t essential, they won’t cause any damage and could be passed down to future generations.
Mutations that destroy an essential switch, on the other hand, likely won’t be passed down. Instead, they can kill a mammal, for example by turning off genes essential for organ development. You just won’t have a kidney, said Kerstin Lindblad-Toh, a geneticist at the Broad Institute and Uppsala University who started the Zoonomia project.
Dr. Lindblad-Toh and her colleagues determined that they would need to compare more than 200 mammalian genomes to track these mutations over the past 100 million years. They collaborated with wildlife biologists to obtain tissue from species scattered throughout the mammalian evolutionary tree.
Scientists worked out the sequence of genetic letters known as bases in each genome and compared them to sequences in other species to determine how mutations arose in different branches of mammals as they evolved from a common ancestor.
It took a lot of computers, said Katherine Pollard, a data scientist at the University of California, San Francisco who helped build the Zoonomia database.
The researchers found that a relatively small number of bases in the human genome, 330 million, or about 10.7%, got few mutations in any branch of the mammalian tree, a sign that they were essential for the survival of all these species. , including ours. .
Our genes make up a small part of that 10.7%. The rest is found outside our genes and probably includes elements that turn genes on and off.
Mutations in these poorly modified parts of the genome have been harmful for millions of years and remain harmful to us today, the researchers found. Mutations linked to genetic diseases typically alter foundations that the researchers found had evolved little over the past 100 million years.
Nicky Whiffin, a geneticist at the University of Oxford who was not involved in the project, said clinical geneticists struggle to find disease-causing mutations outside of protein-coding genes.
Dr Whiffin said the Zoonomia project could lead geneticists to unexplored regions of the genome with health relevance. That could greatly reduce the number of variants you’re looking at, he said.
The DNA that governs our essential biology has changed very little in the last 100 million years. But of course we are not identical to kangaroo rats or blue whales. The Zoonomia project allows researchers to identify mutations in the human genome that help make us unique.
Dr. Pollard focuses on thousands of stretches of DNA that have not changed in that time period except in our own species. Intriguingly, many of these rapidly evolving pieces of DNA are active in the developing human brain.
Based on the new data, Dr Pollard and her colleagues think they understand how our species broke with a 100-million-year tradition. In many cases, the first step was a mutation that accidentally created an extra copy of a long stretch of DNA. By stretching our DNA, this mutation changed the way it folded.
As our DNA folded, a genetic switch that once controlled a nearby gene no longer made contact with it. Instead, he has now made contact with a new one. The switch eventually gained mutations that allowed it to control its new neighbor. Dr. Pollard’s research suggests that some of these changes helped human brain cells grow for a longer period of time in childhood, a crucial step in the evolution of our large and powerful brains.
Dr. Reilly, of Yale, has found other mutations that may have helped our species build more powerful brains: those that accidentally cut pieces of DNA.
By scanning Zoonomia genomes, Dr. Reilly and his colleagues looked for DNA that survived in species after species but was then deleted in humans. They found 10,000 of these deletions. Most were only a few bases long, but some of them have had profound effects on our species.
One of the more surprising deletions altered an off switch in the human genome. It’s close to a gene called LOXL2, which is active in the developing brain. Our ancestors only lost a strand of DNA as a result of the handover. That small change turned the off switch into an on switch.
Dr Reilly and his researchers conducted experiments to see how the human version of LOXL2 fared in neurons compared to the standard mammalian version. Their experiments suggest that LOXL2 remains active in children longer than it does in young monkeys. LOXL2 is known to keep neurons in a state where they can continue to grow and sprout branches. So staying on longer in childhood could allow our brains to outgrow monkey brains.
It changes our idea of how evolution can work, Dr. Reilly said. Breaking things down in your genome can lead to new functions.
The Zoonomia project team plans to add more mammalian genomes to their comparative database. Zhiping Weng, a computational biologist at UMass Chan Medical School in Worcester, is especially eager to examine another 250 primate species.
His Zoonomia research suggests that virus-like pieces of DNA multiplied in the genomes of our ape-like ancestors, inserting new copies of themselves and rewiring our on-off switches in the process. Comparing more primate genomes will allow Dr. Weng to get a clearer picture of how these changes may have rewired our genome.
I’m still very obsessed with being a human being, she said.