It has been 20 years since scientists put together the first rough draft of the human genome, the three billion genetic letters of DNA tightly wound inside most of our cells. Today, scientists are still struggling to decipher it. But a batch of studies published wasted in Science on Thursday has cast a bright light into the dark recesses of the human genome by comparing it with those of 239 other mammals, including narwhals, cheetahs and screaming hairy armadillos. By tracing this genomic evolution over the past 100 million years , the so- The called Zoonomia Project has revealed millions of stretches of human DNA that have changed little since our shrew-like ancestors scurried in the shadows of dinosaurs. These ancient genetic elements most likely carry out essential functions in our bodies today, the project found, and mutations within they can put us at risk of a range of diseases. The project’s strength lies in the huge amount of data analyzed — not just the 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 the work. “This is the way it needs to be done.” The mammalian genomes also allowed the Zoonomia team to pinpoint pieces of human DNA with radical mutations that set them apart from other mammals. Some of these genetic adaptations may have had a major role in the evolution of our big, complex brains. The researchers have only scraped the surface of potential revelations in their database. Other researchers say it will serve as a treasure map to guide further explorations of the human genome. “Evolution’s crucible sees all,” said Jay Shendure, a geneticist at the University of Washington who was not involved in the project. Essential SwitchesScientists have long known that just a tiny fraction of our DNA contains so-called protein-coding genes , which make crucial proteins like digestive enzymes in our stomach, collagen in our skin and hemoglobin in our blood. All of our 20,000 protein-coding genes make up just 1.5 percent of our genome. The other 98.5 percent is far more mysterious .Scientists have found that some bits of that inscrutable DNA help determine which proteins get made at certain places and at certain times. Other pieces of DNA act like switches, turning on nearby genes. And still others can amplify the production of those genes. And still others act like off switches. Through painstaking experiments, scientists have uncovered thousands of these switches nestled in long stretches of DNA that seem 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 not yet 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 members of the Zoonomia team. When the project began over a decade ago, the researchers recognized that evolution could help them decipher this language. They reasoned that switches that endure for millions of years are probably essential to our survival. In every generation, mutations randomly strike the DNA of every species. If they hit a piece of DNA that isn’t essential, they will cause no harm and may be passed down to future generations. Mutations that destroy an essential switch, on the other hand, probably won’t get passed down. They may instead kill a mammal, such as by turning off genes essential for organ development. a Kidney, “Said Kestin Lindblad-TOH, a Geneticist at the Broad Institute and Uppsala University Who Initiated the zoonblad-TOH A ND Her Colleagues Determine that they will be compare more than 200 mammal geenomes to travel the past 100 million years. They collaborated with wildlife biologists to get tissue from species spread out across the mammalian evolutionary tree. The scientists worked out the sequence of genetic letters — known as bases — in each genome, and compared them with the sequence ences of others species to determine how mutations arose in different mammalian branches as they evolved from a common ancestor. “It took a lot of computer churn,” 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 percent — gained few mutations in any branch of the mammalian tree, a sign that they were essential to the survival of all of these species, including our own. Our genes make up a small portion of that 10.7 percent. The rest lies outside our genes, and probably includes elements that turn genes on and off. Mutations in these little-changed parts of the genome were harmful for millions of years, and They Remain Harmful To US TODAY, The Researches Found. Mutations Linked to Genetic Diseases Typically Alter Bases that the ResearcherS Found Evolution Lit TLE in the Past 100 Million Years.nicky Whiffin, a Geneticist at the University of Oxford Who Was Not Involved in the Project , said that clinical geneticists struggle to find disease-causing mutations outside of protein-coding genes. Dr. Whiffin said the Zoonomia Project could guide geneticists to unexplored regions of the genome with health relevance. “That could massively narrow down the number of variants you ‘re looking at,” she said. Uniquely Human The DNA that governs our essential biology has changed remarkably little over the past 100 million years. But of course, we are not identical to kangaroo rats or blue whales. The Zoonomia Project is allowing researchers to pinpoint mutations in the human genome that help make us unique. Dr. Pollard is focused on thousands of stretches of DNA that have not changed over that period of time — except in our own species. Intriguingly, many of these pieces of fast-evolving DNA are active in the developing human brain. Based on the new data, Dr. Pollard and her colleagues think they now understand how our species broke with 100 million years of tradition. In many cases, the first step was a mutation that accidentally created an extra copy of a long stretch of DNA. By making our DNA longer, this mutation changed the way it folded. As our DNA refolded, a genetic switch that once controlled a nearby gene no longer made contact with it. Instead, it now made contact with a new one. The switch eventually gained mutations allowing it to control its new neighbor. Dr. Pollard’s research suggests that some of these shifts helped human brain cells grow for a longer period of time during childhood — a crucial step in the evolution of our large , powerful brains. Dr. Reilly, of Yale, has found other mutations that might have also helped our species build a more powerful brain: those that accidentally snip out pieces of DNA. Scanning the Zoonomia genomes, Dr. Reilly and his colleagues looked for DNA that survived in species after species — but were then deleted in humans. They found 10,000 of these deletions. Most were just a few bases long, but some of them had profound effects on our species. One of the most striking deletions altered an off switch in the human genome. It is near a gene called LOXL2, which is active in the developing brain. Our ancestors lost just one base of DNA from the switch. That tiny change turned the off switch into an on switch. Dr. Reilly and his researchers ran experiments to see how the human version of LOXL2 behaved in neurons compared with the standard mammalian version. Their experiments suggest that LOXL2 stays active in children longer than it does in young apes. LOXL2 is known to keep neurons s in a state where they can keep growing and sprouting branches. So staying switched on longer in childhood could allow our brains to grow more than ape brains. “It changes our idea of how evolution can work” Dr. Reilly said. “Breaking stuff in your genome can lead to new functions.”The Zoonomia Project team has plans to add more mammalian genomes to their comparative database. Zhiping Weng, a computational biologist at UMass Chan Medical School in Worcester, is particularly eager to look at 250 additional species of primates. Her own Zoonomia research suggests that virus-like pieces of DNA multiplied in the genomes of our monkey-like ancestors, inserting new copies of themselves and rewiring our on-off switches in the process. Comparing more primate genomes will let Dr. Weng get a clearer picture of how Those changes may have rewired our genome. “I’m still very obsessed with being a human,” she said.