What makes humans unique are 10,000 missing bits of DNA

Comparative genomic studies of 240 species shed light on the origin and evolution of mammals, and the special attributes of people

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A girl and a gorilla at the San Francisco Zoo.GENNA MARTIN (Hearst Newspapers/Getty Images)

Humans are missing 10,032 pieces of DNA in certain genome regions that are present in every other mammal, including our close hominid relatives. This genetic information must have disappeared in the evolution of the species. The scientists who have studied these missing elements say their function is related to neurological system regulation and cognition. This is one of the many conclusions of an ambitious international project that conducted a comparative analysis of the genomes of 240 species of placental mammals, from shrews to whales to humans.

Each living being has its own self-replicating and hereditary DNA, which serves as an instruction manual for creating molecules such as proteins in the organism. Each species has its own manual. The Zoonomia Project, an international collaboration to discover the genomic basis of shared and specialized traits in mammals, began more than a decade ago, but made a grand entrance on April 27 in a special issue of Science. Zoonomia presented 11 parallel studies comparing the genomes of 240 species of placental mammals using different scientific approaches. They looked for continuities and differences, and things like what makes bears hibernate, why naked mole rats don’t get cancer, and why whales live so long. Zoonomia also wanted to know what makes the human genome unique.

A study led by scientists from the Broad Institute and Yale University in the United States looked at what are called highly conserved genes – those that can be found in almost every organism. They discovered that humans have 10,032 DNA deletions that are present in every mammal species, even other hominids. The vast majority of the deletions are very short sequences of a few base pairs (the four bases of DNA are adenine, cytosine, guanine and thymine) with unknown functions.

Steven Reilly, a genetics professor at Yale University (USA) and a co-author of this study, told us that “deletions are especially enriched to function in the brain.” Although much of the missing genetic material pertains to genes with neuronal and cognitive functions, some “pertains to metabolic tissues, such as fat cells and the liver, as well as digestive tissues,” said Reilly. The paper reveals that many of the small, deleted pieces of DNA were in regulatory elements that enrich certain genes and switch them on and off.

“When thinking about innovative functions of new phenotypic abilities in humans, many scientists, including us, believe that our DNA encodes new instructions with new genes. Surprisingly, we found that deletions can also generate something new,” said Reilly. “The theory is that evolution is tinkering with the fundamental building blocks and instructions shared by all mammals to give us our unique traits.” Reilly says it was humbling to discover that the huge phenotypic difference between humans and chimpanzees is because of a few minor changes. “Deletion of just one or two DNA bases could suppress a repressor sequence, leading to increased gene expression, or deletion of a base that doesn’t fit well in an activator [gene], and leading to enhanced gene expression. Surprisingly, we see this 30% of the time, where a deletion increases gene activity rather than suppressing it.”

Some human traits we value highly are a consequence of a molecular deletion
Irene Gallego, evolutionary biologist, University of Melbourne, Australia

Irene Gallego, an evolutionary biologist with the University of Melbourne (Australia), also focused on the Broad Institute study, one of 11 Zoonomia Project papers published in the special issue of Science. “We tend to think of evolution as a linear process toward a specific end, as if humans were the most important evolutionary milestone,” said Gallego. “But knowing that mutations and deletions both contribute to the phenotypes that characterize the human species adds a measure of humility to how we view ourselves – some human traits we value highly are a consequence of a molecular deletion!” Another Zoonomia Project study found that both deletions and mutations in the highly conserved regions of the human genome can lead to new functions, which “highlights the complexity and plasticity of the genome and its regulation,” said Gallegos.

Arcadi Navarro, a genetics professor with Pompeu Fabra University in Barcelona, is one of several Spanish scientists involved in the mammoth Zoonomia Project. He said the work would have been impossible “without the decoded genomes of so many mammalian species,” as well as new genetic sequencing, computing and artificial intelligence technologies. Navarro highlighted the significance of aligning the genomes of 240 mammalian species. “It’s like comparing different versions of the same text. Some genes have moved throughout evolution and others have changed function... the job was to match different stories written over millions of years,” he said.

Does this mean that the work is finished? Not at all – 240 species only represent 4% of all mammals, and then there are fish, reptiles, amphibians, birds, plants, microorganisms, etc. The Zoonomia Project’s work needs to be studied in more depth and has been made available to other scientists. “This research doesn’t end here. In fact, it starts now,” said Navarro.

The triumph of the mammals

The genome of the endangered sea otter has now been fully decoded.
The genome of the endangered sea otter has now been fully decoded.Marcos Amend/ Zoonomia Project

About 180 million years ago, the first mammals appeared on Earth. For many, many years, they were insignificant, dwarfed by the giant pterosaurs and dinosaurs that roamed the planet. Millions of years of evolution produced the 6,500 mammal species in our world today and many more that have become extinct. 
Two great cataclysms helped mammals triumph over other living beings. First, the breakup of Pangaea – the enormous "supercontinent" land mass – 100 million years ago. The formation of separate continents isolated populations that began to diversify and occupy new niches. But the final push came from a celestial body crashing to Earth about 66 million years ago. The aftermath wiped out non-avian dinosaurs and pterosaurs and also spurred a mammalian upsurge. Both events are marked in the mammalian genome. 
Despite all the variety we see in mammals, they all share anatomical structures like a four-chambered heart, lungs, skeleton and mammary glands. They also share fundamental processes: embryology, cell growth and division, and the synapses that transmit neurological chemicals through the body and brain. All this is recorded in highly conserved genetic regions. And if they change – something might be amiss. 
One goal of the Zoonomia Project is to broaden the focus of human and animal health care. The quest to cure human disease can no longer depend solely on comparative analyses of healthy and sick people. Nor is it enough to study laboratory animals like mice or monkeys. The causes and cures for many diseases may be found in the genomes of one of those 6,500 mammalian species. 

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