The things that separate chimpanzees from humans appear obvious on the surface. Humans are more graceful ice skaters, and we wear tuxedos with more panache than our closest primate relatives. We are, however, strikingly similar species on the level of our genes. The parts of our DNA that contain instructions for making proteins—the building blocks of our bodies—differ by less than 1 percent, but protein-coding genes are only a small part of our genomes. Some of the biggest differences between humans and chimps lie in the DNA that resides outside of genes.
About 10 years ago Katherine Pollard, a biostatistician at the University of California, San Francisco, compared the two species and identified the parts of the human genome that are unique. Now she is leading a research team that is uncovering how 716 of these human-specific DNA regions work together to create the biological traits that differentiate us from other primates.
Most of these 700 some pieces of DNA lay outside of our genes, and Pollard’s latest study partially solves the mystery of their function. By adapting new techniques from biotechnology, the U.C.S.F. scientists were able to engineer thousands of human and chimpanzee brain cells and test how these 716 “human accelerated regions” (HARs) affected the development of cells from both species. In the process her team has uncovered possible new targets for the treatment of autism, schizophrenia and other neuropsychiatric disorders. The study, which has not yet been peer-reviewed, was posted to the preprint server bioRxiv on January 30.
Since Pollard first published her research on HARs in 2006, deciphering their biological function has been slow going. At that time the only option for studying HARs was to painstakingly splice a single HAR into the DNA of a fertilized mouse egg and observe its effect on the mouse once the animal reached maturity. To make a comprehensive study of the way all of the HARs affect human biology, she needed a much faster way to study them.
A few years ago Pollard began working with Nadav Ahituv, a geneticist who runs a separate lab at U.C.S.F., to create a method for converting human and chimpanzee skin cells into pluripotent stem cells, which have the potential to become nearly any other cell type. The team could have chosen to coax them into liver, heart or bone cells, but for their first study of HARs the obvious choice was the cells that affect our species’s most distinctive trait—intelligence. Pollard and Ahituv created thousands of neurons at a time and spliced the HAR DNA into those cells. Then they examined what the HARs did at two different points in the cells’ development.
They found almost half of these pieces of DNA—which do not appear naturally in the chimpanzee genome—were active in the growing neurons. But the HARs were not producing proteins; they were in the part of the genome scientists once referred to as “junk DNA,” and they were controlling the amount of proteins produced by the neurons’ genes. The result surprised Ahituv: “This is the first comprehensive study of all these sequences, and it shows that 43 percent of them…could have a functional role in neural development.”
According to Pollard, the parts of the chimpanzee genome that are analogous to the HARs have not changed at all in millions of years, and they are nearly identical to the same regions in most animals. Pollard says natural selection was acting to keep these parts of these animals’ genomes from changing, but something must have happened to relieve that evolutionary pressure from humans after our ancestors split from chimps about six million years ago. “Most of [the HARs] have so many changes in them that not only did they acquire random mutations, but…the individuals carrying those changes produced more offspring,” Pollard says. What happened to cause this is an open question. The fact that so many HARs are involved in neuronal development suggests the change may have had something to do with the evolution of intelligence, a vastly complicated trait that is the product of hundreds of mutations in our genomes.
These changes, however, came with some severe downsides. “A lot of these HARs lie near genes that are associated with human-specific disease like autism, schizophrenia and so forth,” Ahituv says. This result suggests these diseases are not caused by brain-development genes themselves but by the way HARs regulate them. Part of Pollard and Ahituv’s research focused on deciphering how each individual mutation within seven different HARs altered a gene’s activity. The team found the individual mutations would increase or decrease the amount of protein a gene was producing. Essentially, natural selection was fine-tuning how the genes were expressed because too much or too little of a specific protein can cause problems. In autism, Pollard explains, “lots of mutations in different parts of the genome are coming together and all making small changes that together put an individual over a threshold where we would say they have autism.” She adds: “The rest of us have some of those mutations and are just below that threshold.”
The experimental approach Pollard and Ahituv used in this study may be able to show medical researchers what parts of the genome to target for new therapies. Maria Chahrour, an autism researcher at The University of Texas Southwestern Medical Center who was not part of the work, has been facing this problem as she tries to understand how autism manifests itself in the genome. “We are doing a lot of whole genome sequencing that will identify a lot of variants in noncoding regions of the genome,” she says. “Now when we find disease variants in these HAR regions we are not going to dismiss them.”
Pollard and Ahituv have received funding from the National Institutes of Health to study the contribution of HARs to brain evolution and their role in disease. They will also be examining how these bits of the genome are involved in the development of sperm and other types of cells. The ability to examine noncoding regions of genomes in thousands of cells at the same time could provide a powerful way to tackle a variety of questions about the genomes of humans as well as other organisms. It may also be the next-best thing to a time machine for learning about the genetic changes that led to the evolution of the modern human species. “We’ll never see what happened in the past in evolutionary time,” Pollard says, “but we were able re-create [this past] in the lab and measure its function.”