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Gene Duplications Associated with Autism Evolved Recently in Human History

Human geneticists have discovered that a region of the genome associated with autism contains genetic variation that evolved in the last 183,000 years, after the divergence of humans from ancient hominids, and likely plays an important role in autism and other diseases. The findings were presented on Saturday evening, October 18, at the opening of the American Society of Human Genetics (ASHG) 2014 Annual Meeting in San Diego, California. Researchers at the University of Washington analyzed the genomes of 2,551 humans, 86 great apes, one Neanderthal, and one Denisovan. The scientists closely examined a region of human chromosome 16 known as 16p11.2, where recurrent deletions and duplications that are major contributors to autism, and also associated with schizophrenia and extremes of body mass and head circumference, occur. Approximately 1% of individuals with simplex autism have deletions or duplication at 16p11.2. These events occur via nonallelic homologous recombination between directly oriented segmental duplications approximately 600 kilobase pairs apart, the presenter, Xander Nuttle, B.S., B.S.E., the first author of the report said. The research team found that certain segments of DNA in this region are repeated a variable number of times in different people and may also be associated with disease. To trace the origins of this variation, the researchers collaborated with colleagues at the University of Lausanne in Switzerland and the University of Bari in Italy to sequence and analyze corresponding regions of ape genomes. Mr. Nuttle also noted that advances in DNA sequencing were particularly important in their research and that, specifically, sequencing technology from Pacific Biosciences allowed the team to obtain especially long reads that permitted them to sequence 200,000-base-pair fragments and obtain accurate sequence information for non-human genomes. This capability was key to the team’s ability to compare the non-human genomes with the human genome. “When we compared the genomes of apes and humans, we found that the humans had evolved complex structural changes at 16p11.2 associated with deletions and duplications that often result in autism. The findings suggest that these changes emerged relatively recently and are unique to humans,” explained Mr. Nuttle, a graduate student in the laboratory of Evan Eichler, Ph.D., Professor of Genome Sciences in the Department of Genome Sciences at the University of Washington School of Medicine, and also a Howard Hughes Medical Institute Investigator. Dr. Eichler was the senior author of this abstract. While this genetic variation has likely made humans more vulnerable to diseases, the scientists believe it also contributed to the formation of novel genes. One such gene is BOLA2, a gene whose function is not yet known, but which is thought to possibly be important in cell proliferation and/or cell cycle regulation. The researchers found that while apes, Neanderthals, and Denisovans had only two copies of BOLA2, all modern humans have between 3 and 14 copies of this gene, with an average of 6 copies, and 98% of humans having 4 or more. This increase in the number of BOLA2 copies occurred in modern humans after their divergence from ancient hominins (Neanderthals and Denisovans) 700,000 years ago and the gene duplication became nearly fixed in the human population in a relatively scant 100,000 years. This makes BOLA2, by far, the most rapidly near-fixed duplicated gene in human evolution, with the previous most rapidly fixed human-specific gene duplication being SRGAP2C, a gene that originated approximately 2.4 million years ago. The research team is currently investigating the function of BOLA2 to understand the potential significance of additional copies for human evolution. “Another question we are exploring is why people with the same duplications and deletions at 16p11.2 vary in disease severity,” Mr. Nuttle said. “Some people are healthy or have mild illness, while others are severely affected and have multiple clinical diagnoses.” One hypothesis is that differences among people in how the region is organized, such as the number of copies of genes like BOLA2 present and the precise locations at which deletions and duplications start and end, contribute to this variability. To examine this possibility, Mr. Nuttle and colleagues are analyzing DNA and medical data from over 125 individuals with deletions or duplications at 16p11.2. “We believe this work will lead to new insights about the genetic underpinnings of autism and other conditions associated with 16p11.2 deletions and duplications, potentially paving the way for more specific diagnostics and treatments for patients in the future,” Mr. Nuttle said. The BOLA2 gene name is derived from the BOLA-like family of proteins initially found in bacteria.