Starting in 2006, comparative genomic studies have identified small regions of the human genome known as Human Accelerated Regions, or HARs, that diverged relatively rapidly from those of chimpanzees — our closest living relatives — during human evolution.
Our genomes contain about 2,700 HAR sequences. And as reported today in Cell, these sequences are often active in the brain and contain a variety of mutations implicated in autism and other neurodevelopmental disorders.
“Since human intellectual and social behavior are so different from other species, many labs have figured that changes in HARs might be important in the evolution of these traits in humans,” says Christopher Walsh, MD, PhD, a neurogeneticist and chief of the Division of Genetics and Genomics at Boston Children’s Hospital. “We hypothesized that if important HARs were damaged, it might also cause defective human social and/or cognitive behavior. And we found that this is indeed the case.”
Altered gene regulators in the brain
Walsh, first author Ryan Doan, PhD, and colleagues undertook the most comprehensive genomic analysis of HARs to date. Their findings open a fascinating window on both cognitive/behavioral disorders and the still-mysterious genetic changes that made human language, culture and civilization possible.
The team used multiple genetic techniques to examine HARs and patterns of mutations within HARs in diverse, healthy human populations, using existing databases. They also looked at HARs in two populations of children with autism spectrum disorder (ASD). Additionally, they looked for evidence of HAR activity in the brain.
The team surveyed HARs not just for protein-coding genes, but also for noncoding DNA sequences, areas that don’t code for proteins but instead regulate gene activity. They then tried to identify what genes these sequences regulate.
“No one had actually looked at HARS as a collective set,” says Doan.
The findings were intriguing.
“We found that most HAR regions contain enhancer or regulatory DNA,” says Doan. “More than 40 percent of those HARs had some sort of regulatory activity in the brain, much more than we would expect by chance.”
In all, the investigators identified about two dozen mutations in HARs that appear to have important roles in brain structure and function. Some HARs, for example, contained regions regulating neurodevelopmental processes that have diverged between humans and chimpanzees, such as synapse development.
Autism and human brain evolution
When the researchers looked at genomic sequence data from 2,100 American children with ASD, they found that they were 6.5 times more likely than their healthy siblings to harbor a de novo (non-inherited) duplication or deletion of a HAR. In all, they estimate that these HAR mutations contributed to 1-2 percent of the ASD cases, by giving children too much or too little of a gene or regulator.
This work brings together the study of evolution and the study of neurological disease.
The team also looked at children with ASD from 218 Middle Eastern families in which the parents were related (usually first cousins), increasing the likelihood of recessive disorders. The children with ASD had a 43 percent excess of recessive mutations in HARs when compared with unaffected children. Overall, the researchers estimate that about 5 percent of these children had recessive mutations in HARS that were related to brain function and likely to be disease-causing.
“The evidence for recessive mutations in HARs was greatest for those HARS that are active in the brain,” says Doan. “This suggests that HARS that are active in brain development are the ones that are contributing to autism.”
Many of the HAR mutations linked to ASD affect noncoding DNA sequences — especially gene enhancers. Here’s a selected list:
Walsh sees hope in finding so many mutations in regulatory sequences. It suggests that ASD can result from disordered levels or patterns of gene expression in the brain that might be amenable to intervention.
“We know from animal models that intensive environmental stimulation can increase gene expression, and that intensive training is often helpful for children on the autism spectrum,” he says. “Non-coding sequences control levels of gene expression, which suggests that a lot of the gene is still good — if there were just a way to turn it on.”
But the evolutionary implications of the study are what most fascinate Walsh and his colleagues.
“This work brings together the study of evolution and the study of neurological disease,” says Walsh. “Studying the kinds of mutations in HARs that cause neurodevelopmental disorders like ASD may tell us about the sorts of changes that led to us having a different brain than other animals. Chimps are social creatures, but they’re different from humans. They don’t live in compact cities of a million people. That requires extraordinary social behavior.”
The study was supported by the Paul G. Allen Family Foundation, the National Institutes of Health (T32 NS007484-14; NINDS 1 R21 NS091865-01; NIMH RC2MH089952 and RO1MH083565; NCRR 1S10RR028832-01), a Nancy Lurie Marks Postdoctoral Fellowship and the Howard Hughes Medical Institute.