Just as evolving to walk upright freed up our hands to use tools but also gave us bad backs and knees, the rapid expansion of our brain size and cognitive abilities may have increased our susceptibility to some psychiatric diseases. In a new study, researchers looked at a DNA sequence inside a key gene controlling neural activity. They found an unusually lengthy array that likely contributed to changes in the gene’s function during human evolution, and may have increased neuropsychiatric disease risk in modern humans.
We spoke to the study’s senior author, David Kingsley of Stanford University, about the work.
David Kingsley: We have long been interested in the DNA changes that underlie important traits in humans and other animals. We previously characterized all the places in the genome where humans are missing sequences that are highly conserved in other animals. The current study began when we decided to look for the reverse: DNA sequences that are present in humans but not found in other animals.
Kingsley: We found that humans have a large and previously unrecognized DNA repeat array located inside a key gene involved in neural functions. Our study shows this novel DNA array modulates gene expression and has different activities in people with different genetic susceptibilities to bipolar disorder and schizophrenia. We think this is a good example of a previously hidden structural DNA feature that may play an important role not only in human brain evolution, but also in human psychiatric disease.
Kingsley: Several studies suggest that the same genes that have led to rapid increase in cognitive abilities in humans may have also increased our susceptibility to psychiatric disease. This may seem paradoxical, but it clearly applies to other systems in the body. For example, humans are one of the few mammals that have evolved the ability to walk regularly on two legs. This new mode of locomotion frees up our hands for manipulating objects and using tools. However, our recent evolutionary transition to walking upright has also brought with it a high incidence of lower back and knee problems in humans. Similarly, rapid expansion of brain size and cognitive abilities in humans has been a key feature of our evolutionary success. But, the very genomic changes that underlie recent brain changes also may increase our susceptibility to some psychiatric diseases.
Our study provides a specific example of how this could happen by expanding a particular regulatory DNA sequence inside a key gene controlling neural activity. The same structural change that produces this genomic feature also generates a tandem array that is prone to further variation and may increase the risk of some common psychiatric diseases.
Kingsley: Now that we know about these sequences, we can begin to further model their effects in experimental systems. We are removing and inserting the sequences in human tissue culture cells and in mice to further characterize what the human arrays do to gene expression, neural activity, and behavior.
Kingsley: Duplicated regions like these tandem arrays are hard to recognize and assemble correctly. Each unit in a repeated region looks very similar to other units, so many of them can be misassembled or left out of the genome. In addition, repeated regions tend to be unstable in standard bacterial cloning systems.
For example, we found that this particular sequence shrinks in size by ten- to a hundred-fold if you try to grow it for a while in the lab. We have now found methods that overcome these problems, but similar issues may exist for other sequences in the genome.
Fifteen years after the initial sequencing of the human genome, we are still finding important pieces of our genomes that have been missed in previous studies. When searching for the possible genomic basis of human traits and diseases, researchers should consider a whole range of possibilities. The human reference genome is continually improving, but it is still a work in progress.