Differences in On/Off Switches Help Explain How the Human Brain Evolved
• Science Update
The evolution of human brain function may be more dependent on mechanisms that turn genes on and off, rather than on changes in DNA sequences. A recent NIMH-funded study identified small regions of the genome that are uniquely regulated in human neurons, but not in primate neurons. The findings provide insight into human intellectual function and risk for human diseases, including autism and Alzheimer’s disease.
Dr. Schahram Akbarian at the Mount Sinai School of Medicine and the University of Massachusetts and colleagues published these findings in the November 20 issue of PLoS Biology.
DNA associates with histone proteins to form chromatin
Source: Richard Wheeler (Zephyris) 2005
Primate genomes are made up of billions of base pairs - the basic building blocks of DNA - making examinations of what makes humans unique a difficult task. Previous studies have shown that there are more than 40 million differences between humans and chimpanzees when comparing base pairs. Many of these differences in DNA appear to reflect random ‘genetic drift’ throughout evolution. As such, the challenge was to identify changes that have functionally important consequences, which may improve our understanding of the genomic basis of the emergence of human-specific neuronal function.
Akbarian and colleagues examined the way that DNA strands of the genome are wrapped in protein - the chromatin structure - which can determine whether a gene is turned on or off. Looking at chromatin structures taken from the frontal cortex - a brain area involved in cognitive function - allowed these researchers to examine the chemical signals that alter how DNA is wrapped, thus turning genes on or off.
Results of the Study
Comparing neurons from human children and adults to neurons from chimpanzees and other monkeys, these researchers identified hundreds of regions throughout the genome which showed a markedly different chromatin structure in humans. For example, a finding distinct in humans was that some of these regulatory chromatin structures appear to physically interact in the cell nucleus, despite being located far apart if the DNA were laid out flat like a string. This “chromosomal looping” suggests involvement in the control of other nearby genes, including several with important roles in human brain development.
These “epigenetic” studies - which involve looking at heritable changes that occur without a change in the DNA sequence - can help us to learn more about human biology and human disease than simple genome sequencing, which revealed more than 40 million base pair differences comparing humans to chimpanzees. The current studies identified small regions of the human genome that are uniquely regulated, many in brain areas involved in cognitive function, thus distinguishing us from other primates. The current findings provide interesting new leads into how the human brain has evolved, and a starting point for studying psychiatric diseases. The finding that some of the genomic regions with human-specific epigenetic regulation physically interact with each other via chromosomal loopings, despite being separated by many hundreds of thousands of base pairs if the DNA were laid out flat, speaks to the importance of the 3-dimensional organization of the genome in our brain cells. The "genome in 3-D" is presently one of the most exciting frontiers in human brain research.
Shulha HP, Crisci JL, Reshetov D, Tushir JS, Cheung I, Bharadwaj R, Chou HJ, Houston IB, Peter CJ, Mitchell AC, Yao WD, Myers RH, Chen JF, Preuss TM, Rogaev EI, Jensen JD, Weng Z, Akbarian S. 2012. Human-specific histone methylation signatures at transcription start sites in prefrontal neurons. PLoS Biology, 10(11): e1001427.