AMHERST, Mass. – Since the 1970s, evolutionary biologist researchers have hypothesized that the reason humans and chimpanzees are so dramatically different from each other, despite the fact that the two genomes are about 98 percent the same, is because human and chimpanzee genes are regulated differently, says evolutionary genomicist Courtney Babbitt at the University of Massachusetts Amherst. But until now research tools were not powerful enough to test this idea.
Now Babbitt has a three-year, $330,000 grant from the National Science Foundation to use new state-of-the-art computational, evolutionary and experimental methods to examine how natural selection has shaped gene expression in the human brain.
Two technologies in particular, a high through-put screening technique called the massively parallel reporter assay (MPRA) and induced pluripotent stem cells (iPSC), have become available only within the past two years to support such comparative studies, she notes.
Babbitt and colleagues will test the hypothesis that there are functional links between adaptation in the genome and changes in neural types that occurred during human evolution. To understand the functional consequences of mutations particular to human regulatory regions, they will measure changes in gene expression associated with particular gene regulatory sequences.
As she explains, “This question has been a huge mystery. Our species diverged over 6 million years ago, and it led to enormous changes, perhaps the biggest is the differences in brains. We’ve been trying to figure out how and why this is so for a long time. This study is starting to get at that very big biological change.”
Babbitt adds, “Genomic studies can tell us much more than ever before about human evolution.” Specifically, “regions of the genome that turn genes on and off, called promoters or enhancers, are critically important in understating the evolution of the human brain. This research will assay regions of the genome showing evidence for adaptations that were important in human evolutionary history, using massively parallel experiments.”
For this study, the evolutionary genomicist and colleagues will grow human and chimp neurons from iPSCs in separate dishes and count gene activity and which genes are active in each species in progenitor cells and mature cells, as well as which genes are being transcribed through RNA sequencing. They can then insert a snip of “regulatory region” into the neuron soup and vary 10,000 different pieces of the genome in a single experiment to observe what things have changed function over time.
“This used to be done one gene at a time,” Babbitt points out, “but now with an expression counter we can get thousands and thousands of answers, observe thousands of differences about groups of genes in one experiment to figure out what they regulate. This is going to give us a large-scale view of what’s important.”
“We can take the known human and chimp genomes and look for regions that have lots of changes in the human in one area in the same area it may be just one change in the chimp. The differences are a lot more than we’d expect by chance and they give us a clue as to what may be an adaptive change. The brain region will give us an idea of what is being regulated.” Babbitt adds.
In nature, she says, “adaptation is expressed as a big beak for a bird that eats seeds. At the DNA level, it looks like a lot of changes over evolutionary time. We will be trying to find functional links between adaptation across the genome and changes in neural cells.”
Babbitt’s genomics laboratory is part of UMass Amherst’s Institute of Applied Life Sciences, where she collaborates with other researchers in its Models to Medicine Center translating fundamental biology into new disease models, treatment approaches and personalized medicine.
Babbitt and colleagues plan to publish catalogs of neuronal differences they observe between chimpanzee and human brains. Their data will show if these regions are functional and what role they played in driving the differences in neural differentiation between humans and non-human primates. For example, the regulatory region that controls genes related to metabolism may turn out to have a major role in the difference between human and chimpanzee brains, because human brains are about twice as metabolically active than a chimpanzee brain.
In addition, as part of this study Babbitt and colleagues plan outreach to local elementary schools through a partnership with the annual summer Eureka! Program for STEM retention of women at UMass Amherst.