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Gene Expression Study Reveals Transcription Network Differences in Human, Chimp Brains

NEW YORK (GenomeWeb News) – Widespread gene expression differences in human and chimpanzee brains can be largely traced back to differences in fewer than 100 transcription factors, according to a paper scheduled to appear online this week in the Proceedings of the National Academy of Sciences.

Researchers from the University of Illinois at Urbana-Champaign and the Norwegian University of Science and Technology used a new analytical approach to re-assess expression data for five human and chimpanzee tissues. In so doing, they found 90 transcription factors that are differentially expressed in the brains of humans compared with chimpanzees — apparently working in concert to regulate a host of genes in the brain.

"Our results suggest that concerted changes in a relatively small number of interacting [transcription factors] may coordinate major gene expression differences in human and chimpanzee brain," senior author Lisa Stubbs, a cell and developmental biology researcher at the University of Illinois, and her co-authors wrote.

Although evolutionarily related, human and chimpanzees have obvious differences in appearance, physiology, and cognitive skills. But with genomes that are roughly 97 percent similar, pinning down the genetic sources of these differences has not been trivial.

Past studies have found disparities in brain size and metabolic activity between humans and chimps — along with differences in gene expression in the brain.

Stubbs and her colleagues speculated that transcription factors sequence and expression levels might also contribute to the observed differences between the species.

To test this, the team re-assessed published gene expression data for five tissues — brain, heart, kidney, liver, and testis — from six men and five chimps. All of the data had been generated using Affymetrix HG U133 Plus 2.0 microarrays.

In an effort to mine more accurate gene expression information from the existing resources, Stubbs told GenomeWeb Daily News, the team weeded out probes that interacted with more than one gene — a situation that can occur for recently duplicated genes and genes belonging to the same family.

The researchers obtained very different expression profiles for the tissues once they had developed a computational method to mask out these cross-reacting probes, she added.

"We really changed the pattern of expression you would assign to a gene by doing this," Stubbs said. "It just sharpened our ability to detect transcription factor — and other gene expression patterns — more accurately."

The team identified 90 transcription factors whose expression differed between human and chimpanzee brain tissues. More than a third of these belonged to a large family of transcription factors called the KRAB-zinc finger family.

Based on such findings, the researchers suspect that these KRAB-ZNF transcription factors have played a key role in the processes that led to distinct human and chimp species.

Next, the team wanted to explore how changes in transcription factor expression affected the regulation of other genes. To do this, they developed a network integrating transcription factor and other gene data from human brain tissue samples.

The network revealed extensive overlap between transcription factors and the genes they regulated, Stubbs said, with transcription factors apparently acting within interconnected modules, some amplifying the expression of certain genes and others curbing their expression.

Although they found that the chimpanzee brain network was similar to the human network, the team noted that transcription factors appear to be more highly interconnected in the human brain than in chimps. In addition, some transcription factors had distinct integration patterns in each brain network.

"Once this network of transcription factors is established, changes in the network can be amplified because transcription factors control other genes," lead author Katja Nowick, a post-doctoral researcher in Stubbs' lab, said in a statement. "Even a small change in transcription factor expression can therefore produce a large effect on overall gene expression differences between chimpanzees and humans."

Since many KRAB-ZNFs and other primate genes appear to have arisen through duplication, Stubbs explained, it's likely that the masking method used for the current analysis missed some genes. Even so, the team is confident in the overall network they have identified so far.

In the future, Stubbs said, she and her team are interested in exploring recent duplications and their role in evolution in general. For her part, Nowick plans to continue looking more specifically at recent primate history, testing the expression network experimentally by targeting specific genes within the network.

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