What Makes a Man a Man?

468px-ham_the_chimpOne goal of the Human Genome Project was an elemental question: what makes humans different? It’s a mistake to think of mankind as the culmination of evolution, but the fact remains that we are the only species on Earth capable of a feat such as, say, sequencing genomes. So what separates humans from our closest relatives in the primate lineage? Do genetic differences hold the answer?

That idea was shaken by a couple of genetic discoveries. First to fall was the simplistic assumption that humans might be more complex because we have more active genes – the roughly 25,000 genes found active in humans is not appreciably more than either our close primate relatives or more distant cousins such as mice, flies, and worms. When the human genome is placed alongside our closest relatives the chimpanzee, the similarities are even more pronounced; as often mentioned, 98.8% of the human and chimp genomes are identical, leaving only a small number of DNA changes to explain why humans hang out in shopping malls instead of trees.

But in the world of genes, tiny changes can produce massive differences, depending on where those changes occur. In the end, the difference between humans and other species may not be so much the genes themselves, but how those genes are used. Changes in regulatory segments of the DNA – the switches that turn gene expression on and off – can have dramatic effects on how much of each gene product or protein is produced. And alternative splicing, the post-expression modification of gene products, can also magnify small genotypic differences into large phenotypic differences.

To track down these important needles in the genetic haystack, new methods are necessary. In a paper published last month in Genome Research, a group from the laboratory of Yoav Gilad at the University of Chicago applied a new approach to examine what may be different on a genetic level between humans, chimpanzees and rhesus monkeys, essentially looking at the final protein stew instead of the DNA recipe.

“Many recent studies have shown that differences in gene regulation can be functional and may be the source for some of the phenotypic differences that we see between individuals and species,” said Ran Blekhman, graduate student in department of human genetics and lead author of the study. “Examining differences in gene expression in primates could give us hints towards the genetic sources for some of the differences between humans and their close relatives.”

Blekhman and colleagues John Marioni, Paul Zumbo and Matthew Stephens searched for these differences by looking not at DNA but RNA – the temporary intermediate between an active gene and the protein it specifies. By looking at RNA, the researchers could look past hard-coded genetic differences to how often those genes are turned on across the three species and the ways that alternative splicing creates unique variants of those genes.

A microarray traditionally used to assess gene expression.

A microarray traditionally used to assess gene expression.

Others have previously looked at gene expression using microarrays – chips that can compare thousands of RNA types at once. But the construction of a microarray that can comprehensively compare gene expression across different species is a difficult task. So Blekhman and his collaborators used RNA sequencing methods, looking at all of the RNA present in liver tissue samples from humans, chimps and rhesus monkeys for a more direct and complete comparison.

The group found about 13,000 genes expressed in each of the three species; another clue to the remarkable genetic similarities between humans and other primates. But of those 13,000, about 900 genes were expressed differently in humans, compared to similar expression in chimps and rhesus monkeys. Many of these genes were related to transcriptional regulation – the control of other genes – reinforcing the view that a small change in one of those genes can ripple out to large differences in how very similar DNA is utilized in humans vs. other primates. The other major group of genes seen to be expressed differently in humans had less to do with complex genetic principles than with…lunch.

“Changes in genes involved in metabolism are also interesting considering one of the major differences between us and other primates – our diet,” Blekhman said. “Humans have a very different diet, and unlike other primates, eat cooked food, and consume milk products as adults.”

Blekhman and co. also examined the alternative splicing of genes across the three species – genes that may look the same at the DNA level, but which are cut, shuffled and processed differently through their RNA and protein forms. As one would expect for three closely related species, the researchers found many genes were spliced the same way in humans and the other two primates. But human-specific splice forms were also found, Blekhman said, with many intriguingly occurring in genes related to anatomy and development that could account for why humans look so different from their forest-dwelling ancestors. 

“These results suggest that alternative splicing is important in the context of differences between species…supporting the hypothesis that alternative splicing could be a very important mechanism in recent human evolution,” Blekhman said. 

Together, these results sketch out a more nuanced view of how life derives complexity from simplicity. Already wondrous is the fact that the four nucleotides of DNA can be endlessly reshuffled to create all the living things we find on Earth, from bacteria to plants to people. But through differences in gene expression and alternative splicing, nature can do that complexity one better, producing Ted Williams and Ed from genomes that are only 1% different. There’s almost definitely not a single trigger that split humans off from their primate ancestors. But a few simple changes, splices and the ensuing cascades of gene expression may have been all it took to produce an unusual species, one capable of studying its own origins.

About Rob Mitchum (526 Articles)

Rob Mitchum is communications manager at the Computation Institute, a joint initiative between The University of Chicago and Argonne National Laboratory.

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