Evolutionary Fast-Track for Human Brains

More than 35 years ago, Allan Wilson and Mary-Claire King made an astonishing proposal. Maybe what separates humans and chimps is not just our genes. Maybe it’s also how our genes are expressed or regulated.

Research published in today’s issue of PLoS Biology builds on decades of intervening advances in evolution and genetics and take the question much further. The difference between humans and nonhuman primates in cognitive ability is explained in large part by differences in gene expression, especially during the critical periods when young brains are being formed.

Humans share many of their genes with other species, especially chimps. In fact, we share so many genes that it is hard to explain how we can be so different in terms of cognitive ability. If genes make all the difference, how can they explain the differences between chimp and human brains? And how can a mere six million years of human-chimp divergence give us enough time to accumulate enough genetic change?

The answer seems to lie in the relatively rapid evolution of differences in gene expression. In other words, while the genes themselves evolved slowly, the regulation of their expression evolved more rapidly. It’s not just the genes but their expression that’s important. It’s not just the evolution of genes but the evolution of gene expression that drives the rapid divergence between human and chimp brains.

This is especially true in the genes that control the development of the prefrontal cortex of the brain. In other words, there has been relatively rapid evolution in the genetic mechanisms that regulate genes directly responsible for the early-childhood neural development of the critically-important prefrontal cortex, which is involved in abstract thinking, planning, social intelligence, and working memory.

According to the article, “humans display a 3-5 times faster evolutionary rate in divergence in developmental patterns, compared to chimpanzees.” Most important, however, is the way this research identifies specific regulators that have evolved rapidly since human-chimp divergence. These regulators are “micro-RNAs,” some of which are specifically identified in the article, with the claim that “changes in the expression of a few key regulators may have been a major driving force behind rapid evolution of the human brain.”

According to the study’s senior author, Philipp Khaitovich, this finding suggests that "identifying the exact genetic changes that made us think and act like humans might be easier than we previously imagined." Kkaitovich was quoted in a press release issued by the journal, PLoS Biology.

The article is entitled "Micro-RNA-Driven Developmental Remodeling in the Brain Distinguishes Humans from Other Primates" and appears in the December 6 issue of PLoS Biology, where it is freely available to the public.

Archaic Interbreeding? So What?

Later this week, I will be speaking at the University of South Florida—Saint Petersburg in their lecture series, a Celebration of the Genome.” My topic is “Finding the Human in the Genome.”

I start with the obvious: Our knowledge of human biology is increasing rapidly, thanks in large part to the Human Genome Project. We can now compare the DNA of one human being with another and ask questions about similarities and differences. We can compare human DNA with the full genomes of chimps and other species.

Most interesting to me is that we can also compare the genome of anatomically modern humans with that of extinct forms of humanity, such as Neandertals or their recently discovered cousins, the Denisovans. What we have found is that in a real sense, they are not extinct at all because their DNA lives on in us.

That leads to something less obvious but more profound. The more we know about human biology, the less we know about human nature. Put another way, the more information we have, the less confident we are that we really know what we mean when we talk about “humanity.”

So what is going on here? Does it really bother anyone—besides me, that is, and perhaps only because I am, after all, a “theologian”? I am asking myself this question a lot these days. Does it really matter that our ancestors interbred with Neandertals and Denisovans and, as time will probably tell, many other forms of archaic humanity?

So what’s the big deal? In some ways I guess it’s like the high school student who runs a paternity test and learns that daddy isn’t daddy.

Or maybe it’s more like this. Years ago, I remember hearing Kári Stefánsson speaking to a roomful of scientists and introducing deCODE Genetics, the Iceland DNA database. He explained the reasons for the project, such as excellent health records, small genetic diversity, and superb genealogical records going back 1,000 years. We Icelanders need to sell more than fish, he said. We want to mine our DNA for all kinds of gene-disease information. Then Stefánsson mentioned that the information sometimes disproved the genealogies. Everyone laughed when he said: “We are not responsible for what our Viking ancestors did back then during the long Icelandic winters.”

Is that it? Is that all that’s happened here, just some forced revisions of the family tree? So what if my ancient ancestors were not exactly what I thought? It happened, after all, some 40,000-100,000 years ago. I am not responsible.

But I am affected. My biology is different from what I once thought. Perhaps I am healthier as a result of the ancient interbreeding, as at least one report has suggested.

More than that, I am coming to see human beings as biologically more diverse and more complicated that we once thought. The diversity part is a bit scary. We have not done well as a species in dealing with our differences.

The complexity part—that’s more of a mystery than a fear. I don’t claim to hear the voices of my Neandertal ancestors calling out from my DNA or reverberating through my metabolic processes. At least not yet.

Evolution and the Human Brain

How did the human brain become so complex so quickly? Did old genes learn new tricks? Or did new genes appear, bringing new functions?

A paper appearing today in PLoS Biology suggests that new genes play a bigger role than previously thought in explaining the complex functions of the human brain. Researchers at the University of Chicago Department of Ecology and Evolution reached this conclusion by comparing the age of genes with transcription data from humans and mice. Where are new genes most often expressed? In humans, it’s in the brain. Even more interestingly, it’s in the developing brain of the fetus and the infant.

One of the researchers, Yong E. Zhang, was motivated to ask these questions because he accompanied his pregnant wife to prenatal ultrasound appointment, according to a press release issued by the University of Chicago Medical Center. According to Zhang, “Newer genes are found in newer parts of the human brain.” The press release also quotes co-author Patrick Long: “What’s really surprising is that the evolutionary newest genes on the block act early….The primate-specific genes act before birth, even when a human embryo doesn’t look very different from a mouse embryo. But the actual differences are laid out early,” Long explained.

In the language of the PLoS Biology paper, the authors “observed an unexpected accelerated origination of new genes which are upregulated in the early developmental stages (fetal and infant) of human brains relative to mouse.” In other words, compared to all the genes in the human genome, younger genes are significantly more involved in those parts of the brain that make us distinctly human. More than that, these genes play a greater than expected role in prenatal and infant development, the very period in which the brains of humans develop so rapidly compared to the brains of other species.

How did these new genes arise? By all the various means by which new genes arise—by various processes of duplication and by de novo origination. Rather remarkably, the authors make this observation: “…young genes created by all major gene origination mechanisms tend to be upregulated in [the] fetal brain. Such generality suggests that a systematic force instead of a mutational bias associate with a specific origination mechanism contributed to the excess of young genes in the fetal brain.”

What “systematic force”? Clearly, the authors are not speculating about anything more than a statistical correlation. But their work will give rise to new questions for research. What role do these young genes actually play in the developing brain? What role did natural selection play in the evolution of these genes? Does this surprising correlation shed any light at all on our rapid rise as a species and the stunning complexity of the human brain?

The paper, "Accelerated Recruitment of New Brain Development Genes into the Human Genome," is published in the October 18 issue of PLoS Biology [10.1371/journal.pbio.1001179].

Still wondering..."What Defines Us?"

Last February the editors of Science marked the 10th anniversary of the publication of the complete human genome. They invited a dozen or so people to contribute short reflections on the meaning of this milestone.

I was given 250 words for my article, entitled “What Defines Us?” In that small space I tried to suggest two things. First I noted a simple irony: As we gain more scientific information about our genome and our evolution, the philosophical and religious concepts of humanity become blurred or defocused. Second, I suggested that this defocusing need not be a cause for discomfort. Precisely because we are humans—whatever exactly that means anymore—we switch almost immediately from discomfort to wonder and excitement. The quick switch is what makes us human. I ended by asking: “Who are we, and where will we go next?”

It is as if we are making ourselves up as we go along. Recent discoveries in human evolution intimate just such a view. Anatomically modern humans are now believed to have interbred with Neandertals and with the more recently discovered Denisovans. Many of us carry the DNA of these extinct forms of humanity in our own genome. In that sense they are not distinct at all but live on in every cell of our bodies. More recently, it has been suggested that similar interbreeding occurred in sub-Saharan Africa.

Interestingly, it has also been suggested that interbreeding enhanced us. In August, a research article in Science suggested that our immune systems are more resilient than they might have been. Why? Because our ancestors interbred with Neandertals and Denisovans.

The evolutionary tree of humanity is beginning to look less like a tree and more like a tangled vine. And now we are led to wonder whether it is the tangle that enhances us. What makes us less clearly Homo sapiens seems, paradoxically, to make us more extraordinary as a species. Well…we’re running far ahead of the science here, but (as I suggested in Science), wondering is what makes us human. It’s not just the DNA; it’s what we dare to do with it.

I have been thinking about this recently because I will be speaking on November 10 on this very topic at the University of South Florida Saint Petersburg. They have planned an exciting lecture series, Festival of the Genome: Celebrating the 10th Anniversary of the Sequencing of the Human Genome, showcasing various perspectives on human genome research.