Sunday, April 26, 2009

SciAM - What Makes Us Human?

A look of human and chimp genetics - there are some stretches of genetic material that our distinctly human.

What Makes Us Human?

Comparisons of the genomes of humans and chimpanzees are revealing those rare stretches of DNA that are ours alone

By Katherine S. Pollard

Key Concepts

  • Chimpanzees are the closest living relatives of humans and share nearly 99 percent of our DNA.
  • Efforts to identify those regions of the human genome that have changed the most since chimps and humans diverged from a common ancestor have helped pinpoint the DNA sequences that make us human.
  • The findings have also provided vital insights into how chimps and humans can differ so profoundly, despite having nearly identical DNA blueprints.

Six years ago I jumped at an opportunity to join the international team that was identifying the sequence of DNA bases, or “letters,” in the genome of the common chimpanzee (Pan troglodytes). As a biostatistician with a long-standing interest in human origins, I was eager to line up the human DNA sequence next to that of our closest living relative and take stock. A humbling truth emerged: our DNA blueprints are nearly 99 percent identical to theirs. That is, of the three billion letters that make up the human genome, only 15 million of them—less than 1 percent—have changed in the six million years or so since the human and chimp lineages diverged.

Evolutionary theory holds that the vast majority of these changes had little or no effect on our biology. But somewhere among those roughly 15 million bases lay the differences that made us human. I was determined to find them. Since then, I and others have made tantalizing progress in identifying a number of DNA sequences that set us apart from chimps.

An Early Surprise
Despite accounting for just a small percentage of the human genome, millions of bases are still a vast territory to search. To facilitate the hunt, I wrote a computer program that would scan the human genome for the pieces of DNA that have changed the most since humans and chimps split from a common ancestor. Because most random genetic mutations neither benefit nor harm an organism, they accumulate at a steady rate that reflects the amount of time that has passed since two living species had a common forebear (this rate of change is often spoken of as the “ticking of the molecular clock”). Acceleration in that rate of change in some part of the genome, in contrast, is a hallmark of positive selection, in which mutations that help an organism survive and reproduce are more likely to be passed on to future generations. In other words, those parts of the code that have undergone the most modification since the chimp-human split are the sequences that most likely shaped humankind.

In November 2004, after months of debugging and optimizing my program to run on a massive computer cluster at the University of California, Santa Cruz, I finally ended up with a file that contained a ranked list of these rapidly evolving sequences. With my mentor David Haussler leaning over my shoulder, I looked at the top hit, a stretch of 118 bases that together became known as human accelerated region 1 (HAR1). Using the U.C. Santa Cruz genome browser, a visualization tool that annotates the human genome with information from public databases, I zoomed in on HAR1. The browser showed the HAR1 sequences of a human, chimp, mouse, rat and chicken—all of the vertebrate species whose genomes had been decoded by then. It also revealed that previous large-scale screening experiments had detected HAR1 activity in two samples of human brain cells, although no scientist had named or studied the sequence yet. We yelled, “Awesome!” in unison when we saw that HAR1 might be part of a gene new to science that is active in the brain.

We had hit the jackpot. The human brain is well known to differ considerably from the chimpanzee brain in terms of size, organization and complexity, among other traits. Yet the developmental and evolutionary mechanisms underlying the characteristics that set the human brain apart are poorly understood. HAR1 had the potential to illuminate this most mysterious aspect of human biology.

We spent the next year finding out all we could about the evolutionary history of HAR1 by comparing this region of the genome in various species, including 12 more vertebrates that were sequenced during that time. It turns out that until humans came along, HAR1 evolved extremely slowly. In chickens and chimps—whose lineages diverged some 300 million years ago—only two of the 118 bases differ, compared with 18 differences between humans and chimps, whose lineages diverged far more recently. The fact that HAR1 was essentially frozen in time through hundreds of millions of years indicates that it does something very important; that it then underwent abrupt revision in humans suggests that this function was significantly modified in our lineage.

A critical clue to the function of HAR1 in the brain emerged in 2005, after my collaborator Pierre Vanderhaeghen of the Free University of Brussels obtained a vial of HAR1 copies from our laboratory during a visit to Santa Cruz. He used these DNA sequences to design a fluorescent molecular tag that would light up when HAR1 was activated in living cells—that is, copied from DNA into RNA. When typical genes are switched on in a cell, the cell first makes a mobile messenger RNA copy and then uses the RNA as a template for synthesizing some needed protein. The labeling revealed that HAR1 is active in a type of neuron that plays a key role in the pattern and layout of the developing cerebral cortex, the wrinkled outermost brain layer. When things go wrong in these neurons, the result may be a severe, often deadly, congenital disorder known as lissencephaly (“smooth brain”), in which the cortex lacks its characteristic folds and exhibits a markedly reduced surface area. Malfunctions in these same neurons are also linked to the onset of schizophrenia in adulthood.

HAR1 is thus active at the right time and place to be instrumental in the formation of a healthy cortex. (Other evidence suggests that it may additionally play a role in sperm production.) But exactly how this piece of the genetic code affects cortex development is a mystery my colleagues and I are still trying to solve. We are eager to do so: HAR1’s recent burst of substitutions may have altered our brains significantly.

Beyond having a remarkable evolutionary history, HAR1 is special because it does not encode a protein. For decades, molecular biology research focused almost exclusively on genes that specify proteins, the basic building blocks of cells. But thanks to the Human Genome Project, which sequenced our own genome, scientists now know that protein-coding genes make up just 1.5 percent of our DNA. The other 98.5 percent—sometimes referred to as junk DNA—contains regulatory sequences that tell other genes when to turn on and off and genes encoding RNA that does not get translated into a protein, as well as a lot of DNA having purposes scientists are only beginning to understand.

Based on patterns in the HAR1 sequence, we predicted that HAR1 encodes RNA—a hunch that Sofie Salama, Haller Igel and Manuel Ares, all at U.C. Santa Cruz, subsequently confirmed in 2006 through lab experiments. In fact, it turns out that human HAR1 resides in two overlapping genes. The shared HAR1 sequence gives rise to an entirely new type of RNA structure, adding to the six known classes of RNA genes. These six major groups encompass more than 1,000 different families of RNA genes, each one distinguished by the structure and function of the encoded RNA in the cell. HAR1 is also the first documented example of an RNA-encoding sequence that appears to have undergone positive selection.

It might seem surprising that no one paid attention to these amazing 118 bases of the human genome earlier. But in the absence of technology for readily comparing whole genomes, researchers had no way of knowing that HAR1 was more than just another piece of junk DNA.

Language Clues
Whole-genome comparisons in other species have also provided another crucial insight into why humans and chimps can be so different despite being much alike in their genomes. In recent years the genomes of thousands of species (mostly microbes) have been sequenced. It turns out that where DNA substitutions occur in the genome—rather than how many changes arise overall—can matter a great deal. In other words, you do not need to change very much of the genome to make a new species. The way to evolve a human from a chimp-human ancestor is not to speed the ticking of the molecular clock as a whole. Rather the secret is to have rapid change occur in sites where those changes make an important difference in an organism’s functioning.

Read the rest of the article.

No comments: