‘Junk DNA’ not without use

In the junkyard of the human genome, Yale scientists have identified a few pieces of DNA that are more than just scrap metal.

Assistant professor of genetics James Noonan and a team of other geneticists recently found a sequence of genes among what was traditionally considered to be “junk DNA” that may have contributed to unique aspects of human-limb development — such as the opposable thumb.

“We’re interested in understanding the genetic basis of human uniqueness,” Noonan said. “We’re different from our closest primate relatives, and we’d like to know what the genetic basis of that is.”

To identify these differences, he said, geneticists have been scouring the human genome and comparing it with primate genomes for evidence of what he called “human-specific accelerated evolution” — sequences that have remained unchanged for long periods of time in other species but have become altered in the human genome.

Noonan said his team examined certain strings of DNA that did not control specific traits by themselves but rather controlled the expression of other genes that did, in fact, control specific traits — in this case, limb development.

The particular sequence they chose to study in depth, called HACNS1, is the most rapidly evolving sequence of its kind, he said. It has remained intact at least since the evolution of frogs 400 million years ago and exists in the same form in most terrestrial vertebrates, from chickens to chimpanzees.

But since humans and chimpanzees diverged about six million years ago, humans have accumulated changes in 16 of the sequence’s base pairs, which Noonan said is four times as many as one might expect, given the time frame.

Based on his previous work, Noonan said he knew that such sequences tend to have smaller subsets that control gene expression in the embryo and could be controlling human-specific aspects of development.

To determine what aspect of development the sequence could be controlling, he said the scientists connected it to a gene containing a blue dye, which served as a reporter, and injected it into a single-celled mouse embryo.

After allowing the mouse to develop, they discovered that the gene — identified by its blue color — was present in the limbs, particularly at the base of the thumb, indicating that the sequence controlled limb development, Noonan said.

“It’s probably the opposable thumb,” said Evan Eichler, an evolution and genomic specialist from the University of Washington. “It’s not quite a magic bullet; it’s still possible to have expression in the digits that has nothing to do with it, but the expression is consistent the opposability of the thumb.”

Noonan said the next step for him and his team is to humanize the mouse. They will replace the equivalent sequence in the mouse with the human DNA sequence and observe whether the mouse’s limb development mirrors human limb development, and in what ways.

The current discovery is useful, he said, because it provides direction about where scientists should look to find the unique sequences.

“We want to know what those sequences are and what it takes to build a human,” he said.

Eichler said Noonan’s work is unique because although many geneticists have identified candidate regions that may contribute to crucial aspects of human evolution, very few have identified the regions’ functions.

Richard Lifton, chairman of Yale Genetics department, said Noonan’s work contributes to crucial understanding in the field.

“This is a new insight into how humans became humans,” Lifton said. “It’s a path forward for identifying more genes that played a fundamental role in the evolution of unique features of our species.”