© 1998 by Oxford University Press
When scientists first began studying human DNA well over a quarter of a century ago, they stumbled onto something strange. Though humans are endowed with 3 billion bases, or units, of DNA, only a fraction of them -- roughly 5% -- encode genes. As for the other 95%, it was anybody's guess what it was doing there.
In 1972, after studying the DNA of a variety of species, Susumu Ohno, Ph.D., a scientist at the City of Hope National Medical Center in Duarte, Calif., put forward a possible explanation. Writing in the Brookhaven Symposium on Biology, he proposed that these millions of "silent DNA base sequences" represented genes that had died off like dinosaurs during the course of human evolution. "The earth is strewn with fossil remains of extinct species; is it a wonder that our genome too is filled with the remains of extinct genes?" wrote Ohno.
However, Ohno's paper is perhaps best remembered today for another reason. He titled his article, "So Much 'Junk' DNA in Our Genome." And thus was born what is today one of the most easily grasped and yet pejorative terms in the genetic lexicon -- junk DNA.
But is human DNA mostly a repetitious collection of junk sequences that have little or no bearing on the survival of the species? Or, is this so-called junk really providing structural support to our genes and chromosomes, offering the raw material for our continued evolution?
According to most scientists, the answer remains unknown. However, a growing body of evidence has begun to accumulate that suggests that not all of the junk sequences ought to be tossed in the scrap heap just yet.
When Ohno published his famous paper in 1972, he focused his attention mainly on the fossilized genes, called pseudogenes, that are strewn like tombstones throughout our DNA. But as the term "junk DNA" caught on in the 1980s, its meaning was extended to all non-coding sequences, the vast stretches of DNA that are not genes and do not produce proteins.
While this might seem on paper like an obvious grouping, it is probably a little like calling every dog a Chihuahua. For non-coding sequences, like canines, come in all varieties and sizes. They range from the simple two-base CA repeats to Alu repeats that run into the hundreds of bases and L1 repeats that drone on for several thousand nucleotides. Scientists also have found that some repeats are no more than genetic parasites, short DNA sequences left behind over the eons by retroviruses or other pathogens that aimlessly copy themselves in an endless signature of C, G, A, and Ts.
But as the human genome has become more accessible to scientists, some have begun to scrap the notion that all non-coding DNA is junk. They note that all of the regulatory elements -- the so-called promoters and enhancers needed for gene transcription -- reside in non-coding DNA. Moreover, changes in the non-coding introns that are present in human gene sequences, like black spaces on a checkerboard, could have a profound effect on everything from protein synthesis to human evolution.
"I don't think people take the term junk DNA very seriously anymore," said Eric Green, M.D., Ph.D., a scientist with National Institutes of Health's National Human Genome Research Institute, whose group is mapping chromosome 7 as part of the Human Genome Project. "I mean, within the 'junk DNA' are all of the regulatory elements. So, if people don't think that regulatory elements are important in the complexity of genetic networks, then that's just naive."
Robert Weinberg, Ph.D., a scientist at Whitehead Institute, Cambridge, Mass., and an outspoken critic a decade ago of the Human Genome Project's plan to sequence junk DNA, said he agrees that the regulatory elements ought to be excluded from under the junk rubric.
However, Weinberg said he remains unpersuaded about the rest of the non-coding sequences. "Many people may regard the term as a relic of an earlier debate," he said. "I'm not sticking to the notion of junk to justify what I said 10 years ago, because I am happy to change my opinions about a lot of things. But, in this case, I remain unpersuaded that I was far off the mark."
Even the most hard-core junkologists admit that a significant portion of human DNA is probably dispensable. For instance, Ohno, now semi-retired from City of Hope, points out several reported cases of people born with millions of bases missing from their X chromosome. And yet, these people lead perfectly healthy lives, an indication that the lost bases probably add nothing to human life.
What remains murky is just how much of the human genome is dispensable. "I'm sure there is some junk DNA in the human genome, but I would be real hesitant to say which proportion it is," said Katheleen Gardiner, Ph.D., a scientist at the Eleanor Roosevelt Institute in Denver, who studies human chromosome 21.
The problem is, although they have learned a lot about the human genome, there still is much more to know. And right now, scientists remain extremely myopic in their ability to see how chromosomes work. As many investigators readily admit, it is not a farfetched idea that repetitive sequences that were once written off as worthless scraps of junk DNA, could turn out tomorrow to play important roles in maintaining the structure of chromosomes.
"The fact that we don't know something has a function doesn't mean that in reality it does nothing," said Carl Schmid, Ph.D., a chemist at the University of California at Davis, who recently published a paper indicating that Alu repeats are involved in regulating human protein synthesis in response to certain cellular stresses.
A fundamental question that researchers will need to answer is simply why some human chromosomes have more repeats than others? For example, Gardiner noted that her group at Eleanor Roosevelt Institute trudged through just over 4 million bases on human chromosome 21 and found a grand total of 35 genes. Conversely, she said a group at the Oak Ridge National Laboratory in Tennessee scanned through roughly the same number of bases on human chromosome 19 and encountered 147 genes.
"What does this say?" said Gardiner. "Is this another piece of evidence that says there is a lot on chromosome 21 that does not do much compared to what the same amount of DNA does elsewhere?"
One place to more systematically study junk repeats is the model organisms, such as the fruit fly, pufferfish, or budding yeast. Because their genomes are more compact and better understood than humans, researchers have an easier time working with them and are able to ask more targeted questions about the role of repeat sequences in genome structure.
Last May, having searched the full-sequence database of budding yeast, a team of American researchers published in the journal Genome Research a comprehensive, A-to-Z index of the different types of so-called retrotransposon repeats present in budding yeast, their locations in the genome, and the number of repeats found. Retrotranspons, also known as "jumping genes" for their uncanny ability to hop from one chromosome to the next and insert themselves, replicate their sequence using the same reverse transcriptase enzyme as retroviruses. Jumping genes also are found across most species.
Among their many findings, the scientists discovered that different retrotranspons appear to target specific regions of the yeast genome. "There really is a lot of pattern to what is going on between genes and the way that these transposable elements are organized," said Daniel Voytas, Ph.D., a scientist at Iowa State University in Ames and senior author on the paper. "It is not a random process."
Almost 30 years ago, the legendary Russian biologist Theodosius Dobzhansky wrote, "In biology nothing makes sense except in the light of evolution." As many scientists have noted, junk repeats, with their ancient origins and tremendous diversity, offer one of the best vantage points into the evolution of human life.
However, a concerted effort to open this evolutionary window likely will not be imminent. Researchers say science, like business, has to set its priorities. And right now, finding genes continues to be where the money is for biotech companies and whence future healthcare advances will emanate.
"I think from the public's perspective, it's clearly going to be the coding information that is going to be of most immediate interest and value," noted Voytas.
"But from a basic biological perspective," he added, "if you want to understand how genomes are organized, how they change, and the forces involved in genomic evolution, my feeling is you need to have a more complete picture."
-- Bob Kuska
(Next issue: The Semantics of "Junk.")
Should Scientists Scrap the Notion of Junk DNA?
Pejorative Terminology
Naive Idea
Much More to Know
Window Into the Past
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