Quotes of interest -- long neglected, some noncoding DNA is actually functional.

I have started a series listing quotes from papers published during the supposed period of neglect of noncoding DNA that, we are told repeatedly by authors of various persuasions, was inspired by the “junk DNA” and “selfish DNA” ideas. For this installment, I want to quote at length from one article which represents a typical discussion of some eukaryotic “junk DNA” turning out to have functions. This is the sort of thing we see regularly in the media and in the scientific literature, so a single example should be sufficient.

The protein-coding portions of the genes account for only about 3% of the DNA in the human genome; the other 97% encodes no proteins. Most of this enormous, silent genetic majority has long been thought to have no real function — hence its name: “junk DNA”. But one researcher’s trash is another researcher’s treasure, and a growing number of scientists believe that hidden in the junk DNA are intellectual riches that will lead to a better understanding of diseases (possibly including cancer), normal genome repair and regulation, and perhaps even the evolution of multicellular organisms.
Rather than the genes, junk DNA “is actually the challenge right now,” says Eric Lander of the Massachusetts Institute of Technology, who is himself a prominent Human Genome Project researcher. And in rising to meet that challenge, geneticists are beginning to formulate a new view of the genome. Rather than being considered a catalogue of useful genes interspersed with useless junk, each chromosome is beginning to be viewed as a complex “information organelle,” replete with sophisticated maintenance and control systems — some embedded in what was thought to be mere waste.

…when geneticists started studying complex, multicellular organisms, it was easy to dismiss the vast reaches of non-protein-coding DNA as a wasteland. Now, however, that notion is being overturned as researchers find that junk DNA is not a single midden heap, but a complex mix of different types of DNA, many of which are vital to the life of the cell.

Some of the earliest indications that junk DNA might have important functions came from studies on gene control. Those studies found that genes have regulatory sequences, short segments of DNA that serve as targets for the “transcription factors” that activate genes. Many of the regulatory sequences lie outside the protein-coding sequences — in the genetic garbage can. “There’s at least five regulatory elements for each [human] gene, probably many more,” says gene control expert Robert Tjian of the University of California, Berkeley. “For a long time it wasn’t appreciated how widespread those elements can be, but now it seems that patches of really important regulatory elements can be buried among the junk DNA.”

Now, however, it appears that some repetitive sequences may contain stretches of DNA needed for gene regulation. What is more, the function of these stretches must be significant, because if their sequences go astray they may result in cancer.

But housing sequences that control the genes isn’t the only role that so-called genetic trash plays. Some repetitive sequences also seem to have a crucial function in maintaining the structure of the genome.

Thus, in a dramatic reversal, the repetitive sequences, once thought to be the epitome of genetic debris, now seem to be needed to maintain the integrity of the chromosomes. But the repetitive sequences aren’t the only forms of genetic garbage moving up in the world. Whereas the repetitive sequences are usually found outside genes, a second type of genetic junk, the introns, are scattered through the genes of higher organisms.

Koop and Hood have found that the DNA of the T cell receptor complex, a crucial immune system protein, shows 71% identity between humans and mice. That finding is startling, since only 6% of the DNA encodes the actual protein sequence, while the rest consists of introns and noncoding regions. “[The finding] certainly questions the assumption that introns are junk,” says Koop. Instead, he says, “it fits the view that chromosomes are information organelles that carry out a variety of functions besides encoding genes, such as maintenance of genome structure and gene regulation.”
That opinion appeals to John Mattick, a molecular biologist at the University of Queensland in Australia, currently on sabbatical at Cambridge University in England. Mattick has proposed that introns provide a previously unsuspected system for regulating gene expression.

“[Mattick’s] idea is very interesting indeed,” says evolutionary geneticist Laurence Hurst of Cambridge University, England. “And it’s perfectly testable.” For example, he says, Mattick’s model predicts that certain genes, like regulatory developmental genes, that must be finely controlled, will likely bear intron-encoded regulatory RNAs.

“There’s too many cases of odd RNAs,” says molecular geneticist Marvin Wickens of the University of Wisconsin, Madison. “It smells like there might be a whole family of regulatory RNAs.” And if that suspicion proves correct, it would be a big boost for Mattick’s new theory, as well as for the status of junk DNA — a status that is likely to keep on rising over the next couple of years. Enough gems have already been uncovered in the genetic midden to show that what was once thought to be waste is definitely being transmuted into scientific gold.

You may be curious, out of all the discussions like this that are being published, why would this be the one that is singled out?

For a simple reason: it was written in 1994.

Nowak, R. 1994. Mining treasures from ‘junk DNA’. Science 263: 608-610.

I will talk about the timeline of the “junk DNA” discussion more comprehensively later, but here is what we can tell so far. The term “junk DNA” was coined by Ohno (1972), and in the first detailed discussion of the topic (Comings 1972), the likelihood that some noncoding DNA would be functional was explicitly noted. In any case, Ohno (1972) seems not to have had much influence during the first decade after he coined the term, because in 1980, when “selfish DNA” was introduced, the overwhelming tendency was to assume that all noncoding DNA was present because it was adaptive — this is why Orgel and Crick (1980) and Doolittle and Sapienza (1980) wrote their papers. There was strong resistance to the idea of selfish DNA for at least the first few years after the idea was proposed (Doolittle 1982), and even in the late 1980s there was at most discussion about how much noncoding DNA might be parasitic versus functional. Keep in mind also that DNA sequencing did not become a common method until the late 1970s/early 1980s, and that introns weren’t even discovered until 1977, and then much of the study focused on seeing how abundant they were and on their origin (were they present from the beginning, or did they arise only among eukaryotes?). The term “pseudogene” was coined in 1977 as well. So, the kind of work that people expect when they say detailed functional research wasn’t done could not have started until the 1980s in any case, and in fact there was abundant research investigating possible roles of satellite DNA, introns, and transposable elements during that decade. By the early 1990s, people had begun proposing additional functions for noncoding DNA, including Mattick’s idea about regulatory RNA sequences.

In other words, there was no real period in which noncoding DNA was dismissed by the scientific community, though there was a much-needed shift away from strictly adaptive interpretations in the 1980s. Some individual researchers ignored noncoding regions, but there is no gap in the literature other than limits on what could be done in a methodological capacity. The “new” view of noncoding DNA as potentially important has been proclaimed regularly for at least as long as the claimed period of neglect between 1980 and 1994.

One wonders just how long we will be told that we have long been neglecting noncoding DNA.

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Part of the Quotes of interest series.
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Comings, D.E. 1972. The structure and function of chromatin. Advances in Human Genetics 3: 237-431.

Doolittle, W.F. and C. Sapienza. 1980. Selfish genes, the phenotype paradigm and genome evolution. Nature 284: 601-603.

Doolittle, W.F. 1982. Selfish DNA after fourteen months. In Genome Evolution (eds. G.A. Dover and R.B. Flavell), pp. 3-28. Academic Press, New York.

Ohno, S. 1972. So much “junk” DNA in our genome. In Evolution of Genetic Systems (ed. H.H. Smith), pp. 366-370. Gordon and Breach, New York.

Orgel, L.E. and F.H.C. Crick. 1980. Selfish DNA: the ultimate parasite. Nature 284: 604-607.

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Part of the Quotes of interest series.


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