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Tuesday, July 24, 2007

Junk DNA in New Scientist

I just got my copy of the July 14th issue of New Scientist so I can comment on the article Why 'junk DNA' may be useful after all by Aria Pearson. RPM at evolvgen thinks it's pretty good [Junk on Junk] and so does Ryan Gregory at Genomicron [New Scientist gets it right]. I agree. It's one of the best articles on the subject that I've seen in a long time.

First off, Aria Pearson does not make the common mistake of assuming that junk DNA is equivalent to non-coding DNA. The article makes this very clear by pointing out that we've known about regulatory sequences since the 1970's. The main point of the article is to discuss recent results that reveal new functions for some of the previously unidentified non-coding DNA that was classified as junk.

One such result is that reported Pennacchio et al. (2006) in Nature last year. They analyzed sequences in the human genome that showed a high degree of identity to sequences in the pufferfish genome. The idea is that these presumably conserved sequences must have a function. Pennacchio et al. (2006) tested them to see it they would help regulate gene expression and they found that 45% of the ones they tested functioned as enhancers. In other words, they stimulated the expression of adjacent genes in a tissue specific manner. The authors estimate that about half of the "conserved" elements play a role in regulating gene expression.

There are a total of 3,124 conserved elements and their average length is 1,270 bp. This accounts for 3.9 × 106 bp out of a total genome size of 3.2 × 109 bp or about 0.1% of the genome. The New Scientist article acknowledges, correctly, that more than 95% of the genome could still be junk.

Is this all junk DNA? Unlike most other science journalists, Pearson addresses this question with a certain amount of skepticism and she makes an effort to quote conflicting opinions. For example, Pearson mentions experiments claiming that ~90% of the genome is transcribed. Rather than just repeating the hype of the researchers making this claim, Pearson quotes skeptics who argue that this RNA might be just "noise."

Most articles on junk DNA eventually get around to mentioning John Mattick who has been very vocal about his claim that the Central Dogma has been overturned and most of the genome consists of genes that encode regulatory RNAs (Mattick, 2004; Mattick, 2007). This article quotes a skeptic to provide some sense of balance and demonstrate that the scientific community is not overly supportive of Mattick.
Others are less convinced. Ewan Birney of the European Bioinformatics Institute in Cambridge, UK, has bet Mattick that of the processed RNAs yet to be assigned a function - representing 14 per cent of the entire genome - less than 20 per cent will turn out to be useful. "I'll get a case of vintage champagne if I win," Birney says.
Under the subtitle "Mostly Useless," Pearson correctly summarizes the scientific consensus. (I wish she had used this as the title of the article. The actual title is somewhat misleading. Editors?)
Whatever the answer turns out to be, no one is saying that most of our genome is vital after all. "You could chuck three-quarters of it," Birney speculates. "If you put a gun to my head, I'd say 10 per cent has a function, maybe," says Lunter. "It's very unlikely to be higher than 50 per cent."

Most researchers agree that 50 per cent is the top limit because half of our genome consists of endless copies of parasitic DNA or "transposons", which do nothing except copy and paste themselves all over the genome until they are inactivated by random mutations. A handful are still active in our genome and can cause diseases such as breast cancer if they land in or near vital genes.
The ENCODE project made a big splash in the blogosphere last month (ENCODE Project Consortium, 2007). This study purported to show that much of the human genome was transcribed, leading to the suggestion that most of what we think is junk actually has some function. Aria Pearson interviewed Ewan Birney (see above) who is involved in the ENCODE project.

The real surprise is that ENCODE has identified many non-coding sequences in humans that seem to have a function, yet are not conserved in rats and mice. There seem to be just as many of these non-conserved functional sequences as there are conserved ones. One explanation is that these are the crucial sequences that make humans different from mice. However, Birney thinks this is likely to be true of only a tiny proportion of these non-conserved yet functional sequences. Instead, he thinks most are neutral. "They have appeared by chance and neither hinder nor help the organism."

Put another way, just because a certain piece of DNA can do something doesn't mean we really need it to do whatever it does. Such DNA may be very like computer bloatware: functional in one sense yet useless as far as users are concerned.
This is a perspective you don't often see in popular articles about junk DNA and Pearson is to be commended for taking the time and effort to find the right scientific perspective.

The article concludes by reporting the efforts to delete large amounts of mouse DNA in order to test whether they are junk or not. The results show that much of the conserved bits of DNA can be removed without any harmful effects. Some researchers urge caution by pointing out that very small effects may not be observed in laboratory mice but may be important for evolution in the long term.

ENCODE Project Consortium (2007) Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447:799-816. [PubMed Abstract]

Mattick, J.S. (2004) The hidden genetic program of complex organisms. Sci. Am. 291:60-7.

Mattick, J.S. (2007) A new paradigm for developmental biology. J. Exp. Biol. 210:1526-47. [PubMed Abstract].

Pennacchio, L.A., Ahituv, N., Moses, A.M., Prabhakar, S., Nobrega, M.A., Shoukry, M., Minovitsky, S., Dubchak, I., Holt, A., Lewis, K.D., Plajzer-Frick, I., Akiyama, J., De Val, S., Afzal, V., Black, B.L., Couronne, O., Eisen, M.B., Visel, A., Rubin, E.M. (2006) In vivo enhancer analysis of human conserved non-coding sequences. Nature 444(7118):499-502.

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