Larry Moran Defends "Junk DNA"
On his Sandwalk blog, University of Toronto biochemist Larry Moran has posted a response to my article. Since the post is relatively civil (unusually for Moran, he refrains from calling me an "IDiot") and offers some scientific criticisms of what I wrote, I will offer a rebuttal.
The Function of Introns
Responding to my comments on intron function, Moran writes,
Each intron has about 50-80 bp of essential information that's required for proper splicing. The rest of the intron, which can be a thousand of base pairs in length, is mostly junk. Some introns contain essential gene regulatory regions and some contain essential genes. That does not mean that all intron sequences are functional.It is certainly true that most known cases of intron functions (including the examples I gave) involve only a portion of the full length of the sequence. But the point is that PZ Myers's argument that "since introns are cut out and degraded during mRNA processing, they must be functionless" is not logically sound. Myers doesn't even mention the extensive literature that points to a myriad of cases of introns having function. It is Myers who seeks to show that the preponderance of our genome is junk. The burden of proof must lie with him. Myers protests that he "was simplifying for a lay audience." But since when did "simplifying for a lay audience" provide license for omitting to mention key facts that undermine your position? Regardless of whether or not introns really are "junk," PZ Myers's argument for their being "junk" is completely unsound because the removal of introns prior to translation does not imply lack of function.
Furthermore, the fact that function has been elucidated for one portion of an intron sequence does not imply that the rest of it is "junk." It merely means that, given our current state of knowledge, we don't yet know what the rest of it is doing.
Indeed, when a study examined the human chromosome 21 and its corresponding part of the mouse genome, it was found that exons represent only a third of the conserved sequences (Dermitzakis et al., 2002). This implies that the remainder is found in intronic and intergenic regions. Furthermore, Hardison et al. (1997) report a plethora of conserved intronic regions between mice and humans. Now, it is certainly true that not all intronic sequences are conserved, and introns tend to show poorer levels of conservation than protein-coding (exon) regions. As Sorek and Ast (2003) explain, "homologous human and mouse exons are, on the average, 85% identical in their sequences, but introns are more poorly conserved: 60% of the nonexonic sequences are nonalignable, and in the alignable regions the average identity level is 69%." While conservation usually implies functional constraint, however, the converse does not necessarily follow.
Although sequence conservation has proven useful as a predictor of functional regulatory elements in the genome, the observations by Kunarso et al. are a reminder that it is not justified to assume in turn that all functional regulatory elements show evidence of sequence constraint.These are not isolated results. Another paper was published in 2007 by the ENCODE Project Consortium detailing the results from the ENCODE project. This research similarly reported,
At the outset of the ENCODE Project, many believed that the broad collection of experimental data would nicely dovetail with the detailed evolutionary information derived from comparing multiple mammalian sequences to provide a neat "dictionary" of conserved genomic elements, each with a growing annotation about their biochemical function(s). In one sense, this was achieved; the majority of constrained bases in the ENCODE regions are now associated with at least some experimentally derived information about function. However, we have also encountered a remarkable excess of experimentally identified functional elements lacking evolutionary constraint, and these cannot be dismissed for technical reasons. This is perhaps the biggest surprise of the pilot phase of the ENCODE Project, and suggests that we take a more "neutral" view of many of the functions conferred by the genome. (emphasis added)And so, it seems, while evolutionary constraint may be used to infer function, there is no reason to think that non-constraint implies non-function.
As previously discussed, introns have a myriad of functions. In many cases, introns can possess protein binding sites, or they can act to regulate gene expression by virtue of the ability to form stem loop structures (Lavett et al., 1984; Bornstein et al., 1987). Even the length of introns can be functionally significant (Swinburne and Silver, 2007).
Telomeric Repetitive Elements
Larry Moran agrees with me that "Telomeres are not junk." He also charges me with dishonesty, saying, "PZ Myers agrees that telomeres (and centromeres) are functional DNA (28 minutes into the talk). Jonathan McLatchie claims that PZ describes telomeres as junk DNA...McLatchie is not telling the truth."
Actually, at 29:05, PZ Myers calls these elements "random junk." At 29:29 he asserts that they do have a structural role, but describes it as a kind of "stupid" function. He further asserts that, if God designed them that way, then God is "pathetic." For reasons I gave in my previous article, I disagree with this view. Given that this was one of the three major points of Myers's talk, it seems somewhat disingenuous of Moran to charge me with lying about PZ Myers's view of these elements as "junk." Indeed, he refers to them using the very words "random junk."
On the subject of transposons, Moran writes,
PZ Myers talks about transposons as mobile genetic elements and states that transposons make up more than half of our genome. That's all junk according to PZ Myers. My position is that the small number of active transposons are functional selfish genes and the real junk is the defective transposon sequences that make up most of the genome. Thus, I differ a bit from PZ's position. Jonathan McLatchie, like Jonathan Wells, argues that because the occasional defective transposon in the odd species has acquired a function, this means that most of the defective transposon sequences (~50% of the genome) are functional. This is nonsense.No, that's not the argument at all. The point is that Myers and Moran are wrong to dismiss these elements as "junk DNA" simply because they are transposons. In light of our continually advancing understanding of the important role of transposable elements, to assert that all of these elements to which a function has yet to be assigned are "junk" is to commit the fallacy that ID proponents are constantly accused of making. It is a classic argument from ignorance. At least with the "god of the gaps" the gaps are getting bigger. In the case of the "junk DNA of the gaps," the gaps are getting smaller by the day. Indeed, an excellent review paper was published just recently (Pandey and Murkerji, 2011) entitled "From 'JUNK' to Just Unexplored Noncoding Knowledge: the case of transcribed Alus." The abstract reports,
Non-coding RNAs (ncRNAs) are increasingly being implicated in diverse functional roles. Majority of these ncRNAs have their origin in the repetitive elements of genome. Significantly, increase in genomic complexity has been correlated with increase in repetitive content of the genome. Primate-specific Alu repeats, belonging to SINE class of repeats, is the most abundant repeat class inhabiting the human genome. Of the many possible functional roles of Alu repeats, they have been shown to modulate human transcriptome by virtue of harboring diverse array of functional RNA pol II TFBS, cryptic splice-site-mediated Alu exonization and as probable miRNA targets. Retro-transposition of Alu harboring TFBS has shaped up gene-specific regulatory networks. Alu exonized transcripts are raw material for dsRNA-mediated A-I editing leading to nuclear retention of transcripts and change in miRNA target. miRNA targets within Alu may titrate the effective miRNA or transcript concentration, thus acting as "miRNA sponge." Differential levels of Alu RNA during different conditions of stress also await clear functional understanding. These have contributed toward evolution of complex regulatory repertoire leading to the evolution of primate-specific functions. Recent reports of co-localization of pol II and pol III binding sites near the gene and elsewhere in the genome, increase the possibility of dynamic co-ordination between both pol II and pol III determining the ultimate transcriptional outcome. Dynamic and functional Alu repeats seem to be centrally placed to modulate the transcriptional landscape of human genome.Studies such as these give a very good reason to be cautious about asserting that any given piece of DNA is without function. Today's "junk" may well be tomorrow's "known functional sequence." As months go by, the "junk DNA" position finds itself taking refuge in increasingly narrow gaps.
Summary & Conclusion
Neither Larry Moran nor PZ Myers has offered us positive reason to think that the preponderance of our genome is "junk." In fact, the research literature from the last several years has totally undermined that position, as the dynamic and functionally intergrated nature of the genome has become increasingly apparent.