In “Junk DNA,” Here Are Benefits of Seeking Function
“Junk DNA” is so 1972. Why is it hard to shed worn-out phrases? One bad stain can wear out dozens of wipes. Fortunately, we don’t have to do all the wiping. Science reporters have been getting better at helping clean up this genomic blemish.
An example is a paper in PNAS summarized on Eurekalert!. The paper doesn’t refer to junk DNA, but the news item does. “Punctuating messages encoded in human genome with transposable elements” is the title: The vast majority of the human genome (~98% of the total genetic information) is not dedicated to encoding proteins, and this non-coding sequence was initially designated as “junk DNA” to underscore its lack of apparent function. Much of the so-called junk DNA in our genomes has accumulated over evolutionary time due to the activity of retrotransposable elements (RTEs), which are capable of moving (transposing) from one location to another in the genome and make copies of themselves when they do so. These elements have been considered as genomic parasites that exist by virtue of their ability to replicate themselves to high numbers within genomes without providing any beneficial function for the hosts in which they reside. However
, recent studies on RTEs have shown that they can in fact encode important functions, and much of their functional activity turns out to be related to how genomes are regulated. RTEs have been linked to stem cell function, tissue differentiation, cancer progression and ultimately to aging and age-related pathologies.
Although this statement credits evolution with the accumulation of RTEs, the original paper is loaded with the word “function” and says nothing of significance about evolution. It also never claims that “cancer progression” or “aging” constitute functions for RTEs.
A Design Prediction
Instead, the paper offers a design prediction and finds it largely true. Wang et al. predicted that RTEs act as “insulators” that “help to organize eukaryotic chromatin via enhancer-blocking and chromatin barrier activity.” Of the 1,178 mammalian-wide interspersed repeats (MIRs, a form of RTE) they predicted would be functional, they found that 58 percent of them do, indeed, function as insulators (the rest may have so-far-unknown functions). The news item calls them a form of “punctuation”:
“We randomly picked a hand full of the MIR sequences predicted to serve as boundary elements by the Jordan lab and experimentally validated their activity in mouse cell lines and, with help of our Spanish collaborators, in Zebrafish upon embryonic development,” Dr. [Victoria] Lunyak said. “This testing revealed that MIR sequences can serve as punctuation markswithin our genome that enable cells to correctly read and comprehend the messagetransmitted by the genomic sequences.”
“One thing that is particularly striking is the fact that these punctuation marks, as Victoria calls them, play a role that is deeply evolutionary conserved,” said Dr. [King] Jordan. “The same exact MIR sequences were able to function as boundaries in human CD4+ lymphocytes, in mouse cell models and in Zebrafish.”
You wouldn’t toss out all the punctuation in a book as “junk ABC” now, would you? Punctuation has a function — an important one. It came late in human written language (try reading ancient Greek). Human intelligent agents recognized that punctuation could help the understanding of texts. If it took intelligence to design punctuation, why would we credit genetic punctuation to blind processes? The fact that it is deeply conserved in unrelated animals argues against its being randomly accumulated for no purpose.
Another Function
Here’s another function for these MIR sequences: tissue-specific regulation of gene expression. This helps explain why cell types can differ dramatically even though they all contain the same genetic library:
Boundary elements are epigenetic regulatory sequences that separate transcriptionally active regions of the human genome from transcriptionally silent regions in a cell-type specific manner. In so doing, these critical regulatory elements help to provide distinct identities to different cell types, although they all contain identical sets of information. The regulatory programs that underlie these cell- and tissue-specific functions and identities are based largely on genome packaging. Genes that should not be expressed in a given cell or tissue are located in tightly packaged regions of the genome and inaccessible to the transcription factors that would otherwise turn them on. These boundary elements help to establish the geography of genome packaging by delineating the margins between silent regions in which genes are not expressed and active regions in which they are. In this critical role, boundary elements help to control the timing and extent of gene expression across the entire genome. As a result, defects in the organization of the genome by boundary elements are highly relevant for physiological and pathological processes.
Another benefit of looking for design instead of junk lies in gaining knowledge that has positive applications. Dr. Lunyak comments, “This is an important discovery because the understanding of how RTEs punctuate messages encoded in the human genome can help researchers to develop treatments for a wide variety of human diseases, including aging.” You have to understand punctuation in order to fix it. Would the “junk DNA” concept have led to this productive line of inquiry? Incidentally, we can thank the ENCODE Project for motivating Dr. Jordan’s project.
Functional Transfer-RNA “Litter”
Another example is this research from UC Santa Cruz. The announcement doesn’t mention junk DNA, but it shows the benefit of looking for function. All geneticists know the well-characterized functions of transfer RNA (tRNA), but the research team wondered why the nucleus is “littered” with pieces of tRNA. Notice the focus on function: Transfer RNA was characterized decades ago and plays a well-defined role, together with messenger RNA and ribosomal RNA, in translating the genetic instructions encoded in DNA into proteins. The discovery of RNA interference and genetic regulation by microRNA, however, revolutionized scientists’ understanding of RNA’s role in gene regulation and other cellular functions. Since then, a bewildering abundance and variety of small RNA molecules has been found in cells, and scientists are still struggling to sort out what they all do.
One doesn’t struggle to find out what junk does. The search for function is a good motivation for research. It inquires: these pieces must be there for a reason. As for the “Transfer RNA fragments,” the search for function is only in the early stages, but an important one was found:
“In the past five years, we’re starting to see that transfer RNAs are not just translatinggenes into proteins, they are being chopped up into fragments that do other things in the cell,” Lowe said. “Just recently, a subset of these fragments was found to suppress breast cancer progression.”
Many women can be relieved these UCSC researchers didn’t give up on “litter” they didn’t understand.
Endogenous Retroviruses
As Casey Luskin has Explained, endogenous retroviruses (ERVs) also have functions and are not junk. Current Biology published a “Quick Guide” to ERVs. The authors seem ambivalent about these former poster children for useless, selfish invaders in our genome. On one hand, they point to examples that appear invasive and parasitic. On the other, they show examples of function, where ERVs are expressed purposefully by the “host”: At each end of the ERV genome are long terminal repeats (LTRs), which contain regulatory sequences that can alter the expression, splicing, and polyadenylation of those host genes located near the ERV insertion site. LTRs regulate the cell type that the virus replicates in by controlling its expression, and so can be co-opted by their hosts as alternative promoters, resulting in tissue-specific expression of host genes. Often, solitary LTRs have been generated by homologous recombination between the two LTRs present in a single ERV, resulting in loss of the internal sequence. Consequently, host genomes are peppered with solo LTRs of potential regulatory significance.
The best evolutionary story the authors come up with is that the host learns to “co-opt” its ERVs and turn them into benefits. However, a search for design of ERVs would be more productive. Why must we always view viruses as destructive invaders? Many are neutral or beneficial. Why not look at ERVs as functional at the ecological level, instead of portraying them in the Dawkins selfish-gene way? The latter would motivate scientists to want to eliminate them, overlooking their potential benefits. It certainly is not helpful to ascribe mental planning to evolution, as the authors say in conclusion:
Taken together, the evidence suggests that sequences sequestered from ERVs have had a considerable influence on the evolution of their vertebrate hosts. So, not only is evolution a tinkerer, but it is also a conscientious recycler.
That word “recycler” represents a tacit admission that there was function there in the first place.
The Future of Genomics
PLOS Biology published a collection of short essays under the title, “Where Next for Genetics and Genomics?” Gil McVean looked back at the revolution in understanding when geneticists turned their attention from junk to gems:
The study of genetic variation has, over the last decade, been turned from a polite discipline focused on the finer points of evolutionary modelling to a fast, exhilarating, and sometimes messy hunt for gems hiding within the mines of genome-wide, population-scale datasets, most of which have been from humans. The coming years will only see the data rush grow: bigger samples, new species, extinct species, data linked to phenotype, temporal data, and so on. What, in this great whirlwind, am I most excited by?
Data are at their most fun when they bring to light things you would never have imagined.
Although he thinks the future will revisit “some of those big questions in evolution that never went away,” like “How does adaptation actually work?” (You mean that after 156 years they don’t know?), one thing is clear: focusing on “the finer points of evolutionary modelling” is passé. What’s “exhilarating” now is “the hunt for gems.” Things evolutionists “would never have imagined” — like finding functions in assumed junk — have been the “most fun.”
Death of a Meme
The demise of the “junk DNA” meme is a powerful reminder of the positive benefit of design thinking. “Junk DNA” was a science stopper, relegating non-coding sequences in the genome to the trash basket. Many years of fruitful research were lost because of it. Had scientists been focused on design and function back in the 1970s, who knows how much further along we would be?
Here is a challenge to all researchers to look at nature with a different focus. When something in a cell or organism appears useless, learn to think: It must be there for a reason. History has shown that approach often leads to fundamental new insights into the design of life, yielding practical applications for health and understanding.
