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Knockout Mice Study: Long Noncoding RNAs "Play Central Roles in Mammalian Development and Physiology"

A few years ago I wrote about challenges to the claim that "junk DNA" wasn't necessary for development. In experiments with mice, researchers had supposedly "knocked out" non-coding DNA, yet the mice themselves as they grew turned out to be healthy. Now a new study in eLife, "Multiple knockout mouse models reveal lincRNAs are required for life and brain development," shows that in fact noncoding DNA, in the form of long non-coding RNAs (lincRNAs), is vital for normal development in mice -- and researchers are suggesting that even when such "knockouts" don't produce nonviable mice, we should be very hesitant in claiming the noncoding DNA is unimportant. As the "digest" section of the article states:

Sauvageau et al. have developed several lines of knockout mice to investigate a subset of noncoding RNA molecules known as long intergenic noncoding RNAs (lincRNAs). These experiments reveal that lincRNAs have a strong influence on the overall viability of mice, and also on a number of developmental processes, including the development of lungs and the cerebral cortex.
The study knocked out 18 lincRNAs in mice, and found that lincRNAs "play central roles" in development:
This approach led us to identify 18 lincRNAs for targeted deletion in mouse. Initial characterization of these new knockout strains demonstrated key functional roles in viability, development of the cerebral cortex and other developmental processes. In this study, we describe the observed phenotypes for five strains within this collection. Collectively, these data provide evidence that lincRNAs play central roles in mammalian development and physiology.
These results are relevant to debates over the ENCODE project. Some have claimed that even where DNA is transcribed into RNA, that RNA might still be "junk." But this article suggests that human noncoding RNA may have important functions:
Given that the vast majority of the human genome is transcribed, the mouse models developed by Sauvageau et al. represent an important step in determining the physiological relevance, on a genetic level, of the noncoding portion of the genome in vivo. ... This supports our hypothesis that lincRNAs can be required for normal organ development and misregulated in pathological states, which could translate to human disease.
It concludes, "This study demonstrates that lncRNAs play critical roles in vivo and provides a framework and impetus for future larger-scale functional investigation into the roles of lncRNA molecules." In other words, don't assume that non-coding RNAs are junk.

Now not all of the 18 knockouts resulted in developmental defects. Commenting on the article in eLife, RNA researcher John Mattick explains that the failure to immediately find a "discernable phenotype" from a noncoding RNA knockout doesn't necessarily mean that noncoding RNA is functionless. As Mattick explains, "Other mutants that did not exhibit overt developmental defects showed brain-specific expression patterns and may be associated with cognitive defects that are not grossly apparent at the developmental level." He continues:

The work of Sauvageau, Goff, Lodata et al. is a mini tour-de-force that shows that there are lncRNAs with important developmental functions in vivo, and it joins a small number of studies from other pioneering groups that show the same thing (Lewejohann et al., 2004; Gutschner et al., 2013; Li et al., 2013), although not all of the targeted lncRNAs showed a phenotype. Similarly, other knockout experiments of widely expressed lncRNAs, as well as some of the most highly conserved elements in the mammalian genome, also did not yield discernable phenotypes (Ahituv et al., 2007; Nakagawa et al., 2011), which should sound a note of caution about the interpretation of negative results.

Indeed, since most lncRNAs are expressed in the brain (Mercer et al., 2008) and many are primate-specific (Derrien et al., 2012), it may be that much of the lncRNA-mediated genetic information in humans (and in mammals generally) is devoted to brain function, and therefore not easily detectable in developmental, as opposed to cognitive, screens. A good example is a noncoding RNA called BC1 that is widely expressed in the brain: knockout of BC1 causes no visible anatomical consequences, but it leads to a behavioural phenotype that would be lethal in the wild (Lewejohann et al., 2004).

Although evidence for the hypothesis that lncRNAs have a role in mammalian development, brain function and physiology is growing, there is also a clear need for more sophisticated and comprehensive phenotypic screens, especially with respect to cognitive function.

(John S. Mattick, "Genetics: Probing the phenomics of noncoding RNA," eLife, 2:e01968 (December 31, 2013).)

In other words, even when we "knockout" noncoding DNA/RNA and find that a viable organism develops, that knocked-out DNA/RNA might still have important functions, and some researchers may have prematurely concluded that the knocked-out DNA/RNA was junk. This might be exactly what's happening when long noncoding RNAs perform important functions in mammals related to cognition and behavior. The moral of the story is that we shouldn't prematurely conclude something is "junk," and it's going to take a lot of new types of research to answer these questions.

After ENCODE's finding that the vast majority of our DNA is transcribed into RNA, many Darwinian biologists have comforted themselves with the belief that most of that RNA is still useless, and our cells are full of "junk RNA." But a few independent-minded folks sought out evidence of function for that RNA. And they've consistently found it. As Mattick says: "For many years, it was assumed that untranslated RNA molecules served no useful purpose but, starting in the mid-1990s, a small body of researchers, including the present author (Mattick, 1994), have been arguing that these RNAs transmit regulatory information, possibly associated with the emergence of multicellular organisms." Hurray for Dr. Mattick and others who have had the courage to challenge unfruitful Darwinian assumptions.