Junk DNA

In molecular biology, "junk" DNA is a collective label for the portions of the DNA sequence of a chromosome or a genome for which no function has yet been identified. About 80-90% of the human genome has been designated as "junk", including most sequences within introns and most intergenic DNA. While much of this sequence may be an evolutionary artifact that serves no present-day purpose, some is believed to function in ways that are not currently understood. Moreover, the conservation of some junk DNA over many millions of years of evolution may imply an essential function. Some consider the "junk" label as something of a misnomer, but others consider it apposite as junk is stored away for possible new uses, rather than thrown out; others prefer the term "noncoding DNA" (although junk DNA often includes transposons that encode proteins with no clear value to their host genome). However it now appears that, although protein-coding DNA makes up barely 2% of the human genome, about 80% of the bases in the genome may be being expressed, which supports the view that the term "junk DNA" may be a misnomer.^[1]

Broadly, the science of functional genomics has developed widely accepted techniques to characterize protein-coding genes, RNA genes, and regulatory regions. In the genomes of most plants and animals, however, these together constitute only a small percentage of genomic DNA (less than 2% in the case of humans). The function, if any, of the remainder remains under investigation. Most of it can be identified as repetitive elements that have no known biological function for their host (although they are useful to geneticists for analyzing lineage and phylogeny). Still, a large amount of sequence in these genomes falls under no existing classification other than "junk".

Overall genome size, and by extension the amount of junk DNA, appears to have little relationship to organism complexity: the genome of the unicellular Amoeba dubia has been reported to contain more than 200 times the amount of DNA in humans"^{[2] [3]}.

The pufferfish Takifugu rubripes genome is only about one tenth the size of the human genome, yet seems to have a comparable number of genes. Most of the difference appears to lie in what is now known only as junk DNA. This puzzle is known as the C-value enigma or, more conventionally, the C-value paradox^[4].

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Hypotheses of origin and function

There are some hypotheses, none conclusively established, from the most academic to the less expected, for how junk DNA arose and why it persists in the genome:

• These chromosomal regions could be composed of the now-defunct remains of ancient genes, known as pseudogenes, which were once functional copies of genes but have since lost their protein-coding ability (and, presumably, their biological function). After non-functionalization, pseudogenes are free to acquire genetic noise in the form of random mutations.
• 8% of human junk DNA has been shown to be formed by retrotransposons of Human Endogenous Retroviruses (HERVs)^[5], although as much as 25% is recognisably formed of retrotransposons^[6]. This is a lower limit on how much of the genome is retrotransposons because older remains might not be recognizable having accumulated too much mutation. New research suggests that genome size variation in at least two kinds of plants is mostly because of retrotransposons.^[7]
• Junk DNA may act as a protective buffer against genetic damage and harmful mutations. For example, a high proportion of nonfunctional sequence makes it unlikely that a functional element will be destroyed in a chromosomal crossover event, possibly making a species more tolerant to this important mechanism of genetic recombination.
• Junk DNA might provide a reservoir of sequences from which potentially advantageous new genes can emerge. In this way, it may be an important genetic basis for evolution^[8].
• Some junk DNA could simply be spacer material that allows enzyme complexes to form around functional elements more easily. In this way, the junk DNA could serve an important function even though the actual sequence information it contains is irrelevant.
• Some portions of junk DNA could serve presently unknown regulatory functions, controlling the expression of certain genes, the development of an organism from embryo to adult^[9], and/or development of certain organs/organelles^[10].
• More and more scientists believe that in fact regulatory layer(s) in the "junk DNA", such as through non-coding RNAs, altogether contain genetic programming at least on par with, and possibly much more important than protein coding genes.^[11] But still how much of the 98% would be involved in such activity is unknown.
• Junk DNA may have no function. For example, recent experiments removed 1% of the mouse genome and were unable to detect any effect on the phenotype^[12]. This result suggests that the DNA is, in fact, non-functional. However, it remains a possibility that there is some function that the experiments performed on the mice were merely insufficient to detect.

Evolutionary conservation of "junk" DNA

Comparative genomics is a promising direction in studying the function of junk DNA. Biologically functional sequences, as the theory goes, tend to undergo mutation at a slower rate than nonfunctional sequence, since mutations in these sequences are likely to be selected against. For example, the coding sequence of a human protein-coding gene is typically about 80% identical to its mouse ortholog, while their genomes as a whole are much more widely diverged. Analyzing the patterns of conservation between the genomes of different species can suggest which sequences are functional, or at least which functional sequences are shared by those species. Functional elements stand out in such analyses as having diverged less than the surrounding sequence.

Comparative studies of several mammalian genomes suggest that approximately 5% of the human genome has evolved under purifying selection^[13] since the divergence of the mammals. Since known functional sequence comprises less than 2% of the human genome, it appears that there may be more functional "junk" DNA in the human genome than there is known functional sequence.

A surprising recent finding was the discovery of nearly 500 ultraconserved elements^[14], which are shared at extraordinarily high fidelity among the available vertebrate genomes, in what had previously been designated as junk DNA. The function of these sequences is currently under intense scrutiny, and there are preliminary indications^[14][15][16] that some may play a regulatory role in vertebrate development from embryo to adult.

It must be noted that all present results concerning evolutionarily conserved human "junk" DNA are expressed in highly preliminary, probabilistic terms, since only a handful of related genomes are available. As more vertebrate, and especially mammalian, genomes are sequenced, scientists will develop a clearer picture of this important class of sequence. However, it is always possible, though highly unlikely, that there are significant quantities of functional human DNA that are not shared among these species, and which would thus not be revealed by these studies. Conversely there are even some questions about basic hypothesis that conserved sequences all must function ^[12].

On a theoretical note, it is often observed that the presence of high proportions of truly nonfunctional "junk" DNA would seem to defy evolutionary logic. Replication of such a large amount of useless information each time a cell divides would waste energy. Organisms with less nonfunctional DNA would thus enjoy a selective advantage, and over an evolutionary time scale, nonfunctional DNA would tend to be eliminated. If one assumes that most junk DNA is indeed nonfunctional, then there are several hypotheses for why it has not been eliminated by evolution: (1) The energy required to replicate even large amounts of nonfunctional DNA is in fact relatively insignificant on the cellular or organismal scale, so no selective pressure results (selection coefficients less than one over the population size are effectively neutral); (2) The aforementioned possible advantage of having extra DNA as a reservoir of potentially useful sequences and similarly as a protective buffer against harmful genetic damage or mutations; and (3) Retrotransposon insertions of nonfunctional sequence occurring faster than evolution can eliminate it. These are all hypotheses for which the time scales involved in evolution may make it difficult for humans to investigate rigorously.

Functions for Junk DNA

• A 2002 study from the University of Michigan showed that segments of junk DNA called LINE-1 elements, once thought to be "leftovers from the distant evolutionary past" now "deserve more respect" because they are capable of repairing broken strands of DNA. ^[17]

• A 2003 study from Tel Aviv University found crucial uses for "junk" sequences in human DNA. [3]

• A 2004 study from the Cell Press suggests that "more than one third of the mouse and human genomes, previously thought to be non-functional, may play some role in the regulation of gene expression and promotion of genetic diversity." [4]

• An article from BioEd Online details DNA which appears crucial although no function has yet been discovered. [5]

• A 2005 study from the National Institutes of Health found that social behavior in rodents (and, possibly humans [6]) was affected by portions of the genetic code once thought to be "junk." [7]

• A 2005 study from University of California-San Diego suggested that junk DNA is "critically important to an organism’s evolutionary survival." [8]

• Findings from Purdue University in 2005 stated that "many DNA sequences previously believed to have no function actually may play specialized roles in cell behavior." [9]

• A 2006 study by the McKusick-Nathans Institute of Genetic Medicine (Johns Hopkins) stated that "Junk DNA may not be so junky after all." [10]

• Researchers at the University of Illinois Society for Experimental Biology found an antifreeze-protein gene in a species of fish which "evolved" from junk DNA. [11]

• A mathematical analysis of the genetic code by IBM identified patterns that suggested junk DNA had an important role after all. [12]

• In 2006, University of Iowa researchers documented segments of RNA (previously considered "junk") that regulated protein production, and could generate microRNAs. [13]

• A 2007 study from Stanford University School of Medicine found that "Large swaths of garbled human DNA once dismissed as junk appear to contain some valuable sections."^[14]

See also

• Atavism
• Alu repeat
• Eukaryotic chromosome fine structure
• Genealogical DNA test
• Intron
• Repeated sequence (DNA)
• Retrotransposon
• Satellite DNA
• Selfish DNA

References

Further reading

• Gibbs W.W. (2003) "The unseen genome: gems among the junk", Scientific American, 289(5): 46-53. (A review, written for non-specialists, of recent discoveries of function within junk DNA.)