Noncoding DNA

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Utricularia gibba has only 3% noncoding DNA.[1]

In genomics and related disciplines, noncoding DNA sequences are components of an organism's DNA that do not encode protein sequences. Some noncoding DNA is transcribed into functional non-coding RNA molecules (e.g. transfer RNA, ribosomal RNA, and regulatory RNAs). Other functions of noncoding DNA include the transcriptional and translational regulation of protein-coding sequences, scaffold attachment regions, origins of DNA replication, centromeres and telomeres.

The amount of noncoding DNA varies greatly among species. Where only a small percentage of the genome is responsible for coding proteins, the percentage of the genome performing regulatory functions is growing. When there is much non-coding DNA, a large proportion appears to have no biological function for the organism, as theoretically predicted in the 1960s. Since that time, this non-functional portion has often been referred to as "junk DNA", a term that has elicited strong responses over the years.[2]

The international Encyclopedia of DNA Elements (ENCODE) project uncovered, by direct biochemical approaches, that at least 80% of human genomic DNA has biochemical activity.[3] Though this was not necessarily unexpected due to previous decades of research discovering many functional noncoding regions,[4][5] some scientists criticized the conclusion for conflating biochemical activity with biological function.[6][7][8][9][10] Estimates for the biologically functional fraction of our genome based on comparative genomics range between 8 and 15%.[11][12][13] However, others have argued against relying solely on estimates from comparative genomics due to its limited scope because non-coding DNA has been found to be involved in epigenetic activity and complex networks of genetic interactions, being explored in evolutionary developmental biology.[5][12][14][15]

Fraction of noncoding genomic DNA[edit]

The amount of total genomic DNA varies widely between organisms, and the proportion of coding and noncoding DNA within these genomes varies greatly as well. For example, it was originally suggested that over 98% of the human genome does not encode protein sequences, including most sequences within introns and most intergenic DNA,[16] whilst 20% of a typical prokaryote genome is noncoding.[4]

While overall genome size, and by extension the amount of noncoding DNA, are correlated to organism complexity, there are many exceptions. For example, the genome of the unicellular Polychaos dubium (formerly known as Amoeba dubia) has been reported to contain more than 200 times the amount of DNA in humans.[17] The pufferfish Takifugu rubripes genome is only about one eighth the size of the human genome, yet seems to have a comparable number of genes; approximately 90% of the Takifugu genome is noncoding DNA.[16] The extensive variation in nuclear genome size among eukaryotic species is known as the C-value enigma or C-value paradox.[18] Most of the genome size difference appears to lie in the noncoding DNA.

In 2013, a new "record" for the most efficient eukaryotic genome was discovered with Utricularia gibba, a bladderwort plant that has only 3% noncoding DNA and 97% of coding DNA. Parts of the noncoding DNA were being deleted by the plant and this suggested that noncoding DNA may not be as critical for plants, even though noncoding DNA is useful for humans.[1] Other studies on plants have discovered crucial functions in portions noncoding DNA that were previously thought to be negligible and have added a new layer to the understanding of gene regulation.[19]

Types of noncoding DNA sequences[edit]

Noncoding functional RNA[edit]



Cis- and trans-regulatory elements[edit]

Cis-regulatory elements are sequences that control the transcription of a nearby gene. Many such elements are involved in the evolution and control of development.[21] Cis-elements may be located in 5' or 3' untranslated regions or within introns. Trans-regulatory elements control the transcription of a distant gene.








Repeat sequences, transposons and viral elements[edit]






Junk DNA[edit]

The term "junk DNA" became popular in the 1960s.[35][36] According to T. Ryan Gregory, a genomic biologist, David Comings was the first to discuss the nature of junk DNA explicitly in 1972, and he applied the term to all noncoding DNA.[37] The term was formalized in 1972 by Susumu Ohno,[38] who noted that the mutational load from deleterious mutations placed an upper limit on the number of functional loci that could be expected given a typical mutation rate. Ohno hypothesized that mammal genomes could not have more than 30,000 loci under selection before the "cost" from the mutational load would cause an inescapable decline in fitness, and eventually extinction. This prediction remains robust, with the human genome containing approximately 20,000 genes. Another source for Ohno's theory was the observation that even closely related species can have widely (orders-of-magnitude) different genome sizes, which had been dubbed the C-value paradox in 1971.[7]


Several lines of evidence indicate that some "junk DNA" sequences are likely to have unidentified functional activity and that the process of exaptation of fragments of originally selfish or non-functional DNA has been commonplace throughout evolution.[43] In 2012, the ENCODE project, a research program supported by the National Human Genome Research Institute, reported that 76% of the human genome's noncoding DNA sequences were transcribed and that nearly half of the genome was in some way accessible to genetic regulatory proteins such as transcription factors.[2]

However, the suggestion by ENCODE that over 80% of the human genome is biochemically functional has been criticized by other scientists,[6] who argue that neither accessibility of segments of the genome to transcription factors nor their transcription guarantees that those segments have biochemical function and that their transcription is selectively advantageous. Furthermore, the much lower estimates of functionality prior to ENCODE were based on genomic conservation estimates across mammalian lineages.[7][8][9][10]

In response to such views, other scientists argue that the wide spread transcription and splicing that is observed in the human genome directly by biochemical testing is a more accurate indicator of genetic function than genomic conservation because conservation estimates are relative due to incredible variations in genome sizes of even closely related species, it is partially tautological, and these estimates are not based on direct testing for functionality on the genome.[12][14] Conservation estimates may be used to provide clues to identify possible functional elements in the genome, but it does not limit or cap the total amount of functional elements that could possibly exist in the genome since elements that do things at the molecular level can be missed by comparative genomics.[12] Furthermore, much of the apparent junk DNA is involved in epigenetic regulation and appears to be necessary for the development of complex organisms.[5][14][15]

In a 2014 paper, ENCODE researchers tried to address "the question of whether nonconserved but biochemically active regions are truly functional". They noted that in the literature, functional parts of the genome have been identified differently in previous studies depending on the approaches used. There have been three general approaches used to identify functional parts of the human genome: genetic approaches (which rely on changes in phenotype), evolutionary approaches (which rely on conservation) and biochemical approaches (which rely on biochemical testing and was used by ENCODE). All three have limitations: genetic approaches may miss functional elements that do not manifest physically on the organism, evolutionary approaches have difficulties using accurate multispecies sequence alignments since genomes of even closely related species vary considerably, and with biochemical approaches, though having high reproducibility, the biochemical signatures do not always automatically signify a function.[12]

They noted that 70% of the transcription coverage was less than 1 transcript per cell. They noted that this "larger proportion of genome with reproducible but low biochemical signal strength and less evolutionary conservation is challenging to parse between specific functions and biological noise". Furthermore, assay resolution often is much broader than the underlying functional sites so some of the reproducibly “biochemically active but selectively neutral” sequences are unlikely to serve critical functions, especially those with lower-level biochemical signal. To this they added, "However, we also acknowledge substantial limitations in our current detection of constraint, given that some human-specific functions are essential but not conserved and that disease-relevant regions need not be selectively constrained to be functional." On the other hand, they argued that the 12–15% fraction of human DNA under functional constraint, as estimated by a variety of extrapolative evolutionary methods, may still be an underestimate. They concluded that in contrast to evolutionary and genetic evidence, biochemical data offer clues about both the molecular function served by underlying DNA elements and the cell types in which they act. Ultimately genetic, evolutionary, and biochemical approaches can all be used in a complementary way to identify regions that may be functional in human biology and disease.[12]


Functions of noncoding DNA[edit]

Many noncoding DNA sequences have important biological functions as indicated by comparative genomics studies that report some regions of noncoding DNA that are highly conserved, sometimes on time-scales representing hundreds of millions of years, implying that these noncoding regions are under strong evolutionary pressure and positive selection.[45] For example, in the genomes of humans and mice, which diverged from a common ancestor 65–75 million years ago, protein-coding DNA sequences account for only about 20% of conserved DNA, with the remaining 80% of conserved DNA represented in noncoding regions.[46] Linkage mapping often identifies chromosomal regions associated with a disease with no evidence of functional coding variants of genes within the region, suggesting that disease-causing genetic variants lie in the noncoding DNA.[46] The significance of noncoding DNA mutations in cancer was explored in April 2013.[47]

Noncoding genetic polymorphisms have also been shown to play a role in infectious disease susceptibility, such as hepatitis C.[48] Moreover, noncoding genetic polymorphisms were shown to contribute to susceptibility to Ewing sarcoma - a highly aggressive pediatric bone cancer.[49]


According to a comparative study of over 300 prokaryotic and over 30 eukaryotic genomes,[51] eukaryotes appear to require a minimum amount of non-coding DNA. This minimum amount can be predicted using a growth model for regulatory genetic networks, implying that it is required for regulatory purposes. In humans the predicted minimum is about 5% of the total genome.

There is evidence that a significant proportion (over 10%) of 32 mammalian genomes may function through the formation of specific RNA secondary structures.[52] The study used comparative genomics to identify compensatory DNA mutations that maintain RNA base-pairings, a distinctive feature of RNA molecules. Over 80% of the genomic regions presenting evolutionary evidence of RNA structure conservation do not present strong DNA sequence conservation.

Protection of the genome[edit]

Main article: Mutation

Noncoding DNA separate genes from each other with long gaps, so mutation in one gene or part of a chromosome, for example deletion or insertion, does not have the frame shift effect (as in "frameshift mutation") on the whole chromosome. When genome complexity is relatively high, like in the case of human genome, not only between different genes, but also inside many genes, there are gaps of introns to protect the entire coding segment and minimise the changes caused by mutation.

It has been suggested that non-coding DNA may serve to decrease the chance of gene disruption during chromosomal crossover.[53]

Genetic switches[edit]

Some noncoding DNA sequences are genetic "switches" that regulate when and where genes are expressed.[54] For example, a long non-coding RNA (lncRNA) molecule was recently found to assist in preventing breast cancer, by stopping a genetic switch from getting stuck.[55]

Regulation of gene expression[edit]

Some noncoding DNA sequences determine the expression levels of various genes.[56] In addition, some noncoding variants have been associated to variation in expression levels of mRNAs through mapping of Expression quantitative trait loci (eQTLs). When eQTLs are combined with Genome-wide association study (GWAS), some independent risk variants for the same disease impacted on expression of the same mRNAs, or on mRNAs with similar functions.[57]

Transcription factor sites[edit]

Main article: Transcription factor

Some noncoding DNA sequences determine where transcription factors attach.[56] A transcription factor is a protein that binds to specific non-coding DNA sequences, thereby controlling the flow (or transcription) of genetic information from DNA to mRNA. Transcription factors act at very different locations on the genomes of different people.


Main article: Operator (biology)



Main article: Enhancer (genetics)



Main article: Silencer (DNA)



Main article: Promoter (biology)



Main article: Insulator (genetics)

A genetic insulator is a boundary element that plays two distinct roles in gene expression, either as an enhancer-blocking code, or rarely as a barrier against condensed chromatin. An insulator in a DNA sequence is comparable to a linguistic word divider such as a comma (,) in a sentence, because the insulator indicates where an enhanced or repressed sequence ends.

Uses of noncoding DNA[edit]

Noncoding DNA and evolution[edit]

Shared sequences of apparently non-functional DNA are a major line of evidence of common descent.[58]


Long range correlations[edit]

A statistical distinction between coding and noncoding DNA sequences has been found. It has been observed that nucleotides in non-coding DNA sequences display long range power law correlations while coding sequences do not.[60][61][62]

Forensic anthropology[edit]


"The current standard for forensic DNA testing relies on an analysis of the chromosomes located within the nucleus of all human cells. “The DNA material in chromosomes is composed of ‘coding’ and ‘noncoding’ regions. The coding regions are known as genes and contain the information necessary for a cell to make proteins. . . . Non-protein coding regions . . . are not related directly to making proteins, [and] have been referred to as ‘junk’ DNA.” The adjective “junk” may mislead the lay person, for in fact this is the DNA region used with near certainty to identify a person.

See also[edit]


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Further reading[edit]

Bennett, Michael D.; Leitch, Ilia J. (2005). "Genome size evolution in plants". In Gregory, T. Ryan. The Evolution of the Genome. San Diego: Elsevier. pp. 89–162. ISBN 978-0-08-047052-8. 
Gregory, T.R (2005). "Genome size evolution in animals". In T.R. Gregory. The Evolution of the Genome. San Diego: Elsevier. ISBN 0-12-301463-8. 
Shabalina SA, Spiridonov NA; Spiridonov (2004). "The mammalian transcriptome and the function of non-coding DNA sequences". Genome Biol. 5 (4): 105. doi:10.1186/gb-2004-5-4-105. PMC 395773Freely accessible. PMID 15059247. 
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