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), while others are not transcribed or give rise to RNA transcripts of unknown function. The amount of noncoding DNA varies greatly among species. For example, over 98% of the human genome is noncoding DNA, while only about 2% of a typical bacterial genome is noncoding DNA.
Initially, a large proportion of noncoding DNA had no known biological function and was therefore sometimes referred to as "junk DNA", particularly in the lay press. However, it has been known for decades that many noncoding sequences are functional. These include genes for functional RNA molecules (see above) and sequences such as origins of replication, centromeres, and telomeres.
Some sequences may have no biological function for the organism, such as endogenous retroviruses. However, many types of noncoding DNA sequences do have important biological functions, including the transcriptional and translational regulation of protein-coding sequences, origins of DNA replication, centromeres, telomeres, scaffold attachment regions (SARs), genes for functional RNAs, and many others. Other noncoding sequences have likely, but as-yet undetermined, functions. (This is inferred from high levels of sequence similarity seen in different species.)
The Encyclopedia of DNA Elements (ENCODE) project suggested in September 2012 that over 80% of DNA in the human genome "serves some purpose, biochemically speaking". This conclusion however is strongly criticized by other scientists, with a recent article claiming that "8.2% of the human genome is likely to be functional, while only 2.2% has maintained constraint in both human and mouse since these species diverged".
- 1 Fraction of noncoding genomic DNA
- 2 Types of noncoding DNA sequences
- 3 Junk DNA
- 4 Functions of noncoding DNA
- 5 Uses of noncoding DNA
- 6 See also
- 7 References
- 8 Further reading
- 9 External links
Fraction of noncoding genomic DNA
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. More than 98% of the human genome does not encode protein sequences, including most sequences within introns and most intergenic DNA.
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. 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. In 2013, a new "record" for most efficient genome was discovered. Utricularia gibba, a bladderwort plant, has only 3% noncoding DNA. The discovery led project co-lead Victor Albert to declare "At least for a plant, junk DNA really is just junk - it's not required." The extensive variation in nuclear genome size among eukaryotic species is known as the C-value enigma or C-value paradox. Most of the genome size difference appears to lie in the noncoding DNA.
Types of noncoding DNA sequences
Noncoding functional RNA
MicroRNAs are predicted to control the translational activity of approximately 30% of all protein-coding genes in mammals and may be vital components in the progression or treatment of various diseases including cancer, cardiovascular disease, and the immune system response to infection.
Cis- and Trans-regulatory elements
Cis-regulatory elements are sequences that control the transcription of a nearby gene. Cis-elements may be located in 5' or 3' untranslated regions or within introns. Trans-regulatory elements control the transcription of a distant gene.
Promoters facilitate the transcription of a particular gene and are typically upstream of the coding region. Enhancer sequences may also exert very distant effects on the transcription levels of genes.
Introns are non-coding sections of a gene, transcribed into the precursor mRNA sequence, but ultimately removed by RNA splicing during the processing to mature messenger RNA. Many introns appear to be mobile genetic elements.
Studies of group I introns from Tetrahymena protozoans indicate that some introns appear to be selfish genetic elements, neutral to the host because they remove themselves from flanking exons during RNA processing and do not produce an expression bias between alleles with and without the intron. Some introns appear to have significant biological function, possibly through ribozyme functionality that may regulate tRNA and rRNA activity as well as protein-coding gene expression, evident in hosts that have become dependent on such introns over long periods of time; for example, the trnL-intron is found in all green plants and appears to have been vertically inherited for several billions of years, including more than a billion years within chloroplasts and an additional 2–3 billion years prior in the cyanobacterial ancestors of chloroplasts.
Pseudogenes are DNA sequences, related to known genes, that have lost their protein-coding ability or are otherwise no longer expressed in the cell. Pseudogenes arise from retrotransposition or genomic duplication of functional genes, and become "genomic fossils" that are nonfunctional due to mutations that prevent the transcription of the gene, such as within the gene promoter region, or fatally alter the translation of the gene, such as premature stop codons or frameshifts. Pseudogenes resulting from the retrotransposition of an RNA intermediate are known as processed pseudogenes; pseudogenes that arise from the genomic remains of duplicated genes or residues of inactivated genes are nonprocessed pseudogenes.
While Dollo's Law suggests that the loss of function in pseudogenes is likely permanent, silenced genes may actually retain function for several million years and can be "reactivated" into protein-coding sequences and a substantial number of pseudogenes are actively transcribed. Because pseudogenes are presumed to change without evolutionary constraint, they can serve as a useful model of the type and frequencies of various spontaneous genetic mutations.
Transposons and retrotransposons are mobile genetic elements. Retrotransposon repeated sequences, which include long interspersed nuclear elements (LINEs) and short interspersed nuclear elements (SINEs), account for a large proportion of the genomic sequences in many species. Alu sequences, classified as a short interspersed nuclear element, are the most abundant mobile elements in the human genome. Some examples have been found of SINEs exerting transcriptional control of some protein-encoding genes.
Endogenous retrovirus sequences are the product of reverse transcription of retrovirus genomes into the genomes of germ cells. Mutation within these retro-transcribed sequences can inactivate the viral genome.
Over 8% of the human genome is made up of (mostly decayed) endogenous retrovirus sequences, as part of the over 42% fraction that is recognizably derived of retrotransposons, while another 3% can be identified to be the remains of DNA transposons. Much of the remaining half of the genome that is currently without an explained origin is expected to have found its origin in transposable elements that were active so long ago (> 200 million years) that random mutations have rendered them unrecognizable. Genome size variation in at least two kinds of plants is mostly the result of retrotransposon sequences.
The term "junk DNA" became popular in the 1960s. It was formalized in 1972 by Susumu Ohno, 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 predicted 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.
Junk DNA remains a label for the portions of a genome sequence for which no discernible function has been identified and that through comparative genomics analysis appear under no functional constraint suggesting that the sequence itself has provided no adaptive advantage. Since the late 70s it has become apparent that the majority of non-coding DNA in large genomes finds its origin in the selfish amplification of transposable elements, of which W.Ford Doolittle and Carmen Sapienza in 1980 wrote in the journal Nature: "When a given DNA, or class of DNAs, of unproven phenotypic function can be shown to have evolved a strategy (such as transposition) which ensures its genomic survival, then no other explanation for its existence is necessary." The amount of junk DNA can be expected to depend on the rate of amplification of these elements and the rate at which non-functional DNA is lost. In the same issue of Nature, Leslie Orgel and Francis Crick, wrote that junk DNA has "little specificity and conveys little or no selective advantage to the organism". The term is used mainly in popular science and in a colloquial way in scientific publications and it has occasionally been suggested that its connotations may have delayed interest in the biological functions of noncoding DNA.
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. 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. However, the suggestion by ENCODE that over 80% of the human genome is biochemically functional has been sharply criticized by other scientists, 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. In a 2014 paper the leaders of the ENCODE project tried to address "the question of whether nonconserved but biochemically active regions are truly functional". They acknowledged that "the larger proportion of genome with reproducible but low biochemical signal strength and less evolutionary conservation [e.g. 70% of the documented transcribed coverage] is challenging to parse between specific functions and biological noise", that the essay resolution often is much broader than the underlying functional sites, and that therefore some of the reproducibly “biochemically active but selectively neutral” sequences are unlikely to serve critical functions. On the other hand, they argued that the 12–15% fraction of human DNA under functional constraint, as estimated by a variety of extrapolative methods, may still be an underestimate.
Functions of noncoding DNA
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. 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. 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. The significance of noncoding DNA mutations in cancer was explored in 
According to a comparative study of over 300 prokaryotic and over 30 eukaryotic genomes, 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. 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
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 "frameshift mutation" on the whole chromosome. When genome complexity is relatively high, like in the case of human genome, not only different genes, but also inside one gene there are gaps of introns to protect the entire coding segment to minimise the changes caused by mutation.
Some noncoding DNA sequences are genetic "switches" that regulate when and where genes are expressed.
Regulation of gene expression
Some noncoding DNA sequences determine the expression levels of various genes.
Transcription factor sites
Some noncoding DNA sequences determine where transcription factors attach. 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.
An operator is a segment of DNA to which a repressor binds. A repressor is a DNA-binding protein that regulates the expression of one or more genes by binding to the operator and blocking the attachment of RNA polymerase to the promoter, thus preventing transcription of the genes. This blocking of expression is called repression.
An enhancer is a short region of DNA that can be bound with proteins (trans-acting factors), much like a set of transcription factors, to enhance transcription levels of genes in a gene cluster.
A silencer is a region of DNA that inactivates gene expression when bound by a regulatory protein. It functions in a very similar way as enhancers, only differing in the inactivation of genes.
A promoter is a region of DNA that facilitates transcription of a particular gene. Promoters are typically located near the genes they regulate.
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
Noncoding DNA and evolution
Pseudogene sequences appear to accumulate mutations more rapidly than coding sequences due to a loss of selective pressure. This allows for the creation of mutant alleles that incorporate new functions that may be favored by natural selection; thus, pseudogenes can serve as raw material for evolution and can be considered "protogenes".
Long range correlations
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.
"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.
- Conserved non-coding sequence
- Eukaryotic chromosome fine structure
- Gene-centered view of evolution
- Gene regulatory network
- Intergenic region
- Intragenomic conflict
- Phylogenetic footprinting
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