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In genomics and related disciplines, noncoding DNA
DNA
sequences are components of an organism's DNA
DNA
that do not encode protein sequences. Some noncoding DNA
DNA
is transcribed into functional non-coding RNA molecules (e.g. transfer RNA, ribosomal RNA, and regulatory RNAs). Other functions of noncoding DNA
DNA
include the transcriptional and translational regulation of protein-coding sequences, scaffold attachment regions, origins of DNA
DNA
replication, centromeres and telomeres. The amount of noncoding DNA
DNA
varies greatly among species. Often, only a small percentage of the genome is responsible for coding proteins, but a rising percentage is being shown to have regulatory functions. When there is much non-coding DNA, a large proportion appears to have no biological function, as predicted in the 1960s. Since that time, this non-functional portion has controversially been called "junk DNA".[1] The international Encyclopedia of DNA
DNA
Elements (ENCODE) project uncovered, by direct biochemical approaches, that at least 80% of human genomic DNA
DNA
has biochemical activity.[2] Though this was not necessarily unexpected due to previous decades of research discovering many functional noncoding regions,[3][4] some scientists criticized the conclusion for conflating biochemical activity with biological function.[5][6][7][8][9] Estimates for the biologically functional fraction of our genome based on comparative genomics range between 8 and 15%.[10][11][12] However, others have argued against relying solely on estimates from comparative genomics due to its limited scope. Non-coding DNA
DNA
has been found to be involved in epigenetic activity and complex networks of genetic interactions, and is being explored in evolutionary developmental biology.[4][11][13][14]

Contents

1 Fraction of noncoding genomic DNA 2 Types of noncoding DNA
DNA
sequences

2.1 Noncoding functional RNA 2.2 Cis- and trans-regulatory elements 2.3 Introns 2.4 Pseudogenes 2.5 Repeat sequences, transposons and viral elements 2.6 Telomeres

3 Junk DNA 4 Evidence of functionality 5 Regulating gene expression

5.1 Transcription factors 5.2 Operators 5.3 Enhancers 5.4 Silencers 5.5 Promoters 5.6 Insulators

6 Uses

6.1 Evolution 6.2 Long range correlations 6.3 Forensic anthropology

7 See also 8 References 9 Further reading 10 External links

Fraction of noncoding genomic DNA[edit]

Utricularia gibba
Utricularia gibba
has only 3% noncoding DNA.[15]

The amount of total genomic DNA
DNA
varies widely between organisms, and the proportion of coding and noncoding DNA
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.[3] 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
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
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
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
DNA
is useful for humans.[15] Other studies on plants have discovered crucial functions in portions of noncoding DNA
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
DNA
sequences[edit] Main article: Conserved non-coding sequence Noncoding functional RNA[edit]

Transfer RNA
Transfer RNA
and ribosomal RNA
RNA
are not translated into protein, but they are functional, synthesising proteins by translating the coding messenger RNA.

Noncoding RNAs are functional RNA
RNA
molecules that are not translated into protein. Examples of noncoding RNA
RNA
include ribosomal RNA, transfer RNA, Piwi-interacting RNA
RNA
and microRNA. 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.[20] 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. 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.[22] Introns[edit]

Simple illustration of an unspliced m RNA
RNA
precursor, with two introns and three exons (top). After the introns have been removed via splicing, the mature m RNA
RNA
sequence is ready for translation (bottom).

Introns
Introns
are non-coding sections of a gene, transcribed into the precursor m RNA
RNA
sequence, but ultimately removed by RNA
RNA
splicing during the processing to mature messenger RNA. Many introns appear to be mobile genetic elements.[23] Studies of group I introns from Tetrahymena
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.[23] Some introns appear to have significant biological function, possibly through ribozyme functionality that may regulate t RNA
RNA
and r RNA
RNA
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.[23] Pseudogenes[edit] Pseudogenes are DNA
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.[24] Pseudogenes resulting from the retrotransposition of an RNA
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.[24] While Dollo's Law
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[25] and a substantial number of pseudogenes are actively transcribed.[24][26] 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.[27] Repeat sequences, transposons and viral elements[edit]

Mobile genetic elements
Mobile genetic elements
in the cell (left) and how they can be acquired (right)

Transposons and retrotransposons are mobile genetic elements. Retrotransposon
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.[28][29][30] Endogenous retrovirus
Endogenous retrovirus
sequences are the product of reverse transcription of retrovirus genomes into the genomes of germ cells. Mutation
Mutation
within these retro-transcribed sequences can inactivate the viral genome.[31] 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
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.[32] Genome size
Genome size
variation in at least two kinds of plants is mostly the result of retrotransposon sequences.[33][34] Telomeres[edit] Telomeres are regions of repetitive DNA
DNA
at the end of a chromosome, which provide protection from chromosomal deterioration during DNA replication. Junk DNA[edit] The term "junk DNA" became popular in the 1960s.[35][36] According to T. Ryan Gregory, the nature of junk DNA
DNA
was first discussed explicitly in 1972 by a genomic biologist, David Comings, who applied the term to all noncoding DNA.[37] The term was formalized that same year 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.[6] Though the fruitfulness of the term "junk DNA" has been questioned on the grounds that it provokes a strong a priori assumption of total non-functionality and though some have recommended using more neutral terminology such as "noncoding DNA" instead;[37] "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
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."[39] The amount of junk DNA
DNA
can be expected to depend on the rate of amplification of these elements and the rate at which non-functional DNA
DNA
is lost.[40] In the same issue of Nature, Leslie Orgel and Francis Crick
Francis Crick
wrote that junk DNA
DNA
has "little specificity and conveys little or no selective advantage to the organism".[41] The term occurs mainly in popular science and in a colloquial way in scientific publications, and it has been suggested that its connotations may have delayed interest in the biological functions of noncoding DNA.[42] 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
Human
Genome Research Institute, reported that 76% of the human genome's noncoding DNA
DNA
sequences were transcribed and that nearly half of the genome was in some way accessible to genetic regulatory proteins such as transcription factors.[1] However, the suggestion by ENCODE
ENCODE
that over 80% of the human genome is biochemically functional has been criticized by other scientists,[5] 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
ENCODE
were based on genomic conservation estimates across mammalian lineages.[6][7][8][9] 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.[11][13] 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.[11] Furthermore, much of the apparent junk DNA
DNA
is involved in epigenetic regulation and appears to be necessary for the development of complex organisms.[4][13][14] In a 2014 paper, ENCODE
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.[11] 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
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.[11] Some critics have argued that functionality can only be assessed in reference to an appropriate null hypothesis. In this case, the null hypothesis would be that these parts of the genome are non-functional and have properties, be it on the basis of conservation or biochemical activity, that would be expected of such regions based on our general understanding of molecular evolution and biochemistry. According to these critics, until a region in question has been shown to have additional features, beyond what is expected of the null hypothesis, it should provisionally be labelled as non-functional.[44] Evidence of functionality[edit] Many noncoding DNA
DNA
sequences must have some important biological function. This is indicated by comparative genomics studies that report highly conserved regions of noncoding DNA, sometimes on time-scales of hundreds of millions of years. This implies 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
DNA
sequences account for only about 20% of conserved DNA, with the remaining 80% of conserved DNA
DNA
represented in noncoding regions.[46] Linkage mapping
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
DNA
mutations in cancer was explored in April 2013.[47] Noncoding genetic polymorphisms play a role in infectious disease susceptibility, such as hepatitis C.[48] Moreover, noncoding genetic polymorphisms contribute to susceptibility to Ewing sarcoma, an aggressive pediatric bone cancer.[49] Some specific sequences of noncoding DNA
DNA
may be features essential to chromosome structure, centromere function and homolog recognition in meiosis.[50] 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. The 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. Over 10% of 32 mammalian genomes may function through the formation of specific RNA
RNA
secondary structures.[52] The study used comparative genomics to identify compensatory DNA
DNA
mutations that maintain RNA base-pairings, a distinctive feature of RNA
RNA
molecules. Over 80% of the genomic regions presenting evolutionary evidence of RNA
RNA
structure conservation do not present strong DNA
DNA
sequence conservation. Noncoding DNA
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 a frameshift effect 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. Non-coding DNA
DNA
may perhaps serve to decrease the probability of gene disruption during chromosomal crossover.[53] Regulating gene expression[edit] Main article: Regulation of gene expression Some noncoding DNA
DNA
sequences determine the expression levels of various genes, both those that are transcribed to proteins and those that themselves are involved in gene regulation.[54][55][56] Transcription factors[edit] Main article: Transcription factor Some noncoding DNA
DNA
sequences determine where transcription factors attach.[54] A transcription factor is a protein that binds to specific non-coding DNA
DNA
sequences, thereby controlling the flow (or transcription) of genetic information from DNA
DNA
to mRNA.[57][58] Operators[edit] Main article: Operator (biology) An operator is a segment of DNA
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
RNA
polymerase to the promoter, thus preventing transcription of the genes. This blocking of expression is called repression.[59] Enhancers[edit] Main article: Enhancer (genetics) An enhancer is a short region of DNA
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..[60] Silencers[edit] Main article: Silencer (DNA) A silencer is a region of DNA
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.[61] Promoters[edit] Main article: Promoter (biology) A promoter is a region of DNA
DNA
that facilitates transcription of a particular gene when a transcription factor binds to it. Promoters are typically located near the genes they regulate and upstream of them.[62] Insulators[edit] 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.[63] Uses[edit] Evolution[edit] Shared sequences of apparently non-functional DNA
DNA
are a major line of evidence of common descent.[64] Pseudogene
Pseudogene
sequences appear to accumulate mutations more rapidly than coding sequences due to a loss of selective pressure.[27] 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".[65] Long range correlations[edit] A statistical distinction between coding and noncoding DNA
DNA
sequences has been found. It has been observed that nucleotides in non-coding DNA
DNA
sequences display long range power law correlations while coding sequences do not.[66][67][68] Forensic anthropology[edit] Police sometimes gather DNA
DNA
as evidence for purposes of forensic identification. As described in Maryland v. King, a 2013 U.S. Supreme Court decision:[69]

The current standard for forensic DNA
DNA
testing relies on an analysis of the chromosomes located within the nucleus of all human cells. 'The DNA
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
DNA
region used with near certainty to identify a person.[69]

See also[edit]

Conserved non-coding sequence Eukaryotic
Eukaryotic
chromosome fine structure Gene-centered view of evolution Gene
Gene
regulatory network Intergenic region Intragenomic conflict Phylogenetic footprinting Transcriptome Non-coding RNA Gene
Gene
desert

References[edit]

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Further reading[edit]

Bennett, Michael D.; Leitch, Ilia J. (2005). " Genome size
Genome size
evolution in plants". In Gregory, T. Ryan. The Evolution
Evolution
of the Genome. San Diego: Elsevier. pp. 89–162. ISBN 978-0-08-047052-8.  Gregory, T.R (2005). " Genome size
Genome size
evolution in animals". In T.R. Gregory. The Evolution
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
DNA
sequences". Genome Biol. 5 (4): 105. doi:10.1186/gb-2004-5-4-105. PMC 395773 . PMID 15059247.  Castillo-Davis CI (October 2005). "The evolution of noncoding DNA: how much junk, how much func?". Trends Genet. 21 (10): 533–6. doi:10.1016/j.tig.2005.08.001. PMID 16098630. 

External links[edit]

Plant DNA
DNA
C-values Database at Royal Botanic Gardens, Kew Fungal Genome
Genome
Size Database at Estonian Institute of Zoology and Botany ENCODE: The human encyclopaedi

.