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Non-coding DNA

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Utricularia gibba has 3% noncoding DNA,[1] which is low for flowering plants.

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 noncoding 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,[2] 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. 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. Other noncoding sequences have likely, but as-yet undetermined, functions. (This is inferred from high levels of homology and conservation seen in sequences that do not encode proteins but, nonetheless, appear to be under heavy selective pressure.)

The Encyclopedia of DNA Elements (ENCODE) project[3] suggested in September 2012 that over 80% of DNA in the human genome "serves some purpose, biochemically speaking".[4] This conclusion however is strongly criticized by other scientists.[5][6]

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.[2]

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.[7] 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.[2] 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."[1] The extensive variation in nuclear genome size among eukaryotic species is known as the C-value enigma or C-value paradox.[8] Most of the genome size difference appears to lie in the noncoding DNA.

About 80 percent of the nucleotide bases in the human genome may be transcribed,[9] but transcription does not necessarily imply function.[10]

Types of noncoding DNA sequences

Main article: Conserved non-coding sequence

Noncoding functional RNA

Noncoding RNAs are functional RNA molecules that are not translated into protein. Examples of noncoding RNA include ribosomal RNA, transfer RNA, Piwi-interacting 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.[11]

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.[12]

Introns

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.[13]

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.[13] 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.[13]

Pseudogenes

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.[14] 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.[14]

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[15] and a substantial number of pseudogenes are actively transcribed.[14][16] 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.[17]

Repeat sequences, transposons and viral elements

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.[18][19][20]

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.[21]

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.[22] Genome size variation in at least two kinds of plants is mostly the result of retrotransposon sequences.[23] [24]

Telomeres

Telomeres are regions of repetitive DNA at the end of a chromosome, which provide protection from chromosomal deterioration during DNA replication.

Junk DNA

"Junk DNA" is a term that was introduced in 1972 by Susumu Ohno,[25] 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.

Junk DNA remains a label for the portions of a genome sequence for which no discernible function had been identified. According to a 1980 review in Nature by Leslie Orgel and Francis Crick, junk DNA has "little specificity and conveys little or no selective advantage to the organism".[26] The term is used mainly in popular science and in a colloquial way in scientific publications. Scientific American claims that its connotations may have slowed research into the biological functions of noncoding DNA.[27]

Several lines of evidence indicate that some "junk DNA" sequences are likely to have unidentified functional activity, and other sequences may have had functions in the past.[28] Recently junk DNA sequences were artificially expressed resulting in the synthesis of functional proteins. 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. This, however, does not necessarily mean that all of these segments have true biochemical function.[4] The suggestion by ENCODE that over 80% of the human genome may be functional has been met with sharply critical response from other scientists.[5][6]

Still, a significant amount of the sequence of the genomes of eukaryotic organisms currently appears to fall under no existing classification other than "junk". For example, one experiment removed 0.1% of the mouse genome with no detectable effect on the phenotype.[29] This result suggests that the removed DNA was largely nonfunctional. However, more recent research directly contradicts this view, finding that mice and other mammalian genomic noncoding elements possess functions that contribute noticeably to organism fitness in natural populations. [30]

In addition, these sequences are enriched for the heterochromatic histone modification H3K9me3.[31]

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.[32] 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.[33] 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.[33]

Some specific sequences of noncoding DNA may be features essential to chromosome structure, centromere function and homolog recognition in meiosis.[34]

According to a comparative study of over 300 prokaryotic and over 30 eukaryotic genomes,[35] 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.

Protection of the genome

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 "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.

Genetic switches

Some noncoding DNA sequences are genetic "switches" that regulate when and where genes are expressed.[36]

Regulation of gene expression

Main article: Regulation of gene expression

Some noncoding DNA sequences determine the expression levels of various genes.[37]

Transcription factor sites

Main article: Transcription factor

Some noncoding DNA sequences determine where transcription factors attach.[37] 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.

Operators

Main article: Operator (biology)

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.

Enhancers

Main article: Enhancer (genetics)

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.

Silencers

Main article: Silencer (DNA)

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.

Promoters

Main article: Promoter (biology)

A promoter is a region of DNA that facilitates transcription of a particular gene. Promoters are typically located near the genes they regulate.

Insulators

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 of noncoding DNA

Noncoding DNA and evolution

Shared sequences of apparently non-functional DNA are a major line of evidence of common descent.[38]

Pseudogene sequences appear to accumulate mutations more rapidly than coding sequences due to a loss of selective pressure.[17] 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".[39]

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.[40][41][42]

Forensic anthropology

Police sometimes gather DNA as evidence for purposes of forensic identification. As described in Maryland v. King, a 2013 U.S. Supreme Court decision:[43]

"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

References

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Further reading

Bennett, M.D. and I.J. Leitch (2005). "Genome size evolution in plants". In T.R. Gregory (ed.) (ed.). The Evolution of the Genome. San Diego: Elsevier. pp. 89–162. {{cite book}}: |editor= has generic name (help)
Gregory, T.R (2005). "Genome size evolution in animals". In T.R. Gregory (ed.) (ed.). The Evolution of the Genome. San Diego: Elsevier. ISBN 0-12-301463-8. {{cite book}}: |editor= has generic name (help)
Shabalina SA, Spiridonov NA (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 395773. PMID 15059247.{{cite journal}}: CS1 maint: unflagged free DOI (link)
Castillo-Davis CI (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. {{cite journal}}: Unknown parameter |month= ignored (help)
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