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Non-coding DNA sequences are components of an organism's DNA that do not encode protein sequences. Some non-coding DNA is transcribed into functional non-coding RNA molecules (e.g. transfer RNA, ribosomal RNA, and regulatory RNAs) and some others are transcribed into nonfunctional noise. Other functions of non-coding DNA include the transcriptional and translational regulation of protein-coding sequences, scaffold attachment regions, origins of DNA replication, centromeres and telomeres. Its RNA counterpart is non-coding RNA. Function for the classification below is defined as selected-effect function, which means that a sequence is maintained in the genome through natural selection for its function. [1][2]
Functional non-coding DNA sequences
[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.[3] 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.[4]
Telomeres
[edit]Telomeres are regions of repetitive DNA at the end of a chromosome, which provide protection from chromosomal deterioration during DNA replication. Recent studies have shown that telomeres function to aid in its own stability. Telomeric repeat-containing RNA (TERRA) are transcripts derived from telomeres. TERRA has been shown to maintain telomerase activity and lengthen the ends of chromosomes.[5]
RNA specifying genes
[edit]RNA specifying genes are regulatory factors that change the expression of RNA sequences which does not require a protein to achieve. (need to cite)
Origins of replication
[edit]Origins of replication is a sequence that is an initiator for DNA replication [6]
Centromeres
[edit]Centromeres are important regions of a chromosome that allow for microtubule attachment.[7]
Scaffold attachment regions
[edit]Scaffold/matrix attachment regions are DNA elements whose function is to compartmentalize chromatin into functional domains. [8]
Nonfunctional non-coding DNA sequences
[edit]Pseudogenes
[edit]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.[9] 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.[9] Transpositions of once functional mitochondrial genes from the cytoplasm to the nucleus, also known as NUMTs, also qualify as one type of common pseudogene.[10] Numts occur in many eukaryotic taxa.
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[11] and a substantial number of pseudogenes are actively transcribed.[9][12] 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.[13]
Introns
[edit]![](http://upload.wikimedia.org/wikipedia/commons/thumb/5/5a/Pre-mRNA.svg/420px-Pre-mRNA.svg.png)
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. A smaller portion of introns actually are functional through enabling alternative splicing.[14] Many introns appear to be mobile genetic elements.[15]
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.[15] 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.[15]
Transposons
[edit]Transposons are repeated DNA that can sometimes move throughout the genome by a cut-and-paste mechanism, there are active transposons which replicate and inactive called fossils.[16]
Adenoviruses
[edit]Adenoviruses are viruses that infect the human genome in order to replicate. [17]
NUMT
[edit]NUMTs are mitochondrial pseudogenes present in the human genome which have been associated with fossil record and complete mitochondrial genome sequences.[18]
Contents and History
[edit]The amount of non-coding DNA varies greatly among species. Often, only a small percentage of the genome is responsible for coding proteins, but an increasing 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".[19]
The variance of non-coding proportions throughout different species genome’s is highlighted by the fact that H. sapiens genome is 98% non-coding, while C. elegans are 76%, C. cerevisiae are 32%, and E. coli only have 12% of the genome being non-coding. [20] In general the fraction of non-coding DNA in the genome increases with increasing organismal complexity, bacteria typically have 10% non-coding, 32% in yeast, 76-77% in nematodes, and 98-98.5% in mammals. [21]
![](http://upload.wikimedia.org/wikipedia/commons/thumb/0/06/Wiki_project.png/220px-Wiki_project.png)
The use of non-coding DNA took off around the late 1970s [22] Non-coding DNA is a sequence that does not code for amino acids meaning it is either not transcribed or translated [23]. Non-coding DNA represents 98% of the human genome and this 98% is composed of: 54% Fossil transposable elements and viruses, 28% introns, 9% unknown, 5% pseudogenes, 1% centromeres, 0.5% untranscribed regulatory sequences, 0.3% origins of replication, 0.2% active transposable elements and viruses, and 0.1% telomeres [24]. There still is confusion with the term junk DNA being referred to as non-coding DNA [25]. This is wrong for two reasons, junk DNA does not have a function and it can be transcribed and translated while as we see above non-coding can have a function but it does not code for amino acids. [26] Some non-coding DNA can be junk but junk DNA does not have to be non-coding DNA [27]
The Encyclopedia of DNA Elements (ENCODE) project uncovered, by direct biochemical approaches, that at least 80% of human genomic DNA has biochemical activity such as "transcription, transcription factor association, chromatin structure, and histone modification".[28] Though this was not necessarily unexpected due to previous decades of research discovering many functional non-coding regions,[29][30] some scientists criticized the conclusion for conflating biochemical activity with biological function.[31][32][33][34][35] Estimates for the biologically functional fraction of the human genome based on comparative genomics range between 8 and 15%.[36][37][38] However, others have argued against relying solely on estimates from comparative genomics due to its limited scope since non-coding DNA has been found to be involved in epigenetic activity and complex networks of genetic interactions and is explored in evolutionary developmental biology.[30][37][39][40]
Fraction of non-coding genomic DNA
[edit]![](http://upload.wikimedia.org/wikipedia/commons/thumb/b/bd/Utricularia_gibba_flower_01.jpg/170px-Utricularia_gibba_flower_01.jpg)
The amount of total genomic DNA varies widely between organisms, and the proportion of coding and non-coding 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,[42] while 20% of a typical prokaryote genome is non-coding.[29]
In eukaryotes, genome size, and by extension the amount of non-coding DNA, is not correlated to organism complexity, an observation known as the C-value enigma.[43] 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.[44] 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 non-coding DNA.[42] Therefore, most of the difference in genome size is not due to variation in amount of coding DNA, rather, it is due to a difference in the amount of non-coding DNA.[45]
In 2013, a new "record" for the most efficient eukaryotic genome was discovered with Utricularia gibba, a bladderwort plant that has only 3% non-coding DNA and 97% of coding DNA. Parts of the non-coding DNA were being deleted by the plant and this suggested that non-coding DNA may not be as critical for plants, even though non-coding DNA is useful for humans.[41] Other studies on plants have discovered crucial functions in portions of non-coding DNA that were previously thought to be negligible and have added a new layer to the understanding of gene regulation.[46]
Repeat sequences, transposons and viral elements
[edit]![](http://upload.wikimedia.org/wikipedia/commons/thumb/3/3d/Bacterial_mobile_elements.svg/300px-Bacterial_mobile_elements.svg.png)
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.[47][48][49]
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.[50]
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.[51] Genome size variation in at least two kinds of plants is mostly the result of retrotransposon sequences.[52][53]
Evidence of functionality
[edit]Some non-coding DNA sequences must have some important biological function. This is indicated by comparative genomics studies that report highly conserved regions of non-coding DNA, sometimes on time-scales of hundreds of millions of years. This implies that these non-coding regions are under strong evolutionary pressure and positive selection.[54] 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 non-coding regions.[55] 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 non-coding DNA.[55] The significance of non-coding DNA mutations in cancer was explored in April 2013.[56]
Non-coding genetic polymorphisms play a role in infectious disease susceptibility, such as hepatitis C.[57] Moreover, non-coding genetic polymorphisms contribute to susceptibility to Ewing sarcoma, an aggressive pediatric bone cancer.[58]
Some specific sequences of non-coding DNA may be features essential to chromosome structure, centromere function and recognition of homologous chromosomes during meiosis.[59]
According to a comparative study of over 300 prokaryotic and over 30 eukaryotic genomes,[60] 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 secondary structures.[61] 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.
Non-coding DNA may perhaps serve to decrease the probability of gene disruption during chromosomal crossover.[62]
Evidence from Polygenic Scores and GWAS
[edit]![](http://upload.wikimedia.org/wikipedia/commons/thumb/2/23/VarianceAccountedFor_YongRabenLelloHsu.png/220px-VarianceAccountedFor_YongRabenLelloHsu.png)
Genome-wide association studies (GWAS) and machine learning analysis of large genomic datasets has led to the construction of polygenic predictors for human traits such as height, bone density, and many disease risks. Similar predictors exist for plant and animal species and are used in agricultural breeding.[64] The detailed genetic architecture of human predictors has been analyzed and significant effects used in prediction are associated with DNA regions far outside coding regions. The fraction of variance accounted for (i.e., fraction of predictive power captured by the predictor) in coding vs. non-coding regions varies widely for different complex traits. For example, atrial fibrillation and coronary artery disease risk are mostly controlled by variants in non-coding regions (non-coding variance fraction over 70 percent), whereas diabetes and high cholesterol display the opposite pattern (non-coding variance roughly 20-30 percent).[63] Individual differences between humans are clearly affected in a significant way by non-coding genetic loci, which is strong evidence for functional effects. Whole exome genotypes (i.e., which contain information restricted to coding regions only) do not contain enough information to build or even evaluate polygenic predictors for many well-studied complex traits and disease risks.
In 2013, it was estimated that, in general, up to 85% of GWAS loci have non-coding variants as the likely causal association. The variants are often common in populations and were predicted to affect disease risks through small phenotypic effects, as opposed to the large effects of Mendelian variants.[65]
Regulating gene expression
[edit]Some non-coding 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.[66][67][68]
Transcription factors
[edit]Some non-coding DNA sequences determine where transcription factors attach.[66] 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.[69][70]
Scientists showed experimentally, with brain organoids grown from stem cells, how differences between humans and chimpanzees are also substantially caused by non-coding DNA – in particular via cis-regulatory element-regulated expression of the ZNF558 gene for a transcription factor that regulates the SPATA18 gene.[71][72]
Operators
[edit]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.[73]
Enhancers
[edit]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.[74]
Silencers
[edit]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.[75]
Promoters
[edit]A promoter is a region of 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.[76]
Insulators
[edit]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.[77]
Uses
[edit]Evolution
[edit]Shared sequences of apparently non-functional DNA are a major line of evidence of common descent.[78]
Non-functional sequences appear to accumulate mutations more rapidly than fuctional sequences due to a loss of selective pressure.[13] 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".[79]
A study published in 2019 shows that new genes (termed de novo gene birth) can be fashioned from non-coding regions.[80] Some studies suggest at least one-tenth of genes could be made in this way.[80]
Long range correlations
[edit]A statistical distinction between coding and non-coding 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.[81][82][83]
Forensic anthropology
[edit]Police sometimes gather DNA as evidence for purposes of forensic identification. As described in Maryland v. King, a 2013 U.S. Supreme Court decision:[84]
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 "non-coding" 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.[84]
See also
[edit]- Conserved non-coding sequence
- Eukaryotic chromosome fine structure
- Gene-centered view of evolution
- Gene regulatory network
- Intergenic region
- Intragenomic conflict
- Phylogenetic footprinting
- Transcriptome
- Non-coding RNA
- Gene desert
- The Onion Test
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Further reading
[edit]- Bennett MD, Leitch IJ (2005). "Genome size evolution in plants". In Gregory RT (ed.). The Evolution of the Genome. San Diego: Elsevier. pp. 89–162. ISBN 978-0-08-047052-8.
- Gregory TR (2005). "Genome size evolution in animals". In T.R. Gregory (ed.). The Evolution of the Genome. San Diego: Elsevier. ISBN 978-0-12-301463-4.
- Shabalina SA, Spiridonov NA (2004). "The mammalian transcriptome and the function of non-coding DNA sequences". Genome Biology. 5 (4): 105. doi:10.1186/gb-2004-5-4-105. PMC 395773. PMID 15059247.
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: CS1 maint: unflagged free DOI (link) - Castillo-Davis CI (October 2005). "The evolution of noncoding DNA: how much junk, how much func?". Trends in Genetics. 21 (10): 533–6. doi:10.1016/j.tig.2005.08.001. PMID 16098630.