Junk DNA: Difference between revisions
Moving a paragraph in preparation for deleting the entire "Measurements and estimates" section. |
No edit summary |
||
Line 37: | Line 37: | ||
<blockquote>Dear Francis, I am sure that you realize how frightfully angry a lot of people will be if you say that much of the DNA is junk. The geneticists will be angry because they think that DNA is sacred. The Darwinian evolutionists will be outraged because they believe every change in DNA that is accepted in evolution is necessarily an adaptive change. To suggest anything else is an insult to the sacred memory of Darwin.</blockquote> |
<blockquote>Dear Francis, I am sure that you realize how frightfully angry a lot of people will be if you say that much of the DNA is junk. The geneticists will be angry because they think that DNA is sacred. The Darwinian evolutionists will be outraged because they believe every change in DNA that is accepted in evolution is necessarily an adaptive change. To suggest anything else is an insult to the sacred memory of Darwin.</blockquote> |
||
The other point of view was expressed by Britten and Kohne in their seminal paper on repetitive DNA.<ref name = Britten&Kohne1968/> |
The other point of view was expressed by [[Roy John Britten]] and Kohne in their seminal paper on repetitive DNA.<ref name = Britten&Kohne1968/> |
||
<blockquote>A concept that is repugnant to us is that about half of the DNA of higher organisms is trivial or permanently inert (on an evolutionary timescale).</blockquote> |
<blockquote>A concept that is repugnant to us is that about half of the DNA of higher organisms is trivial or permanently inert (on an evolutionary timescale).</blockquote> |
Revision as of 00:39, 27 May 2024
Junk DNA (non-functional DNA) is a DNA sequence that has no relevant biological function.[1][2] Most organisms have some junk DNA in their genomes—mostly pseudogenes and fragments of transposons and viruses—but it is possible that some organisms have substantial amounts of junk DNA.[3]
All protein-coding regions of genes are generally considered as functional elements in genomes. Additionally, non-protein coding regions such as genes for ribosomal RNA and transfer RNA, regulatory sequences controlling expression of those genes, elements of the genome involving origins of replication (in all species), centromeres, telomeres, and scaffold attachment regions (in eukaryotes) are generally considered as functional elements of genomes as well. (See Non-coding DNA for more information.)
It is difficult to determine whether other regions of the genome are functional or nonfunctional. There is considerable controversy over which criteria should be used to identify function. Many scientists have an evolutionary view of the genome and they prefer criteria based on whether DNA sequences are preserved by natural selection.[4][5][6] Other scientists dispute this view or have different interpretations of the data.[7][8][9]
The history of junk DNA
The idea that only a fraction of the human genome could be functional dates back to the late 1940s. The estimated mutation rate in humans suggested that if a large fraction of those mutations were deleterious then the human species could not survive such a mutation load (genetic load). This led to predictions in the late 1940s by one of the founders of population genetics, J.B.S. Haldane, and by Nobel laureate Hermann Muller, that only a small percentage of the human genome contains functional DNA elements (genes) that can be destroyed by mutation.[10][11] (see Genetic load for more information)
In 1966 Muller reviewed these predictions and concluded that the human genome could only contain about 30,000 genes based on the number of deleterious mutations that the species could tolerate.[12] Similar predictions were made by other leading experts in molecular evolution who concluded that the human genome could not contain more than 40,000 genes and that less than 10% of the genome was functional.[13][14][4][15]
The size of genomes in various species was known to vary considerably and there did not seem to be a correlation between genome size and the complexity of the species. Even closely related species could have very different genome sizes. This observation led to what came to be known as the C-value paradox.[16] The paradox was resolved with the discovery of repetitive DNA and the observation that most of the differences in genome size could be attributed to repetitive DNA.[16][17] Some scientists thought that most of the repetitive DNA was involved in regulating gene expression but many scientists thought that the excess repetitive DNA was nonfunctional.[18][16][19][20][21]
At about the same time (late 1960s) the newly developed technique of C0t analysis was refined to include RNA:DNA hybridization leading to the discovery that considerably less than 10% of the human genome was complementary to mRNA and this DNA was in the unique (non-repetitive) fraction. This confirmed the predictions made from genetic load arguments and was consistent with the idea that much of the repetitive DNA is nonfunctional.[22][23][24]
The idea that large amounts of eukaryotic genomes could be nonfunctional conflicted with the prevailing view of evolution in 1968 since it seemed likely that nonfunctional DNA would be eliminated by natural selection. The development of the neutral theory and the nearly neutral theory provided a way out of this problem since it allowed for the preservation of slightly deleterious nonfunctional DNA in accordance with fundamental principles of population genetics.[14][13][25]
The term "junk DNA" began to be used in the late 1950s[26] but Susumu Ohno popularized the term in a 1972 paper titled "So much 'junk' DNA in our genome"[27] where he summarized the current evidence that had accumulated by then.[27] In a second paper that same year, he concluded that 90% of mammalian genomes consisted of nonfunctional DNA.[4] The case for junk DNA was summarized in a lengthy paper by David Comings in 1972 where he listed four reasons for proposing junk DNA:[28]
- some organisms have a lot more DNA than they seem to require (C-value paradox),
- current estimates of the number of genes (in 1972) are much less than the number that can be accommodated,
- the mutation load would be too large if all the DNA were functional, and
- some junk DNA clearly exists.
The discovery of introns in the 1970s seemed to confirm the views of junk DNA proponents because it meant that genes were very large and even huge genomes could not accommodate large numbers of genes. The proponents of junk DNA tended to dismiss intron sequences as mostly nonfunctional DNA (junk) but junk DNA opponents advanced a number of hypotheses attributing functions of various sort to intron sequences.[29][30][31][32][33]
By 1980 it was apparent that most of the repetitive DNA in the human genome was related to transposons. This prompted a series of papers and letters describing transposons as selfish DNA that acted as a parasite in genomes and produced no fitness advantage for the organism.[34][35][36][37][38]
Opponents of junk DNA interpreted these results as evidence that most of the genome is functional and they developed several hypotheses advocating that transposon sequences could benefit the organism or the species.[39] The most important opponent of junk DNA at this time was Thomas Cavalier-Smith who argued that the extra DNA was required to increase the volume of the nucleus in order to promote more efficient transport across the nuclear membrane.[40]
The positions of the two sides of the controversy hardened with one side believing that evolution was consistent with large amounts of junk DNA and the other side believing that natural selection should eliminate junk DNA. These differing views of evolution were highlighted in a letter from Thomas Jukes, a proponent of junk DNA, to Francis Crick on December 20, 1979:[41]
Dear Francis, I am sure that you realize how frightfully angry a lot of people will be if you say that much of the DNA is junk. The geneticists will be angry because they think that DNA is sacred. The Darwinian evolutionists will be outraged because they believe every change in DNA that is accepted in evolution is necessarily an adaptive change. To suggest anything else is an insult to the sacred memory of Darwin.
The other point of view was expressed by Roy John Britten and Kohne in their seminal paper on repetitive DNA.[17]
A concept that is repugnant to us is that about half of the DNA of higher organisms is trivial or permanently inert (on an evolutionary timescale).
Junk DNA and non-coding DNA
There is considerable confusion in the popular press and in the scientific literature about the distinction between non-coding DNA and junk DNA.
According to a recent article published in American Scientist:
Close to 99 percent of our genome has been historically classified as noncoding, useless "junk" DNA. Consequently, these sequences were rarely studied.[42]
A recent book states:
When it was first discovered, the nongenic DNA was sometimes called—somewhat derisively by people who did not know better—"junk DNA" because it had no obvious utility, and they foolishly assumed that if it was not carrying coding information it must be useless trash.[43]
The common theme is that the original proponents of junk DNA thought that all non-coding DNA was junk and generally ignored.[2][6] This claim has been attributed to a paper by David Comings in 1972[28] where he is reported to have said that junk DNA refers to all non-coding DNA.[19] But Comings never said that. In that paper he discusses non-coding genes for ribosomal RNA and tRNAs and non-coding regulatory DNA and he proposes several possible functions for the bulk of non-coding DNA.[28] In another publication from the same year Comings again discusses the term junk DNA with the clear understanding that it does not include non-coding regulatory sequences.[44]
These statements have been criticized by numerous authors for distorting the history of junk DNA;[1][45][46][47][2] for example:
It is simply not true that noncoding DNA has long been dismissed as worthless junk and that functional hypotheses have only recently been proposed - despite the frequency with which this cliché is repeated in media reports and in the introduction of far too many scientific studies.[48]
Some of the criticisms have been strong:
Revisionist claims that equate noncoding DNA with junk merely reveal that people who are allowed to exhibit their logorrhea in Nature and other glam journals are as ignorant as the worst young-earth creationists.[49]
Since the 1960s, proponents of junk DNA were well aware of functional non-coding DNA and even discussed possible functions when new types of non-coding sequences were identified.[2] For instance, the existence of functional non-coding DNA elements such as noncoding genes, regulatory sequences, origins of replication, and centromeres were well known in the late 1960s when the idea of junk DNA was being proposed.[50] Many of the main supporters of junk DNA explicitly mentioned the importance of (non-coding) regulatory sequences and addressed the issue of whether regulatory sequences were a minor part of the functional genome or whether regulatory sequences took up most of the human genome.[16][44][51] Early proponents of junk DNA did not base their arguments on ignorance; they based their arguments on what was known about genome sizes, gene duplication, mutational load, and population genetics.[2] (See The history of junk DNA.)
Some have argued that the term "non-coding DNA" is unfortunate because it sounds like "nonsense sequence which does nothing at all." They suggest that this misleading phrase be replaced with "untranslated DNA."[52]
Identifying function
The phrase "junk DNA" is debatable, and differing precise definitions (and associated approaches) provide wildly disparate estimates of its prevalence.[6] Strong objections to the term "junk DNA" have prompted some to advocate for more neutral nomenclature, such as "nonfunctional DNA."[1]
Proponents of junk DNA define "functional" DNA as DNA that is currently under purifying selection. For instance, Dan Gaur in his textbook "Molecular and Genome Evolution."
- "Functional DNA refers to any segment in the genome whose selected-effect function is that for which it was selected and/or by which it is maintained. Most functional sequences are maintained by purifying selection."[53]
This definition of "function" is called the maintenance function.[54][55] Other similar definitions have been published but they all have in common the idea that junk DNA is DNA that does not have a function and this means that it is not under negative selective pressure.[46][1][45] About 11% or less of the human genome is conserved[56][57] and about 7% is under purifying selection.[58]
Biochemical activity is another criterion that has been used to estimate functional elements. Biochemical activity includes whether a given locus is transcribed or whether it binds a transcription factor. In a series of papers published in 2012, the Encyclopedia of DNA Elements (ENCODE) project reported that detectable biochemical activity was observed in regions covering at least 80% of the human genome.[59] These conclusions were promoted by a publicity campaign announcing the demise of junk DNA.[60][61]
The ENCODE conclusions were challenged in a series of publications over the next few years with some suggesting that many transcripts are spurious transcripts that do not necessarily come from functional regions of the genome. They also suggested that many transcription factor binding sites are nonfunctional sites that occur by chance in large genomes.[62][1][63][64][65][2][46][66][5][45]
In 2014, ENCODE researchers responded that there are both limitations and advantages to the different approaches (genetic, evolutionary, biochemical) used to get estimates of functional elements. They agreed that biochemical activity by itself is not a reliable indicator of function and they did not repeat their earlier claim that 80% of the genome is functional. Their revised position is that the ENCODE data can be used to identify candidate elements that can be further examined to see if they are functional and that this contribution is "far more important than any interim estimate of the fraction of the human genome that is functional."[9]
The most recent attempt to define function using biochemical activity focuses on identifying which transcripts have a function and which transcription factor binding sites are true regulatory sequences.[67] One way of distinguishing between true functional biochemical activity and spurious nonfunctional biochemical activity is to look for evidence of sequence conservation or purifying selection. Opponents of junk DNA argue that biochemical activity detects functional regions of the genome that are not identified by sequence conservation or purifying selection.[68][8][69]
Some scientists 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 scientists, 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.[70]
Measurement and estimates
Different methodologies which rest on different implicit definitions yield different estimates of the non-functional fraction of the genome.[6]
For example, 20% of human genomic DNA shows no detectable biochemical activity,[59] but comparative genomics methods estimate a nonfunctional fraction of 85-92%.[71][9][56] Consequently, different exact definitions of junk DNA would yield different exact proportions. Each method has limitations; for example, 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 biochemical signatures do not always automatically signify a function.[9] 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.[9]
Biochemical activity
One criterion that has been used to estimate functional elements is biochemical activity.[72] Detectable biochemical activity (e.g. transcription, transcription factor association, chromatin structure, and histone modification) was observed for at least 80% of human genomic DNA by the Encyclopedia of DNA Elements (ENCODE) project.[59] This forms an upper estimate of the functional portion of the human genome since biochemical activity is not necessarily biological function or selective advantage.[62][1][64][2][46] For example, transcription factor binding sites are short and can be found by chance over the whole genome[73] and 70% of transcribed sequences are below 1 transcript per cell and so may be spurious background transcription.[9]
Genetic function
Contributing to the debate is that there is no consensus on what constitutes a "functional" element in the genome since geneticists, evolutionary biologists, and molecular biologists employ different approaches and definitions of "function",[9] often with a lack of clarity of what they mean in the literature.[55] Due to the ambiguity in the terminology, there are different schools of thought over this matter.[74]
However, widespread transcription and splicing in the human genome has been discussed as another indicator of genetic function in addition to genomic conservation which may miss poorly conserved functional sequences.[9] And much of the apparent junk DNA is involved in epigenetic regulation and appears to be necessary for the development of complex organisms.[75][76][77]
Genome data
Genome sequencing data provides good arguments for junk DNA. For instance, the human genome has thousands of sites that can be lost without noticeable (or known) impact. These sites can span hundreds of thousands of base pairs, and many deletions of more than a million base pairs are known.[78] In fact, hundreds of such loci contain known genes, so that even these genes appear to be dispensable.[78]
Evolutionary impact
One indication of functionality of a genomic region is if that sequence has been maintained by purifying selection (or if mutating away the sequence is deleterious to the organism). Estimates for the functionally constrained fraction of the human genome based on evolutionary conservation using comparative genomics range between 8 and 15%.[71][9][56] These may still be an underestimate when lineage-specific constraints are included. 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.[75][9][76][77]
Biologically functional sequences may also have different evolutionary impacts on the sequence itself or the organism that it is found in. Much of the DNA in large genomes originates from selfish amplification of transposable elements. Some of this sequence has biological function (transposition and self replication in the host genome) but does not provided a selective advantage to the host organism.[79]
An additional complication is that the large body of nonfunctional background transcripts produced by non-functional sequences can evolve into functional elements de novo.[80][81] Therefore, a sequence fitting a strict definition of junk as having no biological function and no fitness effect can still have long-term evolutionary significance.[82][83]
See also
References
- ^ a b c d e f Eddy SR (November 2012). "The C-value paradox, junk DNA and ENCODE". Current Biology. 22 (21): R898–R899. Bibcode:2012CBio...22.R898E. doi:10.1016/j.cub.2012.10.002. PMID 23137679. S2CID 28289437.
- ^ a b c d e f g Palazzo AF, Gregory TR (May 2014). "The case for junk DNA". PLOS Genetics. 10 (5): e1004351. doi:10.1371/journal.pgen.1004351. PMC 4014423. PMID 24809441.
- ^ Gil R, and Latorre A (2012). "Factors behind junk DNA in bacteria". Genes. 3 (4): 634–650. doi:10.3390/genes3040634. PMC 3899985. PMID 24705080.
- ^ a b c Ohno S (1972). "An argument for the genetic simplicity of man and other mammals". Journal of Human Evolution. 1 (6): 651–662. doi:10.1016/0047-2484(72)90011-5.
- ^ a b Morange M (2014). "Genome as a Multipurpose Structure Built by Evolution" (PDF). Perspectives in Biology and Medicine. 57 (1): 162–171. doi:10.1353/pbm.2014.0008. PMID 25345709. S2CID 27613442.
- ^ a b c d Palazzo AF, Kejiou NS (2022). "Non-Darwinian Molecular Biology". Front. Genet. 13: 831068. doi:10.3389/fgene.2022.831068. PMC 8888898. PMID 35251134.
- ^ Germain PL, Ratti E, and Boem F (2014). "Junk or functional DNA? ENCODE and the function controversy". Biology & Philosophy. 29 (6): 807–821. doi:10.1007/s10539-014-9441-3. S2CID 254277794.
- ^ a b Mattick JS (2023). "RNA out of the mist". Trends in Genetics. 39 (3): 187–207. doi:10.1016/j.tig.2022.11.001. PMID 36528415. S2CID 254768457.
- ^ a b c d e f g h i j Kellis M, Wold B, Snyder MP, Bernstein BE, Kundaje A, Marinov GK, et al. (April 2014). "Defining functional DNA elements in the human genome". Proceedings of the National Academy of Sciences of the United States of America. 111 (17): 6131–6138. Bibcode:2014PNAS..111.6131K. doi:10.1073/pnas.1318948111. PMC 4035993. PMID 24753594.
- ^ Muller HJ (1950). "Our load of mutations". American Journal of Human Genetics. 2 (2): 111–175. PMC 1716299. PMID 14771033.
- ^ Haldane J (1949). "The rate of mutation of human genes". Hereditas. 35: 267–273. doi:10.1111/j.1601-5223.1949.tb03339.x.
- ^ Muller HJ (1966). "The gene material as the initiator and the organizing basis of life". American Naturalist. 100 (915): 493–517. doi:10.1086/282445. JSTOR 2459205. S2CID 84202145.
- ^ a b Kimura M (1968). "Evolutionary rate at the molecular level" (PDF). Nature. 217 (5129): 624–626. Bibcode:1968Natur.217..624K. doi:10.1038/217624a0. PMID 5637732. S2CID 4161261.
- ^ a b King JL, and Jukes TH (1969). "Non-Darwinian evolution". Science. 164 (3881): 788–798. Bibcode:1969Sci...164..788L. doi:10.1126/science.164.3881.788. PMID 5767777.
- ^ Ohta T, and Kimura M (1971). "Functional organization of genetic material as a product of molecular evolution". Nature. 233 (5315): 118–119. Bibcode:1971Natur.233..118O. doi:10.1038/233118a0. PMID 16063236. S2CID 13344748.
- ^ a b c d Thomas CA Jr (1971). "The genetic organization of chromosomes". Annual Review of Genetics. 5: 237–256. doi:10.1146/annurev.ge.05.120171.001321. PMID 16097657.
- ^ a b Britten R, and Kohne D (1968). "Repeated Sequences in DNA". Science. 161 (3841): 529–540. Bibcode:1968Sci...161..529B. doi:10.1126/science.161.3841.529. PMID 4874239.
- ^ Britten RJ, and Davidson EH (1969). "Gene regulation for higher cells: a theory". Science. 165 (3891): 349–357. Bibcode:1969Sci...165..349B. doi:10.1126/science.165.3891.349. PMID 5789433.
- ^ a b Gregory TR (2005). "Genome Size Evolution in Animals". The Evolution of the Genome. Elsevier. pp. 3–87.
- ^ Lewin B (1974). "Chapter 4: Sequences of Eukaryotic DNA". Gene Expression-2: Eukaryotic Chromosomes. John Wiley & Sons.
- ^ Lewin B (1974). "Sequence Organization of Eukaryotic DNA: Defining the Unit of Gene Expression". Cell. 1 (3): 107–111. doi:10.1016/0092-8674(74)90125-1.
- ^ Lewin B (1974). "Chapter 5: Transcription and Processing of RNA". Gene Expression-2: Eukaryotic Chromosomes. John Wiley & Sons.
- ^ O'Brian S (1973). "On estimating functional gene number in eukaryotes". Nature New Biology. 242 (115): 52–54. doi:10.1038/newbio242052a0. PMID 4512011.
- ^ Bishop J (1974). "The gene numbers game". Cell. 2 (2): 81–86. doi:10.1016/0092-8674(74)90095-6. PMID 4616752.
- ^ Kimura M, and Ohta T (1971). "Protein polymorphism as a phase of molecular evolution". Nature. 229 (5285): 467–469. Bibcode:1971Natur.229..467K. doi:10.1038/229467a0. PMID 4925204. S2CID 4290427.
- ^ Sweet A (2022). Requiem for a Gene: The Problem of Junk DNA for the Molecular Paradigm (MA). University of Chicago.
- ^ a b Ohno S (1972). "So much "junk" DNA in our genome". Brookhaven Symposia in Biology. 23: 366–370. PMID 5065367.
- ^ a b c Comings DE (1972). "The structure and function of chromatin". Advances in human genetics. Springer. pp. 237–431.
- ^ Morange M (2020). "Chapter 17: Split Genes and Splicing". The Black Box of Biology: A History of the Molecular Revolution. Harvard University Press.
- ^ Gilbert W (1978). "Why genes in pieces?". Nature. 271 (5645): 501. Bibcode:1978Natur.271..501G. doi:10.1038/271501a0. PMID 622185. S2CID 4216649.
- ^ Gilbert W (1985). "Genes-in-pieces revisited". Science. 228 (4701): 823–824. Bibcode:1985Sci...228..823G. doi:10.1126/science.4001923. PMID 4001923.
- ^ Crick F (1979). "Split genes and RNA splicing". Science. 204 (4390): 264–271. Bibcode:1979Sci...204..264C. doi:10.1126/science.373120. PMID 373120.
- ^ Doolittle W (1978). "Genes in pieces: were they ever together?". Nature. 272 (5654): 581–582. Bibcode:1978Natur.272..581D. doi:10.1038/272581a0. S2CID 4162765.
- ^ Doolittle, WF, and Sapienza C (1980). "Selfish genes, the phenotype paradigm and genome evolution". Nature. 284 (5757): 601–603. Bibcode:1980Natur.284..601D. doi:10.1038/284601a0. PMID 6245369. S2CID 4311366.
- ^ Orgel LE, and Crick FH (1980). "Selfish DNA: the ultimate parasite". Nature. 284 (5757): 604–607. Bibcode:1980Natur.284..604O. doi:10.1038/284604a0. PMID 7366731. S2CID 4233826.
- ^ Glover G (1980). "Ignorant DNA?". Nature. 285 (5767): 618–619. Bibcode:1980Natur.285..618D. doi:10.1038/285618a0. PMID 7393318. S2CID 4261755.
- ^ Dover G, and Doolittle WF (1980). "Modes of genome evolution". Nature. 288 (5792): 646–647. Bibcode:1980Natur.288..646D. doi:10.1038/288646a0. PMID 6256636. S2CID 8938434.
- ^ Jain HK (1980). "Incidental DNA". Nature. 288 (5792): 647–648. Bibcode:1980Natur.288..647J. doi:10.1038/288647a0. PMID 7453799. S2CID 31899622.
- ^ Cavalier-Smith T (1980). "How selfish is DNA?". Nature. 285 (5767): 617–618. Bibcode:1980Natur.285..617C. doi:10.1038/285617a0. PMID 7393317. S2CID 27111068.
- ^ Cavalier-Smith T (1978). "Nuclear volume control by nucleoskeletal DNA, selection for cell volume and cell growth rate, and the solution of the DNA C-value paradox". Journal of Cell Science. 34: 247–278. doi:10.1242/jcs.34.1.247. PMID 372199.
- ^ Thomas J (December 29, 1979). "letter to Francis Crick". National Institutes of Health (USA).
- ^ Mortola E, Long M (2021). "Turning Junk into Us: How Genes Are Born". American Scientist. 109: 174–182.
- ^ McHughen A (2020). DNA Demystified: Unraveling the Double Helix. New York, New York, USA: Oxford University Press.
- ^ a b Comings DE (1972). "Review of Evolution of Genetics Systems". American Journal of Human Genetics. 25: 340–342.
- ^ a b c Niu DK, Jiang L (2013). "Can ENCODE tell us how much junk DNA we carry in our genome?". Biochemical and Biophysical Research Communications. 430 (4): 1340–1343. doi:10.1016/j.bbrc.2012.12.074. PMID 23268340.
- ^ a b c d Graur D, Zheng Y, Price N, Azevedo RB, Zufall RA, Elhaik E (2013). "On the immortality of television sets: "function" in the human genome according to the evolution-free gospel of ENCODE". Genome Biology and Evolution. 5 (3): 578–590. doi:10.1093/gbe/evt028. PMC 3622293. PMID 23431001.
- ^ Graur D, Zheng Y, Azevedo RB (2015). "An evolutionary classification of genomic function". Genome Biology and Evolution. 7 (3): 642–645. doi:10.1093/gbe/evv021. PMC 5322545. PMID 25635041.
- ^ Elliott TA, Linquist S, and Gregory TR (2014). "Conceptual and empirical challenges of ascribing functions to transposable elements" (PDF). The American Naturalist. 184 (1): 14–24. doi:10.1086/676588. PMID 24921597. S2CID 14549993.
- ^ Graur D (2017). "Rubbish DNA: The functionless fraction of the human genome". In Saitou N (ed.). Evolution of the Human Genome I. Springer. pp. 19–60.
- ^ Watson J (1965). Molecular Biology of the Gene. New York, New York, USA: W. A. Benjamin, Inc.
- ^ Ohno S (1972). "Simplicity of Mammalian Regulatory Systems". Developmental Biology. 27 (1): 131–136. doi:10.1016/0012-1606(72)90117-0. PMID 4550569.
- ^ Dawkins R, and Wong Y (2016). "The Humped Bladderwort's Tale". The Ancestor's Tale 2nd ed. Weidenfeld & Nicolson.
- ^ Graur D (2016). Molecular and Genome Evolution. Sunderland MA (USA): Sinauer Associates, Inc. ISBN 9781605354699.
- ^ Linquist S (2022). "Causal-role myopia and the functional investigation of junk DNA". Biology & Philosophy. 37 (4): 1–23. doi:10.1007/s10539-022-09853-2.
- ^ a b Linquist S, Doolittle WF, Palazzo AF (April 1, 2020). "Getting clear about the F-word in genomics". PLOS Genetics. 16 (4): e1008702. doi:10.1371/journal.pgen.1008702. PMC 7153884. PMID 32236092.
- ^ a b c Rands CM, Meader S, Ponting CP, Lunter G (July 2014). "8.2% of the Human genome is constrained: variation in rates of turnover across functional element classes in the human lineage". PLOS Genetics. 10 (7): e1004525. doi:10.1371/journal.pgen.1004525. PMC 4109858. PMID 25057982.
- ^ Christmas MJ, Kaplow IM, Genereux DP, Dong MX, Hughes GM, Li X, et al. (2023). "Evolutionary constraint and innovation across hundreds of placental mammals". Science. 380 (6643): 366. doi:10.1126/science.abn3943. hdl:10230/59591. PMID 37104599.
- ^ Halldorsson BV, Eggertsson HP, Moore KH, Hauswedell H, Eiriksson O, Ulfarsson MO, et al. (2022). "The sequences of 150,119 genomes in the UK biobank". Nature. 607 (7920): 732–740. Bibcode:2022Natur.607..732H. doi:10.1038/s41586-022-04965-x. hdl:20.500.11815/3726. PMID 35859178.
- ^ a b c Dunham I, Kundaje A, Aldred SF, Collins PJ, Davis CA, Doyle F, et al. (The ENCODE Project Consortium) (September 2012). "An integrated encyclopedia of DNA elements in the human genome". Nature. 489 (7414): 57–74. Bibcode:2012Natur.489...57T. doi:10.1038/nature11247. PMC 3439153. PMID 22955616..
- ^ Pennisi E (2012). "ENCODE Project Writes Eulogy for Junk DNA". Science. 337 (6099): 1159–1161. doi:10.1126/science.337.6099.1159.
- ^ Casane D, Fumey J, and Laurenti P (2015). "L'apophénie d'ENCODE ou Pangloss examine le génome humain". Médecine/Sciences. 31 (6–7): 680–686. doi:10.1051/medsci/20153106023. PMID 26152174.
- ^ a b McKie R (February 24, 2013). "Scientists attacked over claim that 'junk DNA' is vital to life". The Observer.
- ^ Eddy SR (2013). "The ENCODE project: missteps overshadowing a success". Current Biology. 23 (7): R259–R261. Bibcode:2013CBio...23.R259E. doi:10.1016/j.cub.2013.03.023. PMID 23578867.
- ^ a b Doolittle WF (April 2013). "Is junk DNA bunk? A critique of ENCODE". Proceedings of the National Academy of Sciences of the United States of America. 110 (14): 5294–5300. Bibcode:2013PNAS..110.5294D. doi:10.1073/pnas.1221376110. PMC 3619371. PMID 23479647.
- ^ Brunet TD, and Doolittle WF (2014). "Getting "function" right". Proceedings of the National Academy of Sciences (USA). 111 (33): E3365. Bibcode:2014PNAS..111E3365P. doi:10.1073/pnas.1409762111. PMC 4143013.
- ^ Doolittle WF, Brunet TD, Linquist S, and Gregory TR (2014). "Distinguishing between "function" and "effect" in genome biology". Genome Biology and Evolution. 6 (5): 1234–1237. doi:10.1093/gbe/evu098. PMC 4041003.
- ^ Abascal F, Acosta R, Addleman NJ, Adrian J, et al. (July 30, 2020). "Expanded Encyclopaedias of DNA elements in the Human and Mouse Genomes". Nature. 583 (7818): 699–710. Bibcode:2020Natur.583..699E. doi:10.1038/s41586-020-2493-4. PMC 7410828. PMID 32728249.
Operationally, functional elements are defined as discrete, linearly ordered sequence features that specify molecular products (for example, protein-coding genes or noncoding RNAs) or biochemical activities with mechanistic roles in gene or genome regulation (for example, transcriptional promoters or enhancers).
- ^ Mattick JS, and Dinger ME (2013). "The extent of functionality in the human genome". The HUGO Journal. 7: 2. doi:10.1186/1877-6566-7-2. PMC 4685169.
- ^ Mattick JS (2023). "A Kuhnian revolution in molecular biology: Most genes in complex organisms express regulatory RNAs". BioEssays. 2300080 (9). doi:10.1002/bies.202300080.
- ^ Palazzo AF, Lee ES (2015). "Non-coding RNA: what is functional and what is junk?". Frontiers in Genetics. 6: 2. doi:10.3389/fgene.2015.00002. PMC 4306305. PMID 25674102.
- ^ a b Ponting CP, Hardison RC (November 2011). "What fraction of the human genome is functional?". Genome Research. 21 (11): 1769–1776. doi:10.1101/gr.116814.110. PMC 3205562. PMID 21875934.
- ^ Abascal F, Acosta R, Addleman NJ, Adrian J, et al. (July 30, 2020). "Expanded Encyclopaedias of DNA elements in the Human and Mouse Genomes". Nature. 583 (7818): 699–710. Bibcode:2020Natur.583..699E. doi:10.1038/s41586-020-2493-4. PMC 7410828. PMID 32728249.
Operationally, functional elements are defined as discrete, linearly ordered sequence features that specify molecular products (for example, protein-coding genes or noncoding RNAs) or biochemical activities with mechanistic roles in gene or genome regulation (for example, transcriptional promoters or enhancers).
- ^ Lambert SA, Jolma A, Campitelli LF, Das PK, Yin Y, Albu M, et al. (February 2018). "The Human Transcription Factors". Cell. 172 (4): 650–665. doi:10.1016/j.cell.2018.01.029. PMID 29425488. S2CID 3599827.
- ^ Doolittle WF (December 2018). "We simply cannot go on being so vague about 'function'". Genome Biology. 19 (1): 223. doi:10.1186/s13059-018-1600-4. PMC 6299606. PMID 30563541.
- ^ a b Carey M (2015). Junk DNA: A Journey Through the Dark Matter of the Genome. Columbia University Press. ISBN 978-0-231-17084-0.[page needed]
- ^ a b Liu G, Mattick JS, Taft RJ (July 2013). "A meta-analysis of the genomic and transcriptomic composition of complex life". Cell Cycle. 12 (13): 2061–2072. doi:10.1186/1877-6566-7-2. PMC 4685169. PMID 23759593.
- ^ a b Morris K, ed. (2012). Non-Coding RNAs and Epigenetic Regulation of Gene Expression: Drivers of Natural Selection. Norfolk, UK: Caister Academic Press. ISBN 978-1-904455-94-3.[page needed]
- ^ a b Sudmant PH, Rausch T, Gardner EJ, Handsaker RE, Abyzov A, Huddleston J, et al. (October 1, 2015). "An integrated map of structural variation in 2,504 human genomes". Nature. 526 (7571): 75–81. Bibcode:2015Natur.526...75.. doi:10.1038/nature15394. ISSN 0028-0836. PMC 4617611. PMID 26432246.
- ^ Doolittle WF, Sapienza C (April 1980). "Selfish genes, the phenotype paradigm and genome evolution". Nature. 284 (5757): 601–603. Bibcode:1980Natur.284..601D. doi:10.1038/284601a0. PMID 6245369. S2CID 4311366.
- ^ Palazzo AF, Koonin EV (November 2020). "Functional Long Non-coding RNAs Evolve from Junk Transcripts". Cell. 183 (5): 1151–1161. doi:10.1016/j.cell.2020.09.047. PMID 33068526. S2CID 222815635.
- ^ Graur D, Zheng Y, Azevedo RB (January 2015). "An evolutionary classification of genomic function". Genome Biology and Evolution. 7 (3): 642–645. doi:10.1093/gbe/evv021. PMC 5322545. PMID 25635041.
- ^ Schmitz JF, Ullrich KK, Bornberg-Bauer E (September 10, 2018). "Incipient de novo genes can evolve from frozen accidents that escaped rapid transcript turnover". Nature Ecology & Evolution. 2 (10): 1626–1632. Bibcode:2018NatEE...2.1626S. doi:10.1038/s41559-018-0639-7. ISSN 2397-334X. PMID 30201962. S2CID 256705263.
- ^ Neme R, Tautz D (February 2, 2016). "Fast turnover of genome transcription across evolutionary time exposes entire non-coding DNA to de novo gene emergence". eLife. 5: e09977. doi:10.7554/eLife.09977. ISSN 2050-084X. PMC 4829534. PMID 26836309.