Biology:Junk DNA

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Short description: Those parts of a genome with no function

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]

Tomoko Ohta (Tomoko Harada) developed the nearly neutral theory that led to an understanding of how slightly deleterious junk DNA could be maintained in the genomes of species with small effective population sizes. In 2015 she was awarded the Crafoord Prize by the Royal Swedish Academy (with Richard Lewontin).

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]

  1. some organisms have a lot more DNA than they seem to require (C-value paradox),
  2. current estimates of the number of genes (in 1972) are much less than the number that can be accommodated,
  3. the mutation load would be too large if all the DNA were functional, and
  4. 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]

Francis Crick and others promoted the idea that transposons were examples of selfish DNA and were responsible for the proliferation of junk DNA.

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 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]

Terminology

The phrase "junk DNA" is debatable, and differing precise definitions (and associated approaches) provide wildly disparate estimates of its prevalence.[6] According to some authors, the word is only used in popular science and is no longer utilized in professional research articles.[53] It has also been noted that the label "junk" can indicate that its buildup is harmful, but the majority of non-functional sequence is most likely neutral.[54] Strong objections to the term "junk DNA" have prompted some to advocate for more neutral nomenclature, such as "nonfunctional DNA."[1]

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,[55] but comparative genomics methods estimate a nonfunctional fraction of 85-92%.[56][9][57] 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.[58] 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.[55] This forms an upper estimate of the functional portion of the human genome since biochemical activity is not necessarily biological function or selective advantage.[59][1][60][2][46] For example, transcription factor binding sites are short and can be found by chance over the whole genome[61] 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.[62] Due to the ambiguity in the terminology, there are different schools of thought over this matter.[63]

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.[64][65][66]

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.[67]

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%.[56][9][57] 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.[64][9][65][66]

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.[68]

An additional complication is that the large body of nonfunctional background transcripts produced by non-functional sequences can evolve into functional elements de novo.[69][70] 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.[71][72]

See also

References

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  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "The case for junk DNA". PLOS Genetics 10 (5): e1004351. May 2014. doi:10.1371/journal.pgen.1004351. PMID 24809441. 
  3. ↑ "Factors behind junk DNA in bacteria". Genes 3 (4): 634–650. 2012. doi:10.3390/genes3040634. PMID 24705080. 
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  5. ↑ Morange, Michel (2014). "Genome as a Multipurpose Structure Built by Evolution". Perspectives in Biology and Medicine 57 (1): 162–171. doi:10.1353/pbm.2014.0008. PMID 25345709. https://hal.archives-ouvertes.fr/hal-01480552/file/ARTICLE%20ENCODE%20MM%2070114%20corrige%C2%A6%C3%BC.pdf. 
  6. ↑ 6.0 6.1 6.2 6.3 Palazzo, A F; Kejiou, N S (2022). "Non-Darwinian Molecular Biology". Front. Genet. 13: 831068. doi:10.3389/fgene.2022.831068. PMID 35251134. 
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  43. ↑ DNA Demystified: Unraveling the Double Helix. New York, New York, USA: Oxford University Press. 2020. 
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  47. ↑ "An evolutionary classification of genomic function". Genome Biology and Evolution 7 (3): 642–645. 2015. doi:10.1093/gbe/evv021. PMID 25635041. 
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  50. ↑ Molecular Biology of the Gene. New York, New York, USA: W. A. Benjamin, Inc.. 1965. 
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  55. ↑ 55.0 55.1 "An integrated encyclopedia of DNA elements in the human genome". Nature 489 (7414): 57–74. September 2012. doi:10.1038/nature11247. PMID 22955616. Bibcode: 2012Natur.489...57T. .
  56. ↑ 56.0 56.1 "What fraction of the human genome is functional?". Genome Research 21 (11): 1769–1776. November 2011. doi:10.1101/gr.116814.110. PMID 21875934. 
  57. ↑ 57.0 57.1 "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. July 2014. doi:10.1371/journal.pgen.1004525. PMID 25057982. 
  58. ↑ "Expanded Encyclopaedias of DNA elements in the Human and Mouse Genomes". Nature 583 (7818): 699–710. 30 July 2020. doi:10.1038/s41586-020-2493-4. PMID 32728249. Bibcode: 2020Natur.583..699E. "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).". 
  59. ↑ "Scientists attacked over claim that 'junk DNA' is vital to life". The Observer. 24 February 2013. https://www.theguardian.com/science/2013/feb/24/scientists-attacked-over-junk-dna-claim. 
  60. ↑ "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. April 2013. doi:10.1073/pnas.1221376110. PMID 23479647. Bibcode: 2013PNAS..110.5294D. 
  61. ↑ "The Human Transcription Factors". Cell 172 (4): 650–665. February 2018. doi:10.1016/j.cell.2018.01.029. PMID 29425488. 
  62. ↑ Linquist, Stefan; Doolittle, W. Ford; Palazzo, Alexander F. (1 April 2020). "Getting clear about the F-word in genomics". PLOS Genetics 16 (4): e1008702. doi:10.1371/journal.pgen.1008702. PMID 32236092. 
  63. ↑ Doolittle, W. Ford (December 2018). "We simply cannot go on being so vague about 'function'". Genome Biology 19 (1): 223. doi:10.1186/s13059-018-1600-4. PMID 30563541. 
  64. ↑ 64.0 64.1 Junk DNA: A Journey Through the Dark Matter of the Genome. Columbia University Press. 2015. ISBN 978-0-231-17084-0. [page needed]
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  66. ↑ 66.0 66.1 Non-Coding RNAs and Epigenetic Regulation of Gene Expression: Drivers of Natural Selection. Norfolk, UK: Caister Academic Press. 2012. ISBN 978-1-904455-94-3. [page needed]
  67. ↑ "Non-coding RNA: what is functional and what is junk?". Frontiers in Genetics 6: 2. 2015. doi:10.3389/fgene.2015.00002. PMID 25674102. 
  68. ↑ "Selfish genes, the phenotype paradigm and genome evolution". Nature 284 (5757): 601–603. April 1980. doi:10.1038/284601a0. PMID 6245369. Bibcode: 1980Natur.284..601D. 
  69. ↑ "Functional Long Non-coding RNAs Evolve from Junk Transcripts". Cell 183 (5): 1151–1161. November 2020. doi:10.1016/j.cell.2020.09.047. PMID 33068526. 
  70. ↑ "An evolutionary classification of genomic function". Genome Biology and Evolution 7 (3): 642–645. January 2015. doi:10.1093/gbe/evv021. PMID 25635041. 
  71. ↑ Schmitz, Jonathan F.; Ullrich, Kristian K.; Bornberg-Bauer, Erich (2018-09-10). "Incipient de novo genes can evolve from frozen accidents that escaped rapid transcript turnover" (in en). Nature Ecology & Evolution 2 (10): 1626–1632. doi:10.1038/s41559-018-0639-7. ISSN 2397-334X. PMID 30201962. https://www.nature.com/articles/s41559-018-0639-7. 
  72. ↑ Neme, Rafik; Tautz, Diethard (2016-02-02). "Fast turnover of genome transcription across evolutionary time exposes entire non-coding DNA to de novo gene emergence" (in en). eLife 5: e09977. doi:10.7554/eLife.09977. ISSN 2050-084X. PMID 26836309. 



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