Editing Junk DNA (section)

== Functional vs non-functional ==
The main challenge of identifying junk DNA is to distinguish between "functional" and "non-functional" sequences. This is non-trivial, but there is some good evidence for both categories.

=== Functional ===
[[Coding region|Protein-coding sequences]] are the most obvious functional sequences in genomes. However, they make up only 1-2% of most vertebrate genomes. However, there are also ''functional'' but ''non-coding'' DNA sequences<ref name="PalazzoGregory2014" /> such as [[regulatory sequence]]s, [[Origin of replication|origins of replication]], and [[centromere]]s.<ref name="Watson1965">{{cite book | vauthors = Watson J | title = Molecular Biology of the Gene | date = 1965 | publisher = W. A. Benjamin, Inc. | place = New York, New York, USA}}</ref> These sequences are usually conserved in evolution and make up another 3-8% of the human genome.<ref name=":0">{{cite journal | vauthors = Siepel A, Bejerano G, Pedersen JS, Hinrichs AS, Hou M, Rosenbloom K, Clawson H, Spieth J, Hillier LW, Richards S, Weinstock GM, Wilson RK, Gibbs RA, Kent WJ, Miller W, Haussler D | title = Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes | journal = Genome Research | volume = 15 | issue = 8 | pages = 1034–1050 | date = August 2005 | pmid = 16024819 | pmc = 1182216 | doi = 10.1101/gr.3715005 }}</ref>

The Encyclopedia of DNA Elements ([[ENCODE]]) project reported that detectable biochemical activity was observed in regions covering at least 80% of the human genome, with biochemical activity defined primarily as being transcribed.<ref name="Nature489p57">{{cite journal | title = An integrated encyclopedia of DNA elements in the human genome | journal = Nature | volume = 489 | issue = 7414 | pages = 57–74 | date = September 2012 | pmid = 22955616 | pmc = 3439153 | doi = 10.1038/nature11247 | bibcode = 2012Natur.489...57T | collaboration = The ENCODE Project Consortium | vauthors = Dunham I, Kundaje A, Aldred SF, Collins PJ, Davis CA, Doyle F, etal }}</ref> While these findings were announced as the demise of junk DNA<ref name="Pennisi 2012">{{cite journal | vauthors = Pennisi E | title = Genomics. ENCODE project writes eulogy for junk DNA | journal = Science | volume = 337 | issue = 6099 | pages = 1159, 1161 | date = September 2012 | pmid = 22955811 | doi = 10.1126/science.337.6099.1159 }}</ref><ref name="Casane et al 2015">{{cite journal | vauthors = Casane D, Fumey J, Laurenti P | title = [ENCODE apophenia or a panglossian analysis of the human genome] | journal = Médecine/Sciences | volume = 31 | issue = 6–7 | pages = 680–686 | date = 2015 | pmid = 26152174 | doi = 10.1051/medsci/20153106023 }}</ref> it is important to point out that transcription does not mean a sequence is "functional", analogous to some meaningless text that can be transcribed or copied without having any meaning.<ref name="observer">{{cite news |date=February 24, 2013 |title=Scientists attacked over claim that 'junk DNA' is vital to life |work=The Observer |url=https://www.theguardian.com/science/2013/feb/24/scientists-attacked-over-junk-dna-claim |vauthors=McKie R}}</ref><ref name="Eddy2012" /><ref name="Eddy 2013">{{cite journal | vauthors = Eddy SR | title = The ENCODE project: missteps overshadowing a success | journal = Current Biology | volume = 23 | issue = 7 | pages = R259–R261 | date = April 2013 | pmid = 23578867 | doi = 10.1016/j.cub.2013.03.023 | doi-access = free | bibcode = 2013CBio...23.R259E }}</ref><ref name="doolittle2013">{{cite journal | vauthors = Doolittle WF | title = Is junk DNA bunk? A critique of ENCODE | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 14 | pages = 5294–5300 | date = April 2013 | pmid = 23479647 | pmc = 3619371 | doi = 10.1073/pnas.1221376110 | bibcode = 2013PNAS..110.5294D | doi-access = free | author-link = W. Ford Doolittle }}</ref><ref name="Brunet and Doolittle 2014">{{cite journal | vauthors = Brunet TD, Doolittle WF | title = Getting "function" right | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 33 | pages = E3365 | date = August 2014 | pmid = 25107292 | pmc = 4143013 | doi = 10.1073/pnas.1409762111 | doi-access = free | bibcode = 2014PNAS..111E3365P }}</ref><ref name="PalazzoGregory2014" /><ref name="Grauretal2013">{{cite journal | vauthors = Graur D, Zheng Y, Price N, Azevedo RB, Zufall RA, Elhaik E | title = On the immortality of television sets: "function" in the human genome according to the evolution-free gospel of ENCODE | journal = Genome Biology and Evolution | volume = 5 | issue = 3 | pages = 578–590 | year = 2013 | pmid = 23431001 | pmc = 3622293 | doi = 10.1093/gbe/evt028 }}</ref><ref name="Doolittle et al 2014">{{cite journal | vauthors = Doolittle WF, Brunet TD, Linquist S, Gregory TR | title = Distinguishing between "function" and "effect" in genome biology | journal = Genome Biology and Evolution | volume = 6 | issue = 5 | pages = 1234–1237 | date = May 2014 | pmid = 24814287 | pmc = 4041003 | doi = 10.1093/gbe/evu098 }}</ref><ref name="Morange2014" /><ref name="Niu&Jiang2013" /><ref name="kellis" />

=== Non-functional ===
Non-functional DNA is rare in [[bacterial genome]]s which typically have an extremely high gene density, with only a few percent being not protein-coding.<ref>{{cite journal | vauthors = Zhao Z, Cristian A, Rosen G | title = Keeping up with the genomes: efficient learning of our increasing knowledge of the tree of life | journal = BMC Bioinformatics | volume = 21 | issue = 1 | pages = 412 | date = September 2020 | pmid = 32957925 | pmc = 7507296 | doi = 10.1186/s12859-020-03744-7 | doi-access = free }}</ref>

However, in most animal or plant genomes, a large fraction of DNA is non-functional, given that there is no obvious selective pressure on these sequences. More importantly, there is strong evidence that these sequences are not functional in other ways (using the human genome as example):

(1) Repetitive elements, especially mobile elements make up a large fraction of the human genome, such as [[Retrotransposon#LTR retrotransposons|LTR retrotransposons]] (8.3% of total genome), [[Short interspersed nuclear element|SINEs]] (13.1% of total genome) including [[Alu elements]], [[Long interspersed nuclear element|LINEs]] (20.4% of total genome), SVAs (SINE-[[Variable number tandem repeat|VNTR]]-Alu) and [[Transposable element#Classification|Class II DNA transposons]] (2.9% of total genome).<ref>{{cite journal | vauthors = Treangen TJ, Salzberg SL | title = Repetitive DNA and next-generation sequencing: computational challenges and solutions | journal = Nature Reviews. Genetics | volume = 13 | issue = 1 | pages = 36–46 | date = November 2011 | pmid = 22124482 | pmc = 3324860 | doi = 10.1038/nrg3117 }}</ref> Many of these sequences are the descendents of ancient virus infections and are thus "non-functional" in terms of human genome function.

(2) Many sequences can be deleted as shown by comparing genomes. For instance, an analysis of 14,623 individuals identified 42,765 [[Structural variation|structural variants]] in the human genome of which 23.4% affected multiple genes (by deleting them or part of them). This study also found 47 deletions of >1 MB, showing that large chunks of the human genome can get deleted without obvious consequences.<ref>{{cite journal | vauthors = Abel HJ, Larson DE, Regier AA, Chiang C, Das I, Kanchi KL, Layer RM, Neale BM, Salerno WJ, Reeves C, Buyske S, Matise TC, Muzny DM, Zody MC, Lander ES, Dutcher SK, Stitziel NO, Hall IM | title = Mapping and characterization of structural variation in 17,795 human genomes | journal = Nature | volume = 583 | issue = 7814 | pages = 83–89 | date = July 2020 | pmid = 32460305 | pmc = 7547914 | doi = 10.1038/s41586-020-2371-0 | bibcode = 2020Natur.583...83A }}</ref>

(3) Only a small fraction of the human genome is conserved, indicating that there is no strong (functional) [[Evolutionary pressure|selection pressure]] on these sequences, so they can rather freely mutate.<ref name=":0" /><ref>{{cite book | vauthors = Graur D | date = 2016 | title = Molecular and Genome Evolution | publisher = Sinauer Associates, Inc. | place = Sunderland MA (USA) | isbn = 9781605354699}}</ref> About 11% or less of the human genome is conserved<ref name="Rands">{{cite journal | vauthors = Rands CM, Meader S, Ponting CP, Lunter G | title = 8.2% of the Human genome is constrained: variation in rates of turnover across functional element classes in the human lineage | journal = PLOS Genetics | volume = 10 | issue = 7 | pages = e1004525 | date = July 2014 | pmid = 25057982 | pmc = 4109858 | doi = 10.1371/journal.pgen.1004525 | doi-access = free }}</ref><ref name="Christmas et al 2023">{{cite journal | vauthors = Christmas MJ, Kaplow IM, Genereux DP, Dong MX, Hughes GM, Li X, Sullivan PF, Hindle AG, Andrews G, Armstrong JC, Bianchi M, Breit AM, Diekhans M, Fanter C, Foley NM, Goodman DB, Goodman L, Keough KC, Kirilenko B, Kowalczyk A, Lawless C, Lind AL, Meadows JR, Moreira LR, Redlich RW, Ryan L, Swofford R, Valenzuela A, Wagner F, Wallerman O, Brown AR, Damas J, Fan K, Gatesy J, Grimshaw J, Johnson J, Kozyrev SV, Lawler AJ, Marinescu VD, Morrill KM, Osmanski A, Paulat NS, Phan BN, Reilly SK, Schäffer DE, Steiner C, Supple MA, Wilder AP, Wirthlin ME, Xue JR, Birren BW, Gazal S, Hubley RM, Koepfli KP, Marques-Bonet T, Meyer WK, Nweeia M, Sabeti PC, Shapiro B, Smit AF, Springer MS, Teeling EC, Weng Z, Hiller M, Levesque DL, Lewin HA, Murphy WJ, Navarro A, Paten B, Pollard KS, Ray DA, Ruf I, Ryder OA, Pfenning AR, Lindblad-Toh K, Karlsson EK | title = Evolutionary constraint and innovation across hundreds of placental mammals | journal = Science | volume = 380 | issue = 6643 | pages = eabn3943 | date = April 2023 | pmid = 37104599 | pmc = 10250106 | doi = 10.1126/science.abn3943 | hdl-access = free | hdl = 10230/59591 }}</ref> and about 7% is under [[Negative selection (natural selection)|purifying selection]].<ref name="Halldorsonetal2022">{{cite journal | vauthors = Halldorsson BV, Eggertsson HP, Moore KH, Hauswedell H, Eiriksson O, Ulfarsson MO, Palsson G, Hardarson MT, Oddsson A, Jensson BO, Kristmundsdottir S, Sigurpalsdottir BD, Stefansson OA, Beyter D, Holley G, Tragante V, Gylfason A, Olason PI, Zink F, Asgeirsdottir M, Sverrisson ST, Sigurdsson B, Gudjonsson SA, Sigurdsson GT, Halldorsson GH, Sveinbjornsson G, Norland K, Styrkarsdottir U, Magnusdottir DN, Snorradottir S, Kristinsson K, Sobech E, Jonsson H, Geirsson AJ, Olafsson I, Jonsson P, Pedersen OB, Erikstrup C, Brunak S, Ostrowski SR, Thorleifsson G, Jonsson F, Melsted P, Jonsdottir I, Rafnar T, Holm H, Stefansson H, Saemundsdottir J, Gudbjartsson DF, Magnusson OT, Masson G, Thorsteinsdottir U, Helgason A, Jonsson H, Sulem P, Stefansson K | title = The sequences of 150,119 genomes in the UK Biobank | journal = Nature | volume = 607 | issue = 7920 | pages = 732–740 | date = July 2022 | pmid = 35859178 | pmc = 9329122 | doi = 10.1038/s41586-022-04965-x | hdl-access = free | bibcode = 2022Natur.607..732H | hdl = 20.500.11815/3726 }}</ref>

Opponents of junk DNA argue that biochemical activity detects functional regions of the genome that are not identified by sequence conservation or purifying selection.<ref name="Mattick&Dinger2013">{{cite journal | vauthors = Liu G, Mattick JS, Taft RJ | title = A meta-analysis of the genomic and transcriptomic composition of complex life | journal = Cell Cycle | volume = 12 | issue = 13 | pages = 2061–2072 | date = July 2013 | pmc = 4685169 | doi = 10.1186/1877-6566-7-2 | doi-access = free | pmid = 23759593 }}</ref><ref name="Mattick2023" /><ref name="Mattick 2023b">{{cite journal | vauthors = Mattick JS | title = A Kuhnian revolution in molecular biology: Most genes in complex organisms express regulatory RNAs | journal = BioEssays | volume = 45 | issue = 9 | pages = e2300080 | date = September 2023 | pmid = 37318305 | doi = 10.1002/bies.202300080 | doi-access = free }}</ref> According to some 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.<ref name="PalazzoLee2015">{{cite journal | vauthors = Palazzo AF, Lee ES | title = Non-coding RNA: what is functional and what is junk? | journal = Frontiers in Genetics | volume = 6 | pages = 2 | year = 2015 | pmid = 25674102 | pmc = 4306305 | doi = 10.3389/fgene.2015.00002 | doi-access = free }}</ref>