Editing Alu element (section)

== Impact in humans ==

Some ''Alu'' elements have been proposed to affect [[gene expression]] and been found to contain functional [[Promoter (genetics)|promoter]] regions for [[steroid hormone receptor]]s.<ref name=pmid7667273/><ref name=pmid7559405>{{cite journal |pmid=7559405 |year=1995 |last1=Norris |first1=J |title=Identification of a new subclass of Alu DNA repeats that can function as estrogen receptor-dependent transcriptional enhancers |journal=The Journal of Biological Chemistry |volume=270 |issue=39 |pages=22777–82 |last2=Fan |first2=D |last3=Aleman |first3=C |last4=Marks |first4=J. R |last5=Futreal |first5=P. A |last6=Wiseman |first6=R. W |last7=Iglehart |first7=J. D |last8=Deininger |first8=P. L |last9=McDonnell |first9=D. P |doi=10.1074/jbc.270.39.22777|s2cid=45796017 |doi-access=free }}</ref> Due to the abundant content of [[CpG dinucleotides]] found in ''Alu'' elements, these regions can serve as a site of [[DNA methylation|methylation]], contributing to up to 30% of the methylation sites in the human genome.<ref name=pmid9753719>{{cite journal |doi=10.1093/nar/26.20.4541 |pmid=9753719 |pmc=147893 |title=Does SINE evolution preclude Alu function? |journal=Nucleic Acids Research |volume=26 |issue=20 |pages=4541–50 |year=1998 |last1=Schmid |first1=C. W }}</ref> ''Alu'' elements are also a common source of mutations in humans; however, such mutations are often confined to non-coding regions of pre-mRNA ([[introns]]), where they have little discernible impact on the bearer.<ref name=pmid11237011>{{cite journal |doi=10.1038/35057062 |pmid=11237011 |title=Initial sequencing and analysis of the human genome |journal=Nature |volume=409 |issue=6822 |pages=860–921 |year=2001 |last1=Lander |first1=Eric S |last2=Linton |first2=Lauren M |last3=Birren |first3=Bruce |last4=Nusbaum |first4=Chad |last5=Zody |first5=Michael C |last6=Baldwin |first6=Jennifer |last7=Devon |first7=Keri |last8=Dewar |first8=Ken |last9=Doyle |first9=Michael |last10=Fitzhugh |first10=William |last11=Funke |first11=Roel |last12=Gage |first12=Diane |last13=Harris |first13=Katrina |last14=Heaford |first14=Andrew |last15=Howland |first15=John |last16=Kann |first16=Lisa |last17=Lehoczky |first17=Jessica |last18=Levine |first18=Rosie |last19=McEwan |first19=Paul |last20=McKernan |first20=Kevin |last21=Meldrim |first21=James |last22=Mesirov |first22=Jill P |last23=Miranda |first23=Cher |last24=Morris |first24=William |last25=Naylor |first25=Jerome |last26=Raymond |first26=Christina |last27=Rosetti |first27=Mark |last28=Santos |first28=Ralph |last29=Sheridan |first29=Andrew |last30=Sougnez |first30=Carrie |display-authors=29 |bibcode=2001Natur.409..860L |url=https://deepblue.lib.umich.edu/bitstream/2027.42/62798/1/409860a0.pdf }}</ref> Mutations in the introns (or non-coding regions of RNA) have little or no effect on phenotype of an individual if the coding portion of individual's genome does not contain mutations. When Alu insertions occur in coding regions ([[exons]]), or into mRNA after the process of splicing, they're typically detrimental to the host organism.<ref name=pmid10381326>{{cite journal |doi=10.1006/mgme.1999.2864 |pmid=10381326 |title=Alu Repeats and Human Disease |journal=Molecular Genetics and Metabolism |volume=67 |issue=3 |pages=183–93 |year=1999 |last1=Deininger |first1=Prescott L |last2=Batzer |first2=Mark A |s2cid=15651921 }}</ref>

However, the variation generated can be used in studies of the movement and ancestry of human populations,<ref name=pmid11988762>{{cite journal |doi=10.1038/nrg798 |pmid=11988762 |title=Alu Repeats and Human Genomic Diversity |journal=Nature Reviews Genetics |volume=3 |issue=5 |pages=370–9 |year=2002 |last1=Batzer |first1=Mark A |last2=Deininger |first2=Prescott L |s2cid=205486422 }}</ref> and the mutagenic effect of ''Alu''<ref name=pmid21282640>{{cite journal |doi=10.1073/pnas.1012834108 |pmid=21282640 |pmc=3041063 |title=Widespread establishment and regulatory impact of Alu exons in human genes |journal=Proceedings of the National Academy of Sciences |volume=108 |issue=7 |pages=2837–42 |year=2011 |last1=Shen |first1=S |last2=Lin |first2=L |last3=Cai |first3=J. J |last4=Jiang |first4=P |last5=Kenkel |first5=E. J |last6=Stroik |first6=M. R |last7=Sato |first7=S |last8=Davidson |first8=B. L |last9=Xing |first9=Y |bibcode=2011PNAS..108.2837S |doi-access=free }}</ref> and retrotransposons in general<ref name=pmid19763152>{{cite journal |doi=10.1038/nrg2640 |pmid=19763152 |pmc=2884099 |title=The impact of retrotransposons on human genome evolution |journal=Nature Reviews Genetics |volume=10 |issue=10 |pages=691–703 |year=2009 |last1=Cordaux |first1=Richard |last2=Batzer |first2=Mark A }}</ref> has played a major role in the evolution of the human genome. There are also a number of cases where ''Alu'' insertions or deletions are associated with specific effects in humans:

=== Associations with human disease ===
''Alu'' insertions are sometimes disruptive and can result in inherited disorders. However, most ''Alu'' variation acts as markers that segregate with the disease so the presence of a particular ''Alu'' [[allele]] does not mean that the carrier will definitely get the disease.  The first report of ''Alu''-mediated [[Genetic recombination|recombination]] causing a prevalent inherited predisposition to cancer was a 1995 report about ''hereditary nonpolyposis [[colorectal cancer]]''.<ref name=pmid7584997>{{cite journal |doi=10.1038/nm1195-1203 |pmid=7584997 |title=Founding mutations and Alu-mediated recombination in hereditary colon cancer |journal=Nature Medicine |volume=1 |issue=11 |pages=1203–6 |year=1995 |last1=Nyström-Lahti |first1=Minna |last2=Kristo |first2=Paula |last3=Nicolaides |first3=Nicholas C |last4=Chang |first4=Sheng-Yung |last5=Aaltonen |first5=Lauri A |last6=Moisio |first6=Anu-Liisa |last7=Järvinen |first7=Heikki J |last8=Mecklin |first8=Jukka-Pekka |last9=Kinzler |first9=Kenneth W |last10=Vogelstein |first10=Bert |last11=de la Chapelle |first11=Albert |last12=Peltomäki |first12=Päivi |s2cid=39468812 }}</ref> In the human genome, the most recently active have been the 22 AluY and 6 AluS Transposon Element subfamilies due to their inherited activity to cause various cancers. Thus due to their major heritable damage it is important to understand the causes that affect their transpositional activity.<ref name=pmid29219079>{{cite journal |doi=10.1186/s12864-017-4227-z |pmid=29219079 |pmc=5773891 |title=Computational identification of harmful mutation regions to the activity of transposable elements |journal=BMC Genomics |volume=18 |issue=Suppl 9 |pages=862 |year=2017 |last1=Jin |first1=Lingling |last2=McQuillan |first2=Ian |last3=Li |first3=Longhai |doi-access=free }}</ref>

The following human diseases have been linked with ''Alu'' insertions:<ref name=pmid11988762/><ref name=pmid22204421>{{cite journal |doi=10.1186/gb-2011-12-12-236 |pmid=22204421 |pmc=3334610 |title=Alu elements: Know the SINEs |journal=Genome Biology |volume=12 |issue=12 |pages=236 |year=2011 |last1=Deininger |first1=Prescott |doi-access=free }}</ref>
* [[Alport syndrome]]
* [[Breast cancer]]
* [[chorioretinal degeneration]]
* [[Diabetes mellitus type II]]
* [[Ewing's sarcoma]]
* [[Familial hypercholesterolemia]]
* [[Hemophilia]]
* [[Leigh syndrome]]
* [[mucopolysaccharidosis]] VII
* [[Neurofibromatosis]]
* [[Macular degeneration]]<ref name="pnas">{{Cite journal |last1=Fukuda |first1=Shinichi |last2=Varshney |first2=Akhil |last3=Fowler |first3=Benjamin J. |last4=Wang |first4=Shao-bin |last5=Narendran |first5=Siddharth |last6=Ambati |first6=Kameshwari |last7=Yasuma |first7=Tetsuhiro |last8=Magagnoli |first8=Joseph |last9=Leung |first9=Hannah |last10=Hirahara |first10=Shuichiro |last11=Nagasaka |first11=Yosuke |date=2021-02-09 |title=Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration |journal=Proceedings of the National Academy of Sciences |language=en |volume=118 |issue=6 |pages=e2022751118 |doi=10.1073/pnas.2022751118 |pmid=33526699 |pmc=8017980 |bibcode=2021PNAS..11822751F |s2cid=231761522 |issn=0027-8424|doi-access=free }}</ref>

And the following diseases have been associated with [[single-nucleotide DNA variation]]s in Alu elements affecting transcription levels:<ref>{{cite web |url=http://www.snpedia.com/index.php/Rs2333227 |work=SNPedia |title=SNP in the promoter region of the myeloperoxidase MPO gene |access-date=2010-03-14 |archive-url=https://web.archive.org/web/20100521053826/http://www.snpedia.com/index.php/Rs2333227 |archive-date=2010-05-21 |url-status=dead }}{{MEDRS|date=December 2017}}</ref>
* [[Alzheimer's disease]]
* [[Lung cancer]]
* [[Gastric cancer]]

The following disease have been associated with repeat expansion of AAGGG pentamere in Alu element :
* [[RFC1]] mutation responsible of [[Cerebellar ataxia, neuropathy, vestibular areflexia syndrome|CANVAS]] (Cerebellar Ataxia, Neuropathy & Vestibular Areflexia Syndrome) <ref>{{cite journal |title=Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia |journal=Nat Genet |year=2019 |pmid=30926972|pmc=6709527|last1=Cortese |first1=A. |last2=Simone |first2=R. |last3=Sullivan |first3=R. |last4=Vandrovcova |first4=J. |last5=Tariq |first5=H. |last6=Yau |first6=W. Y. |last7=Humphrey |first7=J. |last8=Jaunmuktane |first8=Z. |last9=Sivakumar |first9=P. |last10=Polke |first10=J. |last11=Ilyas |first11=M. |last12=Tribollet |first12=E. |last13=Tomaselli |first13=P. J. |last14=Devigili |first14=G. |last15=Callegari |first15=I. |last16=Versino |first16=M. |last17=Salpietro |first17=V. |last18=Efthymiou |first18=S. |last19=Kaski |first19=D. |last20=Wood |first20=N. W. |last21=Andrade |first21=N. S. |last22=Buglo |first22=E. |last23=Rebelo |first23=A. |last24=Rossor |first24=A. M. |last25=Bronstein |first25=A. |last26=Fratta |first26=P. |last27=Marques |first27=W. J. |last28=Züchner |first28=S. |last29=Reilly |first29=M. M. |last30=Houlden |first30=H. |volume=51 |issue=4 |pages=649–658 |doi=10.1038/s41588-019-0372-4 }}</ref>

=== Associated human mutations ===
* The ''ACE'' gene, encoding [[angiotensin-converting enzyme]], has 2 common variants, one with an ''Alu'' insertion (''ACE''-I) and one with the ''Alu'' deleted (''ACE''-D). This variation has been linked to changes in sporting ability: the presence of the ''Alu'' element is associated with better performance in endurance-oriented events (e.g. triathlons), whereas its absence is associated with strength- and power-oriented performance.<ref name=pmid21615186>{{cite journal |doi=10.2165/11588720-000000000-00000 |pmid=21615186 |title=The ACE Gene and Human Performance |journal=Sports Medicine |volume=41 |issue=6 |pages=433–48 |year=2011 |last1=Puthucheary |first1=Zudin |last2=Skipworth |first2=James RA |last3=Rawal |first3=Jai |last4=Loosemore |first4=Mike |last5=Van Someren |first5=Ken |last6=Montgomery |first6=Hugh E |s2cid=42531424 }}</ref>
* The [[opsin]] [[gene duplication]] which [[Evolution of color vision in primates|resulted]] in the re-gaining of [[trichromacy]] in [[Catarrhini|Old World primates]] (including humans) is flanked by an ''Alu'' element,<ref name=pmid10413401>{{cite journal |pmid=10413401 |url=http://genome.cshlp.org/cgi/pmidlookup?view=long&pmid=10413401 |year=1999 |last1=Dulai |first1=K. S |title=The evolution of trichromatic color vision by opsin gene duplication in New World and Old World primates |journal=Genome Research |volume=9 |issue=7 |pages=629–38 |last2=von Dornum |first2=M |last3=Mollon |first3=J. D |last4=Hunt |first4=D. M |doi=10.1101/gr.9.7.629|s2cid = 10637615|doi-access=free }}</ref> implicating the role of ''Alu'' in the evolution of three colour vision.