The 22q11 low copy repeats are characterized by unprecedented size and structural variability
Low copy repeats (LCRs) are recognized as a significant source of genomic instability, driving genome variability and evolution. The Chromosome 22 LCRs (LCR22s) mediate nonallelic homologous recombination (NAHR) leading to the 22q11 deletion syndrome (22q11DS). However, LCR22s are among the most com...
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| Veröffentlicht in: | Genome research 2019-09, Vol.29 (9), p.1389-1401 |
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| creator | Demaerel, Wolfram Mostovoy, Yulia Yilmaz, Feyza Vervoort, Lisanne Pastor, Steven Hestand, Matthew S Swillen, Ann Vergaelen, Elfi Geiger, Elizabeth A Coughlin, Curtis R Chow, Stephen K McDonald-McGinn, Donna Morrow, Bernice Kwok, Pui-Yan Xiao, Ming Emanuel, Beverly S Shaikh, Tamim H Vermeesch, Joris R |
| description | Low copy repeats (LCRs) are recognized as a significant source of genomic instability, driving genome variability and evolution. The Chromosome 22 LCRs (LCR22s) mediate nonallelic homologous recombination (NAHR) leading to the 22q11 deletion syndrome (22q11DS). However, LCR22s are among the most complex regions in the genome, and their structure remains unresolved. The difficulty in generating accurate maps of LCR22s has also hindered localization of the deletion end points in 22q11DS patients. Using fiber FISH and Bionano optical mapping, we assembled LCR22 alleles in 187 cell lines. Our analysis uncovered an unprecedented level of variation in LCR22s, including LCR22A alleles ranging in size from 250 to 2000 kb. Further, the incidence of various LCR22 alleles varied within different populations. Additionally, the analysis of LCR22s in 22q11DS patients and their parents enabled further refinement of the rearrangement site within LCR22A and -D, which flank the 22q11 deletion. The NAHR site was localized to a 160-kb paralog shared between the LCR22A and -D in seven 22q11DS patients. Thus, we present the most comprehensive map of LCR22 variation to date. This will greatly facilitate the investigation of the role of LCR variation as a driver of 22q11 rearrangements and the phenotypic variability among 22q11DS patients. |
| doi_str_mv | 10.1101/gr.248682.119 |
| format | Article |
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The Chromosome 22 LCRs (LCR22s) mediate nonallelic homologous recombination (NAHR) leading to the 22q11 deletion syndrome (22q11DS). However, LCR22s are among the most complex regions in the genome, and their structure remains unresolved. The difficulty in generating accurate maps of LCR22s has also hindered localization of the deletion end points in 22q11DS patients. Using fiber FISH and Bionano optical mapping, we assembled LCR22 alleles in 187 cell lines. Our analysis uncovered an unprecedented level of variation in LCR22s, including LCR22A alleles ranging in size from 250 to 2000 kb. Further, the incidence of various LCR22 alleles varied within different populations. Additionally, the analysis of LCR22s in 22q11DS patients and their parents enabled further refinement of the rearrangement site within LCR22A and -D, which flank the 22q11 deletion. The NAHR site was localized to a 160-kb paralog shared between the LCR22A and -D in seven 22q11DS patients. Thus, we present the most comprehensive map of LCR22 variation to date. This will greatly facilitate the investigation of the role of LCR variation as a driver of 22q11 rearrangements and the phenotypic variability among 22q11DS patients.</description><identifier>ISSN: 1088-9051</identifier><identifier>EISSN: 1549-5469</identifier><identifier>DOI: 10.1101/gr.248682.119</identifier><identifier>PMID: 31481461</identifier><language>eng</language><publisher>United States: Cold Spring Harbor Laboratory Press</publisher><subject>22q11 Deletion Syndrome - genetics ; Alleles ; Animals ; Cell Line ; Cell lines ; Chromosomal Instability ; Chromosome 22 ; Chromosome Mapping - methods ; Chromosomes, Human, Pair 22 - genetics ; Evolution, Molecular ; Gene mapping ; Genetic variability ; Genomes ; Genomic instability ; Homologous recombination ; Humans ; In Situ Hybridization, Fluorescence ; Localization ; Population genetics ; Primates - genetics ; Repetitive Sequences, Nucleic Acid ; Variation</subject><ispartof>Genome research, 2019-09, Vol.29 (9), p.1389-1401</ispartof><rights>2019 Demaerel et al.; Published by Cold Spring Harbor Laboratory Press.</rights><rights>Copyright Cold Spring Harbor Laboratory Press Sep 2019</rights><rights>2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-12a4e3befdc01671d1701905e3a651f19ad911111c5e5a6212e55b3ac7d9291e3</citedby><cites>FETCH-LOGICAL-c415t-12a4e3befdc01671d1701905e3a651f19ad911111c5e5a6212e55b3ac7d9291e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724673/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724673/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31481461$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Demaerel, Wolfram</creatorcontrib><creatorcontrib>Mostovoy, Yulia</creatorcontrib><creatorcontrib>Yilmaz, Feyza</creatorcontrib><creatorcontrib>Vervoort, Lisanne</creatorcontrib><creatorcontrib>Pastor, Steven</creatorcontrib><creatorcontrib>Hestand, Matthew S</creatorcontrib><creatorcontrib>Swillen, Ann</creatorcontrib><creatorcontrib>Vergaelen, Elfi</creatorcontrib><creatorcontrib>Geiger, Elizabeth A</creatorcontrib><creatorcontrib>Coughlin, Curtis R</creatorcontrib><creatorcontrib>Chow, Stephen K</creatorcontrib><creatorcontrib>McDonald-McGinn, Donna</creatorcontrib><creatorcontrib>Morrow, Bernice</creatorcontrib><creatorcontrib>Kwok, Pui-Yan</creatorcontrib><creatorcontrib>Xiao, Ming</creatorcontrib><creatorcontrib>Emanuel, Beverly S</creatorcontrib><creatorcontrib>Shaikh, Tamim H</creatorcontrib><creatorcontrib>Vermeesch, Joris R</creatorcontrib><title>The 22q11 low copy repeats are characterized by unprecedented size and structural variability</title><title>Genome research</title><addtitle>Genome Res</addtitle><description>Low copy repeats (LCRs) are recognized as a significant source of genomic instability, driving genome variability and evolution. The Chromosome 22 LCRs (LCR22s) mediate nonallelic homologous recombination (NAHR) leading to the 22q11 deletion syndrome (22q11DS). However, LCR22s are among the most complex regions in the genome, and their structure remains unresolved. The difficulty in generating accurate maps of LCR22s has also hindered localization of the deletion end points in 22q11DS patients. Using fiber FISH and Bionano optical mapping, we assembled LCR22 alleles in 187 cell lines. Our analysis uncovered an unprecedented level of variation in LCR22s, including LCR22A alleles ranging in size from 250 to 2000 kb. Further, the incidence of various LCR22 alleles varied within different populations. Additionally, the analysis of LCR22s in 22q11DS patients and their parents enabled further refinement of the rearrangement site within LCR22A and -D, which flank the 22q11 deletion. The NAHR site was localized to a 160-kb paralog shared between the LCR22A and -D in seven 22q11DS patients. Thus, we present the most comprehensive map of LCR22 variation to date. This will greatly facilitate the investigation of the role of LCR variation as a driver of 22q11 rearrangements and the phenotypic variability among 22q11DS patients.</description><subject>22q11 Deletion Syndrome - genetics</subject><subject>Alleles</subject><subject>Animals</subject><subject>Cell Line</subject><subject>Cell lines</subject><subject>Chromosomal Instability</subject><subject>Chromosome 22</subject><subject>Chromosome Mapping - methods</subject><subject>Chromosomes, Human, Pair 22 - genetics</subject><subject>Evolution, Molecular</subject><subject>Gene mapping</subject><subject>Genetic variability</subject><subject>Genomes</subject><subject>Genomic instability</subject><subject>Homologous recombination</subject><subject>Humans</subject><subject>In Situ Hybridization, Fluorescence</subject><subject>Localization</subject><subject>Population genetics</subject><subject>Primates - genetics</subject><subject>Repetitive Sequences, Nucleic Acid</subject><subject>Variation</subject><issn>1088-9051</issn><issn>1549-5469</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1r3DAQxUVpaNK0x16LoJdenGj0ZelSKKFJC4FekmMQY3l218FrO5KdsP3rq2XT0FaX-dCPxxseYx9AnAEIOF-nM6mddbKM_hU7AaN9ZbT1r0svnKu8MHDM3uZ8L4RQ2rk37FiBdqAtnLC7mw1xKR8AeD8-8ThOO55oIpwzx0Q8bjBhnCl1v6jlzY4vw5QoUkvDXBa5rDkOpZnTEuclYc8fMXXYdH03796xoxX2md4_11N2e_nt5uJ7df3z6sfF1-sqajBzBRI1qYZWbRRga2ihFlB8k0JrYAUeWw_7Fw0ZtBIkGdMojHXrpQdSp-zLQXdami21sZgrTsKUui2mXRixC__-DN0mrMfHYGupba2KwOdngTQ-LJTnsO1ypL7HgcYlBymdNla5ui7op__Q-3FJQzlvTzlbewl7wepAxTTmnGj1YgZE2AcX1ikcgiujL_zHvy94of8kpX4DMCuUFA</recordid><startdate>20190901</startdate><enddate>20190901</enddate><creator>Demaerel, Wolfram</creator><creator>Mostovoy, Yulia</creator><creator>Yilmaz, Feyza</creator><creator>Vervoort, Lisanne</creator><creator>Pastor, Steven</creator><creator>Hestand, Matthew S</creator><creator>Swillen, Ann</creator><creator>Vergaelen, Elfi</creator><creator>Geiger, Elizabeth A</creator><creator>Coughlin, Curtis R</creator><creator>Chow, Stephen K</creator><creator>McDonald-McGinn, Donna</creator><creator>Morrow, Bernice</creator><creator>Kwok, Pui-Yan</creator><creator>Xiao, Ming</creator><creator>Emanuel, Beverly S</creator><creator>Shaikh, Tamim H</creator><creator>Vermeesch, Joris R</creator><general>Cold Spring Harbor Laboratory Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20190901</creationdate><title>The 22q11 low copy repeats are characterized by unprecedented size and structural variability</title><author>Demaerel, Wolfram ; 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The Chromosome 22 LCRs (LCR22s) mediate nonallelic homologous recombination (NAHR) leading to the 22q11 deletion syndrome (22q11DS). However, LCR22s are among the most complex regions in the genome, and their structure remains unresolved. The difficulty in generating accurate maps of LCR22s has also hindered localization of the deletion end points in 22q11DS patients. Using fiber FISH and Bionano optical mapping, we assembled LCR22 alleles in 187 cell lines. Our analysis uncovered an unprecedented level of variation in LCR22s, including LCR22A alleles ranging in size from 250 to 2000 kb. Further, the incidence of various LCR22 alleles varied within different populations. Additionally, the analysis of LCR22s in 22q11DS patients and their parents enabled further refinement of the rearrangement site within LCR22A and -D, which flank the 22q11 deletion. The NAHR site was localized to a 160-kb paralog shared between the LCR22A and -D in seven 22q11DS patients. Thus, we present the most comprehensive map of LCR22 variation to date. This will greatly facilitate the investigation of the role of LCR variation as a driver of 22q11 rearrangements and the phenotypic variability among 22q11DS patients.</abstract><cop>United States</cop><pub>Cold Spring Harbor Laboratory Press</pub><pmid>31481461</pmid><doi>10.1101/gr.248682.119</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 22q11 Deletion Syndrome - genetics Alleles Animals Cell Line Cell lines Chromosomal Instability Chromosome 22 Chromosome Mapping - methods Chromosomes, Human, Pair 22 - genetics Evolution, Molecular Gene mapping Genetic variability Genomes Genomic instability Homologous recombination Humans In Situ Hybridization, Fluorescence Localization Population genetics Primates - genetics Repetitive Sequences, Nucleic Acid Variation |
| title | The 22q11 low copy repeats are characterized by unprecedented size and structural variability |
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