NAHR-mediated copy-number variants in a clinical population: mechanistic insights into both genomic disorders and Mendelizing traits
We delineated and analyzed directly oriented paralogous low-copy repeats (DP-LCRs) in the most recent version of the human haploid reference genome. The computationally defined DP-LCRs were cross-referenced with our chromosomal microarray analysis (CMA) database of 25,144 patients subjected to genom...
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| Veröffentlicht in: | Genome research 2013-09, Vol.23 (9), p.1395-1409 |
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| creator | Dittwald, Piotr Gambin, Tomasz Szafranski, Przemyslaw Li, Jian Amato, Stephen Divon, Michael Y Rodríguez Rojas, Lisa Ximena Elton, Lindsay E Scott, Daryl A Schaaf, Christian P Torres-Martinez, Wilfredo Stevens, Abby K Rosenfeld, Jill A Agadi, Satish Francis, David Kang, Sung-Hae L Breman, Amy Lalani, Seema R Bacino, Carlos A Bi, Weimin Milosavljevic, Aleksandar Beaudet, Arthur L Patel, Ankita Shaw, Chad A Lupski, James R Gambin, Anna Cheung, Sau Wai Stankiewicz, Pawel |
| description | We delineated and analyzed directly oriented paralogous low-copy repeats (DP-LCRs) in the most recent version of the human haploid reference genome. The computationally defined DP-LCRs were cross-referenced with our chromosomal microarray analysis (CMA) database of 25,144 patients subjected to genome-wide assays. This computationally guided approach to the empirically derived large data set allowed us to investigate genomic rearrangement relative frequencies and identify new loci for recurrent nonallelic homologous recombination (NAHR)-mediated copy-number variants (CNVs). The most commonly observed recurrent CNVs were NPHP1 duplications (233), CHRNA7 duplications (175), and 22q11.21 deletions (DiGeorge/velocardiofacial syndrome, 166). In the ∼25% of CMA cases for which parental studies were available, we identified 190 de novo recurrent CNVs. In this group, the most frequently observed events were deletions of 22q11.21 (48), 16p11.2 (autism, 34), and 7q11.23 (Williams-Beuren syndrome, 11). Several features of DP-LCRs, including length, distance between NAHR substrate elements, DNA sequence identity (fraction matching), GC content, and concentration of the homologous recombination (HR) hot spot motif 5'-CCNCCNTNNCCNC-3', correlate with the frequencies of the recurrent CNVs events. Four novel adjacent DP-LCR-flanked and NAHR-prone regions, involving 2q12.2q13, were elucidated in association with novel genomic disorders. Our study quantitates genome architectural features responsible for NAHR-mediated genomic instability and further elucidates the role of NAHR in human disease. |
| doi_str_mv | 10.1101/gr.152454.112 |
| format | Article |
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The computationally defined DP-LCRs were cross-referenced with our chromosomal microarray analysis (CMA) database of 25,144 patients subjected to genome-wide assays. This computationally guided approach to the empirically derived large data set allowed us to investigate genomic rearrangement relative frequencies and identify new loci for recurrent nonallelic homologous recombination (NAHR)-mediated copy-number variants (CNVs). The most commonly observed recurrent CNVs were NPHP1 duplications (233), CHRNA7 duplications (175), and 22q11.21 deletions (DiGeorge/velocardiofacial syndrome, 166). In the ∼25% of CMA cases for which parental studies were available, we identified 190 de novo recurrent CNVs. In this group, the most frequently observed events were deletions of 22q11.21 (48), 16p11.2 (autism, 34), and 7q11.23 (Williams-Beuren syndrome, 11). Several features of DP-LCRs, including length, distance between NAHR substrate elements, DNA sequence identity (fraction matching), GC content, and concentration of the homologous recombination (HR) hot spot motif 5'-CCNCCNTNNCCNC-3', correlate with the frequencies of the recurrent CNVs events. Four novel adjacent DP-LCR-flanked and NAHR-prone regions, involving 2q12.2q13, were elucidated in association with novel genomic disorders. Our study quantitates genome architectural features responsible for NAHR-mediated genomic instability and further elucidates the role of NAHR in human disease.</description><identifier>ISSN: 1088-9051</identifier><identifier>EISSN: 1549-5469</identifier><identifier>DOI: 10.1101/gr.152454.112</identifier><identifier>PMID: 23657883</identifier><language>eng</language><publisher>United States: Cold Spring Harbor Laboratory Press</publisher><subject>Adaptor Proteins, Signal Transducing - genetics ; Alleles ; alpha7 Nicotinic Acetylcholine Receptor - genetics ; Base Composition ; Chromosome Deletion ; Chromosome Disorders - genetics ; Chromosome Duplication ; Cytoskeletal Proteins ; DNA Copy Number Variations ; Genetic Diseases, Inborn - genetics ; Genome, Human ; Homologous Recombination ; Humans ; Membrane Proteins - genetics ; Nucleotide Motifs</subject><ispartof>Genome research, 2013-09, Vol.23 (9), p.1395-1409</ispartof><rights>2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c420t-be9cac6d8188d566c137e89967ca00d48d1b2f0049dd3546c0f2fc22fb53e753</citedby><cites>FETCH-LOGICAL-c420t-be9cac6d8188d566c137e89967ca00d48d1b2f0049dd3546c0f2fc22fb53e753</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/PMC3759717/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759717/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,887,27933,27934,53800,53802</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23657883$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dittwald, Piotr</creatorcontrib><creatorcontrib>Gambin, Tomasz</creatorcontrib><creatorcontrib>Szafranski, Przemyslaw</creatorcontrib><creatorcontrib>Li, Jian</creatorcontrib><creatorcontrib>Amato, Stephen</creatorcontrib><creatorcontrib>Divon, Michael Y</creatorcontrib><creatorcontrib>Rodríguez Rojas, Lisa Ximena</creatorcontrib><creatorcontrib>Elton, Lindsay E</creatorcontrib><creatorcontrib>Scott, Daryl A</creatorcontrib><creatorcontrib>Schaaf, Christian P</creatorcontrib><creatorcontrib>Torres-Martinez, Wilfredo</creatorcontrib><creatorcontrib>Stevens, Abby K</creatorcontrib><creatorcontrib>Rosenfeld, Jill A</creatorcontrib><creatorcontrib>Agadi, Satish</creatorcontrib><creatorcontrib>Francis, David</creatorcontrib><creatorcontrib>Kang, Sung-Hae L</creatorcontrib><creatorcontrib>Breman, Amy</creatorcontrib><creatorcontrib>Lalani, Seema R</creatorcontrib><creatorcontrib>Bacino, Carlos A</creatorcontrib><creatorcontrib>Bi, Weimin</creatorcontrib><creatorcontrib>Milosavljevic, Aleksandar</creatorcontrib><creatorcontrib>Beaudet, Arthur L</creatorcontrib><creatorcontrib>Patel, Ankita</creatorcontrib><creatorcontrib>Shaw, Chad A</creatorcontrib><creatorcontrib>Lupski, James R</creatorcontrib><creatorcontrib>Gambin, Anna</creatorcontrib><creatorcontrib>Cheung, Sau Wai</creatorcontrib><creatorcontrib>Stankiewicz, Pawel</creatorcontrib><title>NAHR-mediated copy-number variants in a clinical population: mechanistic insights into both genomic disorders and Mendelizing traits</title><title>Genome research</title><addtitle>Genome Res</addtitle><description>We delineated and analyzed directly oriented paralogous low-copy repeats (DP-LCRs) in the most recent version of the human haploid reference genome. The computationally defined DP-LCRs were cross-referenced with our chromosomal microarray analysis (CMA) database of 25,144 patients subjected to genome-wide assays. This computationally guided approach to the empirically derived large data set allowed us to investigate genomic rearrangement relative frequencies and identify new loci for recurrent nonallelic homologous recombination (NAHR)-mediated copy-number variants (CNVs). The most commonly observed recurrent CNVs were NPHP1 duplications (233), CHRNA7 duplications (175), and 22q11.21 deletions (DiGeorge/velocardiofacial syndrome, 166). In the ∼25% of CMA cases for which parental studies were available, we identified 190 de novo recurrent CNVs. In this group, the most frequently observed events were deletions of 22q11.21 (48), 16p11.2 (autism, 34), and 7q11.23 (Williams-Beuren syndrome, 11). Several features of DP-LCRs, including length, distance between NAHR substrate elements, DNA sequence identity (fraction matching), GC content, and concentration of the homologous recombination (HR) hot spot motif 5'-CCNCCNTNNCCNC-3', correlate with the frequencies of the recurrent CNVs events. Four novel adjacent DP-LCR-flanked and NAHR-prone regions, involving 2q12.2q13, were elucidated in association with novel genomic disorders. Our study quantitates genome architectural features responsible for NAHR-mediated genomic instability and further elucidates the role of NAHR in human disease.</description><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Alleles</subject><subject>alpha7 Nicotinic Acetylcholine Receptor - genetics</subject><subject>Base Composition</subject><subject>Chromosome Deletion</subject><subject>Chromosome Disorders - genetics</subject><subject>Chromosome Duplication</subject><subject>Cytoskeletal Proteins</subject><subject>DNA Copy Number Variations</subject><subject>Genetic Diseases, Inborn - genetics</subject><subject>Genome, Human</subject><subject>Homologous Recombination</subject><subject>Humans</subject><subject>Membrane Proteins - genetics</subject><subject>Nucleotide Motifs</subject><issn>1088-9051</issn><issn>1549-5469</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkUtLHjEUhkOp1FuX3UqW3YzNdSZxIYhoLWgL4j5kksx8KTPJmGQEXfeHm_pZqatzDufhPZcXgC8YHWOM8LcxHWNOGGe1JB_AHuZMNpy18mPNkRCNRBzvgv2cfyOEKBPiE9gltOWdEHQP_Pl5dnXbzM56XZyFJi6PTVjn3iX4oJPXoWToA9TQTD54oye4xGWddPExnMDZmY0OPhdvKpX9uHnBS4R9LBs4uhDn2rI-x2RdylAHC29csG7yTz6MsCTtSz4EO4Oesvv8Gg_A3eXF3flVc_3r-4_zs-vGMIJK0ztptGmtwEJY3rYG084JKdvOaIQsExb3ZECISWtpfYFBAxkMIUPPqes4PQCnW9ll7evFxoU6flJL8rNOjypqr953gt-oMT4o2nHZ4a4KfH0VSPF-dbmo2WfjpkkHF9esMKOSYNEhWdFmi5oUc05ueBuDkfprnBqT2hpXS1L5o_93e6P_OUWfAfE-l9E</recordid><startdate>201309</startdate><enddate>201309</enddate><creator>Dittwald, Piotr</creator><creator>Gambin, Tomasz</creator><creator>Szafranski, Przemyslaw</creator><creator>Li, Jian</creator><creator>Amato, Stephen</creator><creator>Divon, Michael Y</creator><creator>Rodríguez Rojas, Lisa Ximena</creator><creator>Elton, Lindsay E</creator><creator>Scott, Daryl A</creator><creator>Schaaf, Christian P</creator><creator>Torres-Martinez, Wilfredo</creator><creator>Stevens, Abby K</creator><creator>Rosenfeld, Jill A</creator><creator>Agadi, Satish</creator><creator>Francis, David</creator><creator>Kang, Sung-Hae L</creator><creator>Breman, Amy</creator><creator>Lalani, Seema R</creator><creator>Bacino, Carlos A</creator><creator>Bi, Weimin</creator><creator>Milosavljevic, Aleksandar</creator><creator>Beaudet, Arthur L</creator><creator>Patel, Ankita</creator><creator>Shaw, Chad A</creator><creator>Lupski, James R</creator><creator>Gambin, Anna</creator><creator>Cheung, Sau Wai</creator><creator>Stankiewicz, Pawel</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>5PM</scope></search><sort><creationdate>201309</creationdate><title>NAHR-mediated copy-number variants in a clinical population: mechanistic insights into both genomic disorders and Mendelizing traits</title><author>Dittwald, Piotr ; Gambin, Tomasz ; Szafranski, Przemyslaw ; Li, Jian ; Amato, Stephen ; Divon, Michael Y ; Rodríguez Rojas, Lisa Ximena ; Elton, Lindsay E ; Scott, Daryl A ; Schaaf, Christian P ; Torres-Martinez, Wilfredo ; Stevens, Abby K ; Rosenfeld, Jill A ; Agadi, Satish ; Francis, David ; Kang, Sung-Hae L ; Breman, Amy ; Lalani, Seema R ; Bacino, Carlos A ; Bi, Weimin ; Milosavljevic, Aleksandar ; Beaudet, Arthur L ; Patel, Ankita ; Shaw, Chad A ; Lupski, James R ; Gambin, Anna ; Cheung, Sau Wai ; Stankiewicz, Pawel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c420t-be9cac6d8188d566c137e89967ca00d48d1b2f0049dd3546c0f2fc22fb53e753</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adaptor Proteins, Signal Transducing - genetics</topic><topic>Alleles</topic><topic>alpha7 Nicotinic Acetylcholine Receptor - genetics</topic><topic>Base Composition</topic><topic>Chromosome Deletion</topic><topic>Chromosome Disorders - genetics</topic><topic>Chromosome Duplication</topic><topic>Cytoskeletal Proteins</topic><topic>DNA Copy Number Variations</topic><topic>Genetic Diseases, Inborn - genetics</topic><topic>Genome, Human</topic><topic>Homologous Recombination</topic><topic>Humans</topic><topic>Membrane Proteins - genetics</topic><topic>Nucleotide Motifs</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dittwald, Piotr</creatorcontrib><creatorcontrib>Gambin, Tomasz</creatorcontrib><creatorcontrib>Szafranski, Przemyslaw</creatorcontrib><creatorcontrib>Li, Jian</creatorcontrib><creatorcontrib>Amato, Stephen</creatorcontrib><creatorcontrib>Divon, Michael Y</creatorcontrib><creatorcontrib>Rodríguez Rojas, Lisa Ximena</creatorcontrib><creatorcontrib>Elton, Lindsay E</creatorcontrib><creatorcontrib>Scott, Daryl A</creatorcontrib><creatorcontrib>Schaaf, Christian P</creatorcontrib><creatorcontrib>Torres-Martinez, Wilfredo</creatorcontrib><creatorcontrib>Stevens, Abby K</creatorcontrib><creatorcontrib>Rosenfeld, Jill A</creatorcontrib><creatorcontrib>Agadi, Satish</creatorcontrib><creatorcontrib>Francis, David</creatorcontrib><creatorcontrib>Kang, Sung-Hae L</creatorcontrib><creatorcontrib>Breman, Amy</creatorcontrib><creatorcontrib>Lalani, Seema R</creatorcontrib><creatorcontrib>Bacino, Carlos A</creatorcontrib><creatorcontrib>Bi, Weimin</creatorcontrib><creatorcontrib>Milosavljevic, Aleksandar</creatorcontrib><creatorcontrib>Beaudet, Arthur L</creatorcontrib><creatorcontrib>Patel, Ankita</creatorcontrib><creatorcontrib>Shaw, Chad A</creatorcontrib><creatorcontrib>Lupski, James R</creatorcontrib><creatorcontrib>Gambin, Anna</creatorcontrib><creatorcontrib>Cheung, Sau Wai</creatorcontrib><creatorcontrib>Stankiewicz, Pawel</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Genome research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dittwald, Piotr</au><au>Gambin, Tomasz</au><au>Szafranski, Przemyslaw</au><au>Li, Jian</au><au>Amato, Stephen</au><au>Divon, Michael Y</au><au>Rodríguez Rojas, Lisa Ximena</au><au>Elton, Lindsay E</au><au>Scott, Daryl A</au><au>Schaaf, Christian P</au><au>Torres-Martinez, Wilfredo</au><au>Stevens, Abby K</au><au>Rosenfeld, Jill A</au><au>Agadi, Satish</au><au>Francis, David</au><au>Kang, Sung-Hae L</au><au>Breman, Amy</au><au>Lalani, Seema R</au><au>Bacino, Carlos A</au><au>Bi, Weimin</au><au>Milosavljevic, Aleksandar</au><au>Beaudet, Arthur L</au><au>Patel, Ankita</au><au>Shaw, Chad A</au><au>Lupski, James R</au><au>Gambin, Anna</au><au>Cheung, Sau Wai</au><au>Stankiewicz, Pawel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>NAHR-mediated copy-number variants in a clinical population: mechanistic insights into both genomic disorders and Mendelizing traits</atitle><jtitle>Genome research</jtitle><addtitle>Genome Res</addtitle><date>2013-09</date><risdate>2013</risdate><volume>23</volume><issue>9</issue><spage>1395</spage><epage>1409</epage><pages>1395-1409</pages><issn>1088-9051</issn><eissn>1549-5469</eissn><abstract>We delineated and analyzed directly oriented paralogous low-copy repeats (DP-LCRs) in the most recent version of the human haploid reference genome. The computationally defined DP-LCRs were cross-referenced with our chromosomal microarray analysis (CMA) database of 25,144 patients subjected to genome-wide assays. This computationally guided approach to the empirically derived large data set allowed us to investigate genomic rearrangement relative frequencies and identify new loci for recurrent nonallelic homologous recombination (NAHR)-mediated copy-number variants (CNVs). The most commonly observed recurrent CNVs were NPHP1 duplications (233), CHRNA7 duplications (175), and 22q11.21 deletions (DiGeorge/velocardiofacial syndrome, 166). In the ∼25% of CMA cases for which parental studies were available, we identified 190 de novo recurrent CNVs. In this group, the most frequently observed events were deletions of 22q11.21 (48), 16p11.2 (autism, 34), and 7q11.23 (Williams-Beuren syndrome, 11). Several features of DP-LCRs, including length, distance between NAHR substrate elements, DNA sequence identity (fraction matching), GC content, and concentration of the homologous recombination (HR) hot spot motif 5'-CCNCCNTNNCCNC-3', correlate with the frequencies of the recurrent CNVs events. Four novel adjacent DP-LCR-flanked and NAHR-prone regions, involving 2q12.2q13, were elucidated in association with novel genomic disorders. Our study quantitates genome architectural features responsible for NAHR-mediated genomic instability and further elucidates the role of NAHR in human disease.</abstract><cop>United States</cop><pub>Cold Spring Harbor Laboratory Press</pub><pmid>23657883</pmid><doi>10.1101/gr.152454.112</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adaptor Proteins, Signal Transducing - genetics Alleles alpha7 Nicotinic Acetylcholine Receptor - genetics Base Composition Chromosome Deletion Chromosome Disorders - genetics Chromosome Duplication Cytoskeletal Proteins DNA Copy Number Variations Genetic Diseases, Inborn - genetics Genome, Human Homologous Recombination Humans Membrane Proteins - genetics Nucleotide Motifs |
| title | NAHR-mediated copy-number variants in a clinical population: mechanistic insights into both genomic disorders and Mendelizing traits |
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