Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathways
Most heritable traits, including disease susceptibility, are affected by interactions between multiple genes. However, we understand little about how genes interact because very few possible genetic interactions have been explored experimentally. We have used RNA interference in Caenorhabditis elega...
Gespeichert in:
| Veröffentlicht in: | Nature genetics 2006-08, Vol.38 (8), p.896-903 |
|---|---|
| Hauptverfasser: | , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 903 |
|---|---|
| container_issue | 8 |
| container_start_page | 896 |
| container_title | Nature genetics |
| container_volume | 38 |
| creator | Fraser, Andrew G Lehner, Ben Crombie, Catriona Tischler, Julia Fortunato, Angelo |
| description | Most heritable traits, including disease susceptibility, are affected by interactions between multiple genes. However, we understand little about how genes interact because very few possible genetic interactions have been explored experimentally. We have used RNA interference in
Caenorhabditis elegans
to systematically test ∼65,000 pairs of genes for their ability to interact genetically. We identify ∼350 genetic interactions between genes functioning in signaling pathways that are mutated in human diseases, including components of the EGF/Ras, Notch and Wnt pathways. Most notably, we identify a class of highly connected 'hub' genes: inactivation of these genes can enhance the phenotypic consequences of mutation of many different genes. These hub genes all encode chromatin regulators, and their activity as genetic hubs seems to be conserved across animals. We propose that these genes function as general buffers of genetic variation and that these hub genes may act as modifier genes in multiple, mechanistically unrelated genetic diseases in humans. |
| doi_str_mv | 10.1038/ng1844 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_proqu</sourceid><recordid>TN_cdi_proquest_miscellaneous_762278391</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A183393721</galeid><sourcerecordid>A183393721</sourcerecordid><originalsourceid>FETCH-LOGICAL-c651t-842c1955744e697fb785cd1a18e83eeb0168b331df65b8597110bfb7d6676eb23</originalsourceid><addsrcrecordid>eNqN0t1r1TAUAPAiiptT_wKRoqj40Nk0aZI-josfg8HAqa8lTU-7jDapOal6X_zbTbnFy1VRyUPz8ctJTnqS5CHJT0lO5SvbE8nYreSYlIxnRBB5O_ZzTjKWU36U3EO8yXPCWC7vJkeES1bSqjpOvl9tMcCogtHpqKbJ2D51XdqDhWXK2ABe6WCcxThINwqs89eqaU0wmMIAvVpWWrDBdAYw1W4cnU1H1y5jj0u01nyJPUjR9FYNyxGTCtdf1RbvJ3c6NSA8WL8nycc3rz9s3mUXl2_PN2cXmeYlCZlkhSZVWQrGgFeia4QsdUsUkSApQJPHhBpKSdvxspFlJQjJm6hazgWHpqAnyYtd3Mm7zzNgqEeDGoZBWXAz1oIXhZC0IlE-_6vkMjZa0n9CUhWVFKyK8Mkv8MbNPj4E1kVRcMplKSN6ukO9GqA2tnMhvvsSsT4jktKKimK53OkfVGwtjEY7C52J8wcbXh5siCbAt9CrGbE-v3r___by06Fdk9feIXro6smbUfltTfJ6Kch6V5ARPl6Tn5sR2j1bKzCCZytQqNXQeWW1wb0T0cSq3f9BjEu2B79_xd-OfLSTVoXZw89Q6_IPtYH8Qg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>222636858</pqid></control><display><type>article</type><title>Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathways</title><source>MEDLINE</source><source>Nature Journals Online</source><source>SpringerLink Journals - AutoHoldings</source><creator>Fraser, Andrew G ; Lehner, Ben ; Crombie, Catriona ; Tischler, Julia ; Fortunato, Angelo</creator><creatorcontrib>Fraser, Andrew G ; Lehner, Ben ; Crombie, Catriona ; Tischler, Julia ; Fortunato, Angelo</creatorcontrib><description>Most heritable traits, including disease susceptibility, are affected by interactions between multiple genes. However, we understand little about how genes interact because very few possible genetic interactions have been explored experimentally. We have used RNA interference in
Caenorhabditis elegans
to systematically test ∼65,000 pairs of genes for their ability to interact genetically. We identify ∼350 genetic interactions between genes functioning in signaling pathways that are mutated in human diseases, including components of the EGF/Ras, Notch and Wnt pathways. Most notably, we identify a class of highly connected 'hub' genes: inactivation of these genes can enhance the phenotypic consequences of mutation of many different genes. These hub genes all encode chromatin regulators, and their activity as genetic hubs seems to be conserved across animals. We propose that these genes function as general buffers of genetic variation and that these hub genes may act as modifier genes in multiple, mechanistically unrelated genetic diseases in humans.</description><identifier>ISSN: 1061-4036</identifier><identifier>EISSN: 1546-1718</identifier><identifier>DOI: 10.1038/ng1844</identifier><identifier>PMID: 16845399</identifier><identifier>CODEN: NGENEC</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>Agriculture ; Animal Genetics and Genomics ; Animals ; Biological and medical sciences ; Biomedical and Life Sciences ; Biomedicine ; Buffers ; Caenorhabditis elegans ; Caenorhabditis elegans - genetics ; Caenorhabditis elegans - metabolism ; Cancer Research ; Cell physiology ; Chromosome Mapping ; Classical genetics, quantitative genetics, hybrids ; Disease ; Enhancer Elements, Genetic ; Epidermal Growth Factor - genetics ; Female ; Fundamental and applied biological sciences. Psychology ; Gene expression ; Gene Function ; Genes, Helminth ; Genetic aspects ; Genetic diversity ; Genetic variation ; Genetics of eukaryotes. Biological and molecular evolution ; Genomics ; Human Genetics ; Humans ; Inactivation ; Methods, theories and miscellaneous ; Molecular and cellular biology ; Mutation ; Phenotype ; Physiological aspects ; RNA Interference ; Signal Transduction ; Vulva - growth & development ; Worms</subject><ispartof>Nature genetics, 2006-08, Vol.38 (8), p.896-903</ispartof><rights>Springer Nature America, Inc. 2006</rights><rights>2006 INIST-CNRS</rights><rights>COPYRIGHT 2006 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Aug 2006</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c651t-842c1955744e697fb785cd1a18e83eeb0168b331df65b8597110bfb7d6676eb23</citedby><cites>FETCH-LOGICAL-c651t-842c1955744e697fb785cd1a18e83eeb0168b331df65b8597110bfb7d6676eb23</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/ng1844$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/ng1844$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,2725,27922,27923,41486,42555,51317</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17993440$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16845399$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fraser, Andrew G</creatorcontrib><creatorcontrib>Lehner, Ben</creatorcontrib><creatorcontrib>Crombie, Catriona</creatorcontrib><creatorcontrib>Tischler, Julia</creatorcontrib><creatorcontrib>Fortunato, Angelo</creatorcontrib><title>Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathways</title><title>Nature genetics</title><addtitle>Nat Genet</addtitle><addtitle>Nat Genet</addtitle><description>Most heritable traits, including disease susceptibility, are affected by interactions between multiple genes. However, we understand little about how genes interact because very few possible genetic interactions have been explored experimentally. We have used RNA interference in
Caenorhabditis elegans
to systematically test ∼65,000 pairs of genes for their ability to interact genetically. We identify ∼350 genetic interactions between genes functioning in signaling pathways that are mutated in human diseases, including components of the EGF/Ras, Notch and Wnt pathways. Most notably, we identify a class of highly connected 'hub' genes: inactivation of these genes can enhance the phenotypic consequences of mutation of many different genes. These hub genes all encode chromatin regulators, and their activity as genetic hubs seems to be conserved across animals. We propose that these genes function as general buffers of genetic variation and that these hub genes may act as modifier genes in multiple, mechanistically unrelated genetic diseases in humans.</description><subject>Agriculture</subject><subject>Animal Genetics and Genomics</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Buffers</subject><subject>Caenorhabditis elegans</subject><subject>Caenorhabditis elegans - genetics</subject><subject>Caenorhabditis elegans - metabolism</subject><subject>Cancer Research</subject><subject>Cell physiology</subject><subject>Chromosome Mapping</subject><subject>Classical genetics, quantitative genetics, hybrids</subject><subject>Disease</subject><subject>Enhancer Elements, Genetic</subject><subject>Epidermal Growth Factor - genetics</subject><subject>Female</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene expression</subject><subject>Gene Function</subject><subject>Genes, Helminth</subject><subject>Genetic aspects</subject><subject>Genetic diversity</subject><subject>Genetic variation</subject><subject>Genetics of eukaryotes. Biological and molecular evolution</subject><subject>Genomics</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Inactivation</subject><subject>Methods, theories and miscellaneous</subject><subject>Molecular and cellular biology</subject><subject>Mutation</subject><subject>Phenotype</subject><subject>Physiological aspects</subject><subject>RNA Interference</subject><subject>Signal Transduction</subject><subject>Vulva - growth & development</subject><subject>Worms</subject><issn>1061-4036</issn><issn>1546-1718</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqN0t1r1TAUAPAiiptT_wKRoqj40Nk0aZI-josfg8HAqa8lTU-7jDapOal6X_zbTbnFy1VRyUPz8ctJTnqS5CHJT0lO5SvbE8nYreSYlIxnRBB5O_ZzTjKWU36U3EO8yXPCWC7vJkeES1bSqjpOvl9tMcCogtHpqKbJ2D51XdqDhWXK2ABe6WCcxThINwqs89eqaU0wmMIAvVpWWrDBdAYw1W4cnU1H1y5jj0u01nyJPUjR9FYNyxGTCtdf1RbvJ3c6NSA8WL8nycc3rz9s3mUXl2_PN2cXmeYlCZlkhSZVWQrGgFeia4QsdUsUkSApQJPHhBpKSdvxspFlJQjJm6hazgWHpqAnyYtd3Mm7zzNgqEeDGoZBWXAz1oIXhZC0IlE-_6vkMjZa0n9CUhWVFKyK8Mkv8MbNPj4E1kVRcMplKSN6ukO9GqA2tnMhvvsSsT4jktKKimK53OkfVGwtjEY7C52J8wcbXh5siCbAt9CrGbE-v3r___by06Fdk9feIXro6smbUfltTfJ6Kch6V5ARPl6Tn5sR2j1bKzCCZytQqNXQeWW1wb0T0cSq3f9BjEu2B79_xd-OfLSTVoXZw89Q6_IPtYH8Qg</recordid><startdate>20060801</startdate><enddate>20060801</enddate><creator>Fraser, Andrew G</creator><creator>Lehner, Ben</creator><creator>Crombie, Catriona</creator><creator>Tischler, Julia</creator><creator>Fortunato, Angelo</creator><general>Nature Publishing Group US</general><general>Nature Publishing Group</general><scope>IQODW</scope><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SS</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7N</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20060801</creationdate><title>Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathways</title><author>Fraser, Andrew G ; Lehner, Ben ; Crombie, Catriona ; Tischler, Julia ; Fortunato, Angelo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c651t-842c1955744e697fb785cd1a18e83eeb0168b331df65b8597110bfb7d6676eb23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Agriculture</topic><topic>Animal Genetics and Genomics</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Buffers</topic><topic>Caenorhabditis elegans</topic><topic>Caenorhabditis elegans - genetics</topic><topic>Caenorhabditis elegans - metabolism</topic><topic>Cancer Research</topic><topic>Cell physiology</topic><topic>Chromosome Mapping</topic><topic>Classical genetics, quantitative genetics, hybrids</topic><topic>Disease</topic><topic>Enhancer Elements, Genetic</topic><topic>Epidermal Growth Factor - genetics</topic><topic>Female</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene expression</topic><topic>Gene Function</topic><topic>Genes, Helminth</topic><topic>Genetic aspects</topic><topic>Genetic diversity</topic><topic>Genetic variation</topic><topic>Genetics of eukaryotes. Biological and molecular evolution</topic><topic>Genomics</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Inactivation</topic><topic>Methods, theories and miscellaneous</topic><topic>Molecular and cellular biology</topic><topic>Mutation</topic><topic>Phenotype</topic><topic>Physiological aspects</topic><topic>RNA Interference</topic><topic>Signal Transduction</topic><topic>Vulva - growth & development</topic><topic>Worms</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fraser, Andrew G</creatorcontrib><creatorcontrib>Lehner, Ben</creatorcontrib><creatorcontrib>Crombie, Catriona</creatorcontrib><creatorcontrib>Tischler, Julia</creatorcontrib><creatorcontrib>Fortunato, Angelo</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection (ProQuest)</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Nature genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fraser, Andrew G</au><au>Lehner, Ben</au><au>Crombie, Catriona</au><au>Tischler, Julia</au><au>Fortunato, Angelo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathways</atitle><jtitle>Nature genetics</jtitle><stitle>Nat Genet</stitle><addtitle>Nat Genet</addtitle><date>2006-08-01</date><risdate>2006</risdate><volume>38</volume><issue>8</issue><spage>896</spage><epage>903</epage><pages>896-903</pages><issn>1061-4036</issn><eissn>1546-1718</eissn><coden>NGENEC</coden><abstract>Most heritable traits, including disease susceptibility, are affected by interactions between multiple genes. However, we understand little about how genes interact because very few possible genetic interactions have been explored experimentally. We have used RNA interference in
Caenorhabditis elegans
to systematically test ∼65,000 pairs of genes for their ability to interact genetically. We identify ∼350 genetic interactions between genes functioning in signaling pathways that are mutated in human diseases, including components of the EGF/Ras, Notch and Wnt pathways. Most notably, we identify a class of highly connected 'hub' genes: inactivation of these genes can enhance the phenotypic consequences of mutation of many different genes. These hub genes all encode chromatin regulators, and their activity as genetic hubs seems to be conserved across animals. We propose that these genes function as general buffers of genetic variation and that these hub genes may act as modifier genes in multiple, mechanistically unrelated genetic diseases in humans.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>16845399</pmid><doi>10.1038/ng1844</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1061-4036 |
| ispartof | Nature genetics, 2006-08, Vol.38 (8), p.896-903 |
| issn | 1061-4036 1546-1718 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_762278391 |
| source | MEDLINE; Nature Journals Online; SpringerLink Journals - AutoHoldings |
| subjects | Agriculture Animal Genetics and Genomics Animals Biological and medical sciences Biomedical and Life Sciences Biomedicine Buffers Caenorhabditis elegans Caenorhabditis elegans - genetics Caenorhabditis elegans - metabolism Cancer Research Cell physiology Chromosome Mapping Classical genetics, quantitative genetics, hybrids Disease Enhancer Elements, Genetic Epidermal Growth Factor - genetics Female Fundamental and applied biological sciences. Psychology Gene expression Gene Function Genes, Helminth Genetic aspects Genetic diversity Genetic variation Genetics of eukaryotes. Biological and molecular evolution Genomics Human Genetics Humans Inactivation Methods, theories and miscellaneous Molecular and cellular biology Mutation Phenotype Physiological aspects RNA Interference Signal Transduction Vulva - growth & development Worms |
| title | Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathways |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-09T13%3A04%3A43IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Systematic%20mapping%20of%20genetic%20interactions%20in%20Caenorhabditis%20elegans%20identifies%20common%20modifiers%20of%20diverse%20signaling%20pathways&rft.jtitle=Nature%20genetics&rft.au=Fraser,%20Andrew%20G&rft.date=2006-08-01&rft.volume=38&rft.issue=8&rft.spage=896&rft.epage=903&rft.pages=896-903&rft.issn=1061-4036&rft.eissn=1546-1718&rft.coden=NGENEC&rft_id=info:doi/10.1038/ng1844&rft_dat=%3Cgale_proqu%3EA183393721%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=222636858&rft_id=info:pmid/16845399&rft_galeid=A183393721&rfr_iscdi=true |