Characterization and identification of hidden rare variants in the human genome
Identifieur interne : 000110 ( Pmc/Curation ); précédent : 000109; suivant : 000111Characterization and identification of hidden rare variants in the human genome
Auteurs : Alberto Magi [Italie] ; Romina D Urizio [Italie] ; Flavia Palombo [Italie] ; Ingrid Cifola [Italie] ; Lorenzo Tattini [Italie] ; Roberto Semeraro [Italie] ; Tommaso Pippucci [Italie] ; Betti Giusti [Italie] ; Giovanni Romeo [Italie] ; Rosanna Abbate [Italie] ; Gian Franco Gensini [Italie]Source :
- BMC Genomics [ 1471-2164 ] ; 2015.
Abstract
By examining the genotype calls generated by the 1000 Genomes Project we discovered that the human reference genome GRCh37 contains almost 20,000 loci in which the reference allele has never been observed in healthy individuals and around 70,000 loci in which it has been observed only in the heterozygous state.
We show that a large fraction of this rare reference allele (RRA) loci belongs to coding, functional and regulatory elements of the genome and could be linked to rare Mendelian disorders as well as cancer. We also demonstrate that classical germline and somatic variant calling tools are not capable to recognize the rare allele when present in these loci. To overcome such limitations, we developed a novel tool, named RAREVATOR, that is able to identify and call the rare allele in these genomic positions. By using a small cancer dataset we compared our tool with two state-of-the-art callers and we found that RAREVATOR identified more than 1,500 germline and 22 somatic RRA variants missed by the two methods and which belong to significantly mutated pathways.
These results show that, to date, the investigation of around 100,000 loci of the human genome has been missed by re-sequencing experiments based on the GRCh37 assembly and that our tool can fill the gap left by other methods. Moreover, the investigation of the latest version of the human reference genome, GRCh38, showed that although the GRC corrected almost all insertions and a small part of SNVs and deletions, a large number of functionally relevant RRAs still remain unchanged. For this reason, also future resequencing experiments, based on GRCh38, will benefit from RAREVATOR analysis results. RAREVATOR is freely available at
The online version of this article (doi:10.1186/s12864-015-1481-9) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1186/s12864-015-1481-9
PubMed: 25903059
PubMed Central: 4416239
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xml:lang="fr">Italie</country><wicri:regionArea>Department of Experimental and Clinical Medicine, University of Florence, Florence</wicri:regionArea></affiliation></author><author><name sortKey="Gensini, Gian Franco" sort="Gensini, Gian Franco" uniqKey="Gensini G" first="Gian Franco" last="Gensini">Gian Franco Gensini</name><affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Experimental and Clinical Medicine, University of Florence, Florence</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25903059</idno><idno type="pmc">4416239</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416239</idno><idno type="RBID">PMC:4416239</idno><idno type="doi">10.1186/s12864-015-1481-9</idno><date when="2015">2015</date><idno 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first="Romina" last="D Urizio">Romina D Urizio</name><affiliation wicri:level="1"><nlm:aff id="Aff2">Laboratory of Integrative Systems Medicine (LISM), Institute of Informatics and Telematics and Institute of Clinical Physiology, National Research Council, Pisa, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Laboratory of Integrative Systems Medicine (LISM), Institute of Informatics and Telematics and Institute of Clinical Physiology, National Research Council, Pisa</wicri:regionArea></affiliation></author><author><name sortKey="Palombo, Flavia" sort="Palombo, Flavia" uniqKey="Palombo F" first="Flavia" last="Palombo">Flavia Palombo</name><affiliation wicri:level="1"><nlm:aff id="Aff3">Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna</wicri:regionArea></affiliation></author><author><name sortKey="Cifola, Ingrid" sort="Cifola, Ingrid" uniqKey="Cifola I" first="Ingrid" last="Cifola">Ingrid Cifola</name><affiliation wicri:level="1"><nlm:aff id="Aff4">Institute for Biomedical Technologies, National Research Council, Milan, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Institute for Biomedical Technologies, National Research Council, Milan</wicri:regionArea></affiliation></author><author><name sortKey="Tattini, Lorenzo" sort="Tattini, Lorenzo" uniqKey="Tattini L" first="Lorenzo" last="Tattini">Lorenzo Tattini</name><affiliation wicri:level="1"><nlm:aff id="Aff5">Department of Neuroscience, Pharmacology and Child Health, University of Florence, Florence, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Neuroscience, Pharmacology and Child Health, University of Florence, Florence</wicri:regionArea></affiliation></author><author><name sortKey="Semeraro, Roberto" sort="Semeraro, Roberto" uniqKey="Semeraro R" first="Roberto" last="Semeraro">Roberto Semeraro</name><affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Experimental and Clinical Medicine, University of Florence, Florence</wicri:regionArea></affiliation></author><author><name sortKey="Pippucci, Tommaso" sort="Pippucci, Tommaso" uniqKey="Pippucci T" first="Tommaso" last="Pippucci">Tommaso Pippucci</name><affiliation wicri:level="1"><nlm:aff id="Aff3">Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna</wicri:regionArea></affiliation></author><author><name sortKey="Giusti, Betti" sort="Giusti, Betti" uniqKey="Giusti B" first="Betti" last="Giusti">Betti Giusti</name><affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Experimental and Clinical Medicine, University of Florence, Florence</wicri:regionArea></affiliation></author><author><name sortKey="Romeo, Giovanni" sort="Romeo, Giovanni" uniqKey="Romeo G" first="Giovanni" last="Romeo">Giovanni Romeo</name><affiliation wicri:level="1"><nlm:aff id="Aff3">Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna</wicri:regionArea></affiliation></author><author><name sortKey="Abbate, Rosanna" sort="Abbate, Rosanna" uniqKey="Abbate R" first="Rosanna" last="Abbate">Rosanna Abbate</name><affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Experimental and Clinical Medicine, University of Florence, Florence</wicri:regionArea></affiliation></author><author><name sortKey="Gensini, Gian Franco" sort="Gensini, Gian Franco" uniqKey="Gensini G" first="Gian Franco" last="Gensini">Gian Franco Gensini</name><affiliation wicri:level="1"><nlm:aff id="Aff1">Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy</nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea>Department of Experimental and Clinical Medicine, University of Florence, Florence</wicri:regionArea></affiliation></author></analytic><series><title level="j">BMC Genomics</title><idno type="eISSN">1471-2164</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>By examining the genotype calls generated by the 1000 Genomes Project we discovered that the human reference genome GRCh37 contains almost 20,000 loci in which the reference allele has never been observed in healthy individuals and around 70,000 loci in which it has been observed only in the heterozygous state.</p></sec><sec><title>Results</title><p>We show that a large fraction of this rare reference allele (RRA) loci belongs to coding, functional and regulatory elements of the genome and could be linked to rare Mendelian disorders as well as cancer. We also demonstrate that classical germline and somatic variant calling tools are not capable to recognize the rare allele when present in these loci. To overcome such limitations, we developed a novel tool, named RAREVATOR, that is able to identify and call the rare allele in these genomic positions. By using a small cancer dataset we compared our tool with two state-of-the-art callers and we found that RAREVATOR identified more than 1,500 germline and 22 somatic RRA variants missed by the two methods and which belong to significantly mutated pathways.</p></sec><sec><title>Conclusions</title><p>These results show that, to date, the investigation of around 100,000 loci of the human genome has been missed by re-sequencing experiments based on the GRCh37 assembly and that our tool can fill the gap left by other methods. Moreover, the investigation of the latest version of the human reference genome, GRCh38, showed that although the GRC corrected almost all insertions and a small part of SNVs and deletions, a large number of functionally relevant RRAs still remain unchanged. For this reason, also future resequencing experiments, based on GRCh38, will benefit from RAREVATOR analysis results. RAREVATOR is freely available at <ext-link ext-link-type="uri" xlink:href="http://sourceforge.net/projects/rarevator">http://sourceforge.net/projects/rarevator</ext-link>.</p></sec><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1186/s12864-015-1481-9) contains supplementary material, which is available to authorized users.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Wheeler, Da" uniqKey="Wheeler D">DA Wheeler</name></author><author><name sortKey="Srinivasan, M" uniqKey="Srinivasan M">M Srinivasan</name></author><author><name sortKey="Egholm, M" uniqKey="Egholm M">M Egholm</name></author><author><name sortKey="Shen, Y" uniqKey="Shen Y">Y Shen</name></author><author><name sortKey="Chen, L" uniqKey="Chen L">L Chen</name></author><author><name sortKey="Mcguire, A" uniqKey="Mcguire A">A McGuire</name></author></analytic></biblStruct><biblStruct><analytic><author><name 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<front><journal-meta><journal-id journal-id-type="nlm-ta">BMC Genomics</journal-id><journal-id journal-id-type="iso-abbrev">BMC Genomics</journal-id><journal-title-group><journal-title>BMC Genomics</journal-title></journal-title-group><issn pub-type="epub">1471-2164</issn><publisher><publisher-name>BioMed Central</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">25903059</article-id><article-id pub-id-type="pmc">4416239</article-id><article-id pub-id-type="publisher-id">1481</article-id><article-id pub-id-type="doi">10.1186/s12864-015-1481-9</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>Characterization and identification of hidden rare variants in the human genome</article-title></title-group><contrib-group><contrib contrib-type="author" corresp="yes"><name><surname>Magi</surname><given-names>Alberto</given-names></name><address><email>albertomagi@gmail.com</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>D’Aurizio</surname><given-names>Romina</given-names></name><address><email>romina.daurizio@gmail.com</email></address><xref ref-type="aff" rid="Aff2"></xref></contrib><contrib contrib-type="author"><name><surname>Palombo</surname><given-names>Flavia</given-names></name><address><email>palombo.flavia@gmail.com</email></address><xref ref-type="aff" rid="Aff3"></xref></contrib><contrib contrib-type="author"><name><surname>Cifola</surname><given-names>Ingrid</given-names></name><address><email>ingrid.cifola@itb.cnr.it</email></address><xref ref-type="aff" rid="Aff4"></xref></contrib><contrib contrib-type="author"><name><surname>Tattini</surname><given-names>Lorenzo</given-names></name><address><email>lorenzotattini@gmail.com</email></address><xref ref-type="aff" rid="Aff5"></xref></contrib><contrib contrib-type="author"><name><surname>Semeraro</surname><given-names>Roberto</given-names></name><address><email>robybass88@gmail.com</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Pippucci</surname><given-names>Tommaso</given-names></name><address><email>tommaso.pippucci@gmail.com</email></address><xref ref-type="aff" rid="Aff3"></xref></contrib><contrib contrib-type="author"><name><surname>Giusti</surname><given-names>Betti</given-names></name><address><email>betti.giusti@unifi.it</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Romeo</surname><given-names>Giovanni</given-names></name><address><email>egf.giovanni.romeo@gmail.com</email></address><xref ref-type="aff" rid="Aff3"></xref></contrib><contrib contrib-type="author"><name><surname>Abbate</surname><given-names>Rosanna</given-names></name><address><email>rosanna.abbate@unifi.it</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Gensini</surname><given-names>Gian Franco</given-names></name><address><email>gfgensini@gmail.com</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><aff id="Aff1"><label></label>Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy</aff><aff id="Aff2"><label></label>Laboratory of Integrative Systems Medicine (LISM), Institute of Informatics and Telematics and Institute of Clinical Physiology, National Research Council, Pisa, Italy</aff><aff id="Aff3"><label></label>Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy</aff><aff id="Aff4"><label></label>Institute for Biomedical Technologies, National Research Council, Milan, Italy</aff><aff id="Aff5"><label></label>Department of Neuroscience, Pharmacology and Child Health, University of Florence, Florence, Italy</aff></contrib-group><pub-date pub-type="epub"><day>24</day><month>4</month><year>2015</year></pub-date><pub-date pub-type="pmc-release"><day>24</day><month>4</month><year>2015</year></pub-date><pub-date pub-type="collection"><year>2015</year></pub-date><volume>16</volume><issue>1</issue><elocation-id>340</elocation-id><history><date date-type="received"><day>25</day><month>2</month><year>2015</year></date><date date-type="accepted"><day>23</day><month>3</month><year>2015</year></date></history><permissions><copyright-statement>© Magi et al.; licensee BioMed Central. 2015</copyright-statement><license license-type="open-access"><license-p>This is an Open Access article distributed under the terms of the Creative Commons Attribution License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0">http://creativecommons.org/licenses/by/4.0</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.</license-p></license></permissions><abstract id="Abs1"><sec><title>Background</title><p>By examining the genotype calls generated by the 1000 Genomes Project we discovered that the human reference genome GRCh37 contains almost 20,000 loci in which the reference allele has never been observed in healthy individuals and around 70,000 loci in which it has been observed only in the heterozygous state.</p></sec><sec><title>Results</title><p>We show that a large fraction of this rare reference allele (RRA) loci belongs to coding, functional and regulatory elements of the genome and could be linked to rare Mendelian disorders as well as cancer. We also demonstrate that classical germline and somatic variant calling tools are not capable to recognize the rare allele when present in these loci. To overcome such limitations, we developed a novel tool, named RAREVATOR, that is able to identify and call the rare allele in these genomic positions. By using a small cancer dataset we compared our tool with two state-of-the-art callers and we found that RAREVATOR identified more than 1,500 germline and 22 somatic RRA variants missed by the two methods and which belong to significantly mutated pathways.</p></sec><sec><title>Conclusions</title><p>These results show that, to date, the investigation of around 100,000 loci of the human genome has been missed by re-sequencing experiments based on the GRCh37 assembly and that our tool can fill the gap left by other methods. Moreover, the investigation of the latest version of the human reference genome, GRCh38, showed that although the GRC corrected almost all insertions and a small part of SNVs and deletions, a large number of functionally relevant RRAs still remain unchanged. For this reason, also future resequencing experiments, based on GRCh38, will benefit from RAREVATOR analysis results. RAREVATOR is freely available at <ext-link ext-link-type="uri" xlink:href="http://sourceforge.net/projects/rarevator">http://sourceforge.net/projects/rarevator</ext-link>.</p></sec><sec><title>Electronic supplementary material</title><p>The online version of this article (doi:10.1186/s12864-015-1481-9) contains supplementary material, which is available to authorized users.</p></sec></abstract><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2015</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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