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Characterization and identification of hidden rare variants in the human genome.
Magi, Alberto; D'Aurizio, Romina; Palombo, Flavia; Cifola, Ingrid; Tattini, Lorenzo; Semeraro, Roberto; Pippucci, Tommaso; Giusti, Betti; Romeo, Giovanni; Abbate, Rosanna; Gensini, Gian Franco.
Afiliación
  • Magi A; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy. albertomagi@gmail.com.
  • D'Aurizio R; Laboratory of Integrative Systems Medicine (LISM), Institute of Informatics and Telematics and Institute of Clinical Physiology, National Research Council, Pisa, Italy. romina.daurizio@gmail.com.
  • Palombo F; Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy. palombo.flavia@gmail.com.
  • Cifola I; Institute for Biomedical Technologies, National Research Council, Milan, Italy. ingrid.cifola@itb.cnr.it.
  • Tattini L; Department of Neuroscience, Pharmacology and Child Health, University of Florence, Florence, Italy. lorenzotattini@gmail.com.
  • Semeraro R; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy. robybass88@gmail.com.
  • Pippucci T; Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy. tommaso.pippucci@gmail.com.
  • Giusti B; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy. betti.giusti@unifi.it.
  • Romeo G; Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy. egf.giovanni.romeo@gmail.com.
  • Abbate R; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy. rosanna.abbate@unifi.it.
  • Gensini GF; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy. gfgensini@gmail.com.
BMC Genomics ; 16: 340, 2015 Apr 24.
Article en En | MEDLINE | ID: mdl-25903059
ABSTRACT

BACKGROUND:

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.

RESULTS:

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.

CONCLUSIONS:

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 http//sourceforge.net/projects/rarevator .
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Variación Genética / Genoma Humano / Bases de Datos Genéticas Tipo de estudio: Diagnostic_studies Límite: Humans Idioma: En Revista: BMC Genomics Asunto de la revista: GENETICA Año: 2015 Tipo del documento: Article País de afiliación: Italia

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Variación Genética / Genoma Humano / Bases de Datos Genéticas Tipo de estudio: Diagnostic_studies Límite: Humans Idioma: En Revista: BMC Genomics Asunto de la revista: GENETICA Año: 2015 Tipo del documento: Article País de afiliación: Italia