Characterisation and validation of insertions and deletions in 173 patient exomes.

Recent advances in genomics technologies have spurred unprecedented efforts in genome and exome re-sequencing aiming to unravel the genetic component of rare and complex disorders. While in rare disorders this allowed the identification of novel causal genes, the missing heritability paradox in comp...

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Autores principales: Francesco Lescai, Silvia Bonfiglio, Chiara Bacchelli, Estelle Chanudet, Aoife Waters, Sanjay M Sisodiya, Dalia Kasperavičiūtė, Julie Williams, Denise Harold, John Hardy, Robert Kleta, Sebahattin Cirak, Richard Williams, John C Achermann, John Anderson, David Kelsell, Tom Vulliamy, Henry Houlden, Nicholas Wood, Una Sheerin, Gian Paolo Tonini, Donna Mackay, Khalid Hussain, Jane Sowden, Veronica Kinsler, Justyna Osinska, Tony Brooks, Mike Hubank, Philip Beales, Elia Stupka
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Publicado: Public Library of Science (PLoS) 2012
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spelling oai:doaj.org-article:a5b135f4e56341478420eb0c8b20e8d22021-11-18T08:05:07ZCharacterisation and validation of insertions and deletions in 173 patient exomes.1932-620310.1371/journal.pone.0051292https://doaj.org/article/a5b135f4e56341478420eb0c8b20e8d22012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23251486/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Recent advances in genomics technologies have spurred unprecedented efforts in genome and exome re-sequencing aiming to unravel the genetic component of rare and complex disorders. While in rare disorders this allowed the identification of novel causal genes, the missing heritability paradox in complex diseases remains so far elusive. Despite rapid advances of next-generation sequencing, both the technology and the analysis of the data it produces are in its infancy. At present there is abundant knowledge pertaining to the role of rare single nucleotide variants (SNVs) in rare disorders and of common SNVs in common disorders. Although the 1,000 genome project has clearly highlighted the prevalence of rare variants and more complex variants (e.g. insertions, deletions), their role in disease is as yet far from elucidated.We set out to analyse the properties of sequence variants identified in a comprehensive collection of exome re-sequencing studies performed on samples from patients affected by a broad range of complex and rare diseases (N = 173). Given the known potential for Loss of Function (LoF) variants to be false positive, we performed an extensive validation of the common, rare and private LoF variants identified, which indicated that most of the private and rare variants identified were indeed true, while common novel variants had a significantly higher false positive rate. Our results indicated a strong enrichment of very low-frequency insertion/deletion variants, so far under-investigated, which might be difficult to capture with low coverage and imputation approaches and for which most of study designs would be under-powered. These insertions and deletions might play a significant role in disease genetics, contributing specifically to the underlining rare and private variation predicted to be discovered through next generation sequencing.Francesco LescaiSilvia BonfiglioChiara BacchelliEstelle ChanudetAoife WatersSanjay M SisodiyaDalia KasperavičiūtėJulie WilliamsDenise HaroldJohn HardyRobert KletaSebahattin CirakRichard WilliamsJohn C AchermannJohn AndersonDavid KelsellTom VulliamyHenry HouldenNicholas WoodUna SheerinGian Paolo ToniniDonna MackayKhalid HussainJane SowdenVeronica KinslerJustyna OsinskaTony BrooksMike HubankPhilip BealesElia StupkaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 12, p e51292 (2012)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Francesco Lescai
Silvia Bonfiglio
Chiara Bacchelli
Estelle Chanudet
Aoife Waters
Sanjay M Sisodiya
Dalia Kasperavičiūtė
Julie Williams
Denise Harold
John Hardy
Robert Kleta
Sebahattin Cirak
Richard Williams
John C Achermann
John Anderson
David Kelsell
Tom Vulliamy
Henry Houlden
Nicholas Wood
Una Sheerin
Gian Paolo Tonini
Donna Mackay
Khalid Hussain
Jane Sowden
Veronica Kinsler
Justyna Osinska
Tony Brooks
Mike Hubank
Philip Beales
Elia Stupka
Characterisation and validation of insertions and deletions in 173 patient exomes.
description Recent advances in genomics technologies have spurred unprecedented efforts in genome and exome re-sequencing aiming to unravel the genetic component of rare and complex disorders. While in rare disorders this allowed the identification of novel causal genes, the missing heritability paradox in complex diseases remains so far elusive. Despite rapid advances of next-generation sequencing, both the technology and the analysis of the data it produces are in its infancy. At present there is abundant knowledge pertaining to the role of rare single nucleotide variants (SNVs) in rare disorders and of common SNVs in common disorders. Although the 1,000 genome project has clearly highlighted the prevalence of rare variants and more complex variants (e.g. insertions, deletions), their role in disease is as yet far from elucidated.We set out to analyse the properties of sequence variants identified in a comprehensive collection of exome re-sequencing studies performed on samples from patients affected by a broad range of complex and rare diseases (N = 173). Given the known potential for Loss of Function (LoF) variants to be false positive, we performed an extensive validation of the common, rare and private LoF variants identified, which indicated that most of the private and rare variants identified were indeed true, while common novel variants had a significantly higher false positive rate. Our results indicated a strong enrichment of very low-frequency insertion/deletion variants, so far under-investigated, which might be difficult to capture with low coverage and imputation approaches and for which most of study designs would be under-powered. These insertions and deletions might play a significant role in disease genetics, contributing specifically to the underlining rare and private variation predicted to be discovered through next generation sequencing.
format article
author Francesco Lescai
Silvia Bonfiglio
Chiara Bacchelli
Estelle Chanudet
Aoife Waters
Sanjay M Sisodiya
Dalia Kasperavičiūtė
Julie Williams
Denise Harold
John Hardy
Robert Kleta
Sebahattin Cirak
Richard Williams
John C Achermann
John Anderson
David Kelsell
Tom Vulliamy
Henry Houlden
Nicholas Wood
Una Sheerin
Gian Paolo Tonini
Donna Mackay
Khalid Hussain
Jane Sowden
Veronica Kinsler
Justyna Osinska
Tony Brooks
Mike Hubank
Philip Beales
Elia Stupka
author_facet Francesco Lescai
Silvia Bonfiglio
Chiara Bacchelli
Estelle Chanudet
Aoife Waters
Sanjay M Sisodiya
Dalia Kasperavičiūtė
Julie Williams
Denise Harold
John Hardy
Robert Kleta
Sebahattin Cirak
Richard Williams
John C Achermann
John Anderson
David Kelsell
Tom Vulliamy
Henry Houlden
Nicholas Wood
Una Sheerin
Gian Paolo Tonini
Donna Mackay
Khalid Hussain
Jane Sowden
Veronica Kinsler
Justyna Osinska
Tony Brooks
Mike Hubank
Philip Beales
Elia Stupka
author_sort Francesco Lescai
title Characterisation and validation of insertions and deletions in 173 patient exomes.
title_short Characterisation and validation of insertions and deletions in 173 patient exomes.
title_full Characterisation and validation of insertions and deletions in 173 patient exomes.
title_fullStr Characterisation and validation of insertions and deletions in 173 patient exomes.
title_full_unstemmed Characterisation and validation of insertions and deletions in 173 patient exomes.
title_sort characterisation and validation of insertions and deletions in 173 patient exomes.
publisher Public Library of Science (PLoS)
publishDate 2012
url https://doaj.org/article/a5b135f4e56341478420eb0c8b20e8d2
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