Skip navigation
Skip navigation

Recurrent miscalling of missense variation from short-read genome sequence data

Field, Matthew; Burgio, Gaetan; Chuah, Aaron; Al Shekaili, Jalila; Hassan, Batool; Al Sukaiti, Nashat; Foote, Simon; Cook, Matthew; Andrews, Dan

Description

Background Short-read resequencing of genomes produces abundant information of the genetic variation of individuals. Due to their numerous nature, these variants are rarely exhaustively validated. Furthermore, low levels of undetected variant miscalling will have a systematic and disproportionate impact on the interpretation of individual genome sequence information, especially should these also be carried through into in reference databases of genomic variation. Results We find that...[Show more]

dc.contributor.authorField, Matthew
dc.contributor.authorBurgio, Gaetan
dc.contributor.authorChuah, Aaron
dc.contributor.authorAl Shekaili, Jalila
dc.contributor.authorHassan, Batool
dc.contributor.authorAl Sukaiti, Nashat
dc.contributor.authorFoote, Simon
dc.contributor.authorCook, Matthew
dc.contributor.authorAndrews, Dan
dc.date.accessioned2020-09-16T05:03:18Z
dc.date.available2020-09-16T05:03:18Z
dc.identifier.issn1471-2164
dc.identifier.urihttp://hdl.handle.net/1885/210525
dc.description.abstractBackground Short-read resequencing of genomes produces abundant information of the genetic variation of individuals. Due to their numerous nature, these variants are rarely exhaustively validated. Furthermore, low levels of undetected variant miscalling will have a systematic and disproportionate impact on the interpretation of individual genome sequence information, especially should these also be carried through into in reference databases of genomic variation. Results We find that sequence variation from short-read sequence data is subject to recurrent-yet-intermittent miscalling that occurs in a sequence intrinsic manner and is very sensitive to sequence read length. The miscalls arise from difficulties aligning short reads to redundant genomic regions, where the rate of sequencing error approaches the sequence diversity between redundant regions. We find the resultant miscalled variants to be sensitive to small sequence variations between genomes, and thereby are often intrinsic to an individual, pedigree, strain or human ethnic group. In human exome sequences, we identify 2–300 recurrent false positive variants per individual, almost all of which are present in public databases of human genomic variation. From the exomes of non-reference strains of inbred mice, we identify 3–5000 recurrent false positive variants per mouse – the number of which increasing with greater distance between an individual mouse strain and the reference C57BL6 mouse genome. We show that recurrently miscalled variants may be reproduced for a given genome from repeated simulation rounds of read resampling, realignment and recalling. As such, it is possible to identify more than two-thirds of false positive variation from only ten rounds of simulation. Conclusion Identification and removal of recurrent false positive variants from specific individual variant sets will improve overall data quality. Variant miscalls arising are highly sequence intrinsic and are often specific to an individual, pedigree or ethnicity. Further, read length is a strong determinant of whether given false variants will be called for any given genome – which has profound significance for cohort studies that pool datasets collected and sequenced at different points in time.
dc.description.sponsorshipThis work has been funded by National Institutes of Health Grant AI100627 and the National Collaborative Research Infrastructure Strategy (Australia). Publication costs are funded by National Institutes of Health Grant AI100627 and the National Collaborative Research Infrastructure Strategy (Australia).
dc.format.mimetypeapplication/pdf
dc.language.isoen_AU
dc.publisherBioMed Central
dc.rights© The Author(s).
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceBMC Genomics
dc.titleRecurrent miscalling of missense variation from short-read genome sequence data
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume20
dc.date.issued2019
local.identifier.absfor110706 - Immunogenetics (incl. Genetic Immunology)
local.identifier.ariespublicationu3102795xPUB4199
local.publisher.urlhttp://www.biomedcentral.com/bmcgenomics/
local.type.statusPublished Version
local.contributor.affiliationField, Matthew, College of Health and Medicine, ANU
local.contributor.affiliationBurgio, Gaetan, College of Health and Medicine, ANU
local.contributor.affiliationChuah, Aaron, College of Health and Medicine, ANU
local.contributor.affiliationAl Shekaili, Jalila, Sultan Qaboos University Hospital
local.contributor.affiliationHassan, Batool, Sultan Qaboos University Hospital
local.contributor.affiliationAl Sukaiti, Nashat, The Royal Hospital, Oman
local.contributor.affiliationFoote, Simon, College of Health and Medicine, ANU
local.contributor.affiliationCook, Matthew, College of Health and Medicine, ANU
local.contributor.affiliationAndrews, Thomas (Dan), College of Health and Medicine, ANU
local.bibliographicCitation.issue8
local.bibliographicCitation.startpage1
local.bibliographicCitation.lastpage9
local.identifier.doi10.1186/s12864-019-5863-2
local.identifier.absseo920110 - Inherited Diseases (incl. Gene Therapy)
dc.date.updated2020-06-23T00:54:09Z
local.identifier.scopusID2-s2.0-85069468357
dcterms.accessRightsOpen Access
dc.provenance© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
dc.rights.licenseCreative Commons Attribution 4.0 International License
CollectionsANU Research Publications

Download

File Description SizeFormat Image
01_Field_Recurrent_miscalling_of_2019.pdf1.1 MBAdobe PDFThumbnail


This item is licensed under a Creative Commons License Creative Commons

Updated:  19 May 2020/ Responsible Officer:  University Librarian/ Page Contact:  Library Systems & Web Coordinator