A cost-effective sequencing method for genetic studies combining high-depth whole exome and low-depth whole genome
Abstract Whole genome sequencing (WGS) at high-depth (30X) allows the accurate discovery of variants in the coding and non-coding DNA regions and helps elucidate the genetic underpinnings of human health and diseases. Yet, due to the prohibitive cost of high-depth WGS, most large-scale genetic assoc...
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-02-01
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| Series: | npj Genomic Medicine |
| Online Access: | https://doi.org/10.1038/s41525-024-00390-3 |
| _version_ | 1797273726976262144 |
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| author | Claude Bhérer Robert Eveleigh Katerina Trajanoska Janick St-Cyr Antoine Paccard Praveen Nadukkalam Ravindran Elizabeth Caron Nimara Bader Asbah Peyton McClelland Clare Wei Iris Baumgartner Marc Schindewolf Yvonne Döring Danielle Perley François Lefebvre Pierre Lepage Mathieu Bourgey Guillaume Bourque Jiannis Ragoussis Vincent Mooser Daniel Taliun |
| author_facet | Claude Bhérer Robert Eveleigh Katerina Trajanoska Janick St-Cyr Antoine Paccard Praveen Nadukkalam Ravindran Elizabeth Caron Nimara Bader Asbah Peyton McClelland Clare Wei Iris Baumgartner Marc Schindewolf Yvonne Döring Danielle Perley François Lefebvre Pierre Lepage Mathieu Bourgey Guillaume Bourque Jiannis Ragoussis Vincent Mooser Daniel Taliun |
| author_sort | Claude Bhérer |
| collection | DOAJ |
| description | Abstract Whole genome sequencing (WGS) at high-depth (30X) allows the accurate discovery of variants in the coding and non-coding DNA regions and helps elucidate the genetic underpinnings of human health and diseases. Yet, due to the prohibitive cost of high-depth WGS, most large-scale genetic association studies use genotyping arrays or high-depth whole exome sequencing (WES). Here we propose a cost-effective method which we call “Whole Exome Genome Sequencing” (WEGS), that combines low-depth WGS and high-depth WES with up to 8 samples pooled and sequenced simultaneously (multiplexed). We experimentally assess the performance of WEGS with four different depth of coverage and sample multiplexing configurations. We show that the optimal WEGS configurations are 1.7–2.0 times cheaper than standard WES (no-plexing), 1.8–2.1 times cheaper than high-depth WGS, reach similar recall and precision rates in detecting coding variants as WES, and capture more population-specific variants in the rest of the genome that are difficult to recover when using genotype imputation methods. We apply WEGS to 862 patients with peripheral artery disease and show that it directly assesses more known disease-associated variants than a typical genotyping array and thousands of non-imputable variants per disease-associated locus. |
| first_indexed | 2024-03-07T14:48:25Z |
| format | Article |
| id | doaj.art-2b9f92fd459444789439a779da350076 |
| institution | Directory Open Access Journal |
| issn | 2056-7944 |
| language | English |
| last_indexed | 2024-03-07T14:48:25Z |
| publishDate | 2024-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Genomic Medicine |
| spelling | doaj.art-2b9f92fd459444789439a779da3500762024-03-05T19:50:06ZengNature Portfolionpj Genomic Medicine2056-79442024-02-019111210.1038/s41525-024-00390-3A cost-effective sequencing method for genetic studies combining high-depth whole exome and low-depth whole genomeClaude Bhérer0Robert Eveleigh1Katerina Trajanoska2Janick St-Cyr3Antoine Paccard4Praveen Nadukkalam Ravindran5Elizabeth Caron6Nimara Bader Asbah7Peyton McClelland8Clare Wei9Iris Baumgartner10Marc Schindewolf11Yvonne Döring12Danielle Perley13François Lefebvre14Pierre Lepage15Mathieu Bourgey16Guillaume Bourque17Jiannis Ragoussis18Vincent Mooser19Daniel Taliun20Department of Human Genetics, Faculty of Medicine and Health Sciences, McGill UniversityVictor Phillip Dahdaleh Institute of Genomic Medicine at McGill UniversityDepartment of Human Genetics, Faculty of Medicine and Health Sciences, McGill UniversityVictor Phillip Dahdaleh Institute of Genomic Medicine at McGill UniversityVictor Phillip Dahdaleh Institute of Genomic Medicine at McGill UniversityVictor Phillip Dahdaleh Institute of Genomic Medicine at McGill UniversityVictor Phillip Dahdaleh Institute of Genomic Medicine at McGill UniversityDepartment of Human Genetics, Faculty of Medicine and Health Sciences, McGill UniversityDepartment of Human Genetics, Faculty of Medicine and Health Sciences, McGill UniversityVictor Phillip Dahdaleh Institute of Genomic Medicine at McGill UniversityDivision of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of BernDivision of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of BernDivision of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of BernVictor Phillip Dahdaleh Institute of Genomic Medicine at McGill UniversityVictor Phillip Dahdaleh Institute of Genomic Medicine at McGill UniversityVictor Phillip Dahdaleh Institute of Genomic Medicine at McGill UniversityMila - Quebec AI InstituteDepartment of Human Genetics, Faculty of Medicine and Health Sciences, McGill UniversityDepartment of Human Genetics, Faculty of Medicine and Health Sciences, McGill UniversityDepartment of Human Genetics, Faculty of Medicine and Health Sciences, McGill UniversityDepartment of Human Genetics, Faculty of Medicine and Health Sciences, McGill UniversityAbstract Whole genome sequencing (WGS) at high-depth (30X) allows the accurate discovery of variants in the coding and non-coding DNA regions and helps elucidate the genetic underpinnings of human health and diseases. Yet, due to the prohibitive cost of high-depth WGS, most large-scale genetic association studies use genotyping arrays or high-depth whole exome sequencing (WES). Here we propose a cost-effective method which we call “Whole Exome Genome Sequencing” (WEGS), that combines low-depth WGS and high-depth WES with up to 8 samples pooled and sequenced simultaneously (multiplexed). We experimentally assess the performance of WEGS with four different depth of coverage and sample multiplexing configurations. We show that the optimal WEGS configurations are 1.7–2.0 times cheaper than standard WES (no-plexing), 1.8–2.1 times cheaper than high-depth WGS, reach similar recall and precision rates in detecting coding variants as WES, and capture more population-specific variants in the rest of the genome that are difficult to recover when using genotype imputation methods. We apply WEGS to 862 patients with peripheral artery disease and show that it directly assesses more known disease-associated variants than a typical genotyping array and thousands of non-imputable variants per disease-associated locus.https://doi.org/10.1038/s41525-024-00390-3 |
| spellingShingle | Claude Bhérer Robert Eveleigh Katerina Trajanoska Janick St-Cyr Antoine Paccard Praveen Nadukkalam Ravindran Elizabeth Caron Nimara Bader Asbah Peyton McClelland Clare Wei Iris Baumgartner Marc Schindewolf Yvonne Döring Danielle Perley François Lefebvre Pierre Lepage Mathieu Bourgey Guillaume Bourque Jiannis Ragoussis Vincent Mooser Daniel Taliun A cost-effective sequencing method for genetic studies combining high-depth whole exome and low-depth whole genome npj Genomic Medicine |
| title | A cost-effective sequencing method for genetic studies combining high-depth whole exome and low-depth whole genome |
| title_full | A cost-effective sequencing method for genetic studies combining high-depth whole exome and low-depth whole genome |
| title_fullStr | A cost-effective sequencing method for genetic studies combining high-depth whole exome and low-depth whole genome |
| title_full_unstemmed | A cost-effective sequencing method for genetic studies combining high-depth whole exome and low-depth whole genome |
| title_short | A cost-effective sequencing method for genetic studies combining high-depth whole exome and low-depth whole genome |
| title_sort | cost effective sequencing method for genetic studies combining high depth whole exome and low depth whole genome |
| url | https://doi.org/10.1038/s41525-024-00390-3 |
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