New Results
Complex genetic variation in nearly complete human genomes
View ORCID ProfileGlennis A. Logsdon, View ORCID ProfilePeter Ebert, View ORCID ProfilePeter A. Audano, View ORCID ProfileMark Loftus, View ORCID ProfileDavid Porubsky, View ORCID ProfileJana Ebler, View ORCID ProfileFeyza Yilmaz, View ORCID ProfilePille Hallast, View ORCID ProfileTimofey Prodanov, View ORCID ProfileDongAhn Yoo, View ORCID ProfileCarolyn A. Paisie, View ORCID ProfileWilliam T. Harvey, Xuefang Zhao, View ORCID ProfileGianni V. Martino, View ORCID ProfileMir Henglin, View ORCID ProfileKatherine M. Munson, View ORCID ProfileKeon Rabbani, View ORCID ProfileChen-Shan Chin, View ORCID ProfileBida Gu, View ORCID ProfileHufsah Ashraf, View ORCID ProfileOlanrewaju Austine-Orimoloye, View ORCID ProfileParithi Balachandran, View ORCID ProfileMarc Jan Bonder, View ORCID ProfileHaoyu Cheng, View ORCID ProfileZechen Chong, View ORCID ProfileJonathan Crabtree, View ORCID ProfileMark Gerstein, View ORCID ProfileLisbeth A. Guethlein, Patrick Hasenfeld, View ORCID ProfileGlenn Hickey, View ORCID ProfileKendra Hoekzema, View ORCID ProfileSarah E. Hunt, View ORCID ProfileMatthew Jensen, View ORCID ProfileYunzhe Jiang, View ORCID ProfileSergey Koren, Youngjun Kwon, View ORCID ProfileChong Li, View ORCID ProfileHeng Li, View ORCID ProfileJiaqi Li, View ORCID ProfilePaul J. Norman, View ORCID ProfileKeisuke K. Oshima, View ORCID ProfileBenedict Paten, View ORCID ProfileAdam M. Phillippy, View ORCID ProfileNicholas R Pollock, View ORCID ProfileTobias Rausch, View ORCID ProfileMikko Rautiainen, View ORCID ProfileStephan Scholz, View ORCID ProfileYuwei Song, View ORCID ProfileArda Söylev, Arvis Sulovari, View ORCID ProfileLikhitha Surapaneni, View ORCID ProfileVasiliki Tsapalou, View ORCID ProfileWeichen Zhou, View ORCID ProfileYing Zhou, View ORCID ProfileQihui Zhu, Michael C. Zody, View ORCID ProfileRyan E. Mills, View ORCID ProfileScott E. Devine, View ORCID ProfileXinghua Shi, Mike E. Talkowski, View ORCID ProfileMark J.P. Chaisson, View ORCID ProfileAlexander T. Dilthey, View ORCID ProfileMiriam K. Konkel, View ORCID ProfileJan O. Korbel, View ORCID ProfileCharles Lee, View ORCID ProfileChristine R. Beck, View ORCID ProfileEvan E. Eichler, View ORCID ProfileTobias Marschall
doi: https://doi.org/10.1101/2024.09.24.614721
Glennis A. Logsdon
1Perelman School of Medicine, University of Pennsylvania, Department of Genetics, Epigenetics Institute, Philadelphia, PA, USA
2Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
Peter Ebert
3Core Unit Bioinformatics, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
4Center for Digital Medicine, Heinrich Heine University, Düsseldorf, Germany
Peter A. Audano
5The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
Mark Loftus
6Clemson University, Department of Genetics & Biochemistry, Clemson, SC, USA
7Center for Human Genetics, Clemson University, Greenwood, SC, USA
David Porubsky
2Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
Jana Ebler
8Institute for Medical Biometry and Bioinformatics, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
4Center for Digital Medicine, Heinrich Heine University, Düsseldorf, Germany
Feyza Yilmaz
5The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
Pille Hallast
5The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
Timofey Prodanov
8Institute for Medical Biometry and Bioinformatics, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
4Center for Digital Medicine, Heinrich Heine University, Düsseldorf, Germany
DongAhn Yoo
2Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
Carolyn A. Paisie
5The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
William T. Harvey
2Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
Xuefang Zhao
9Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
10Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
Gianni V. Martino
6Clemson University, Department of Genetics & Biochemistry, Clemson, SC, USA
7Center for Human Genetics, Clemson University, Greenwood, SC, USA
11Medical University of South Carolina, College of Graduate Studies, Charleston, SC, USA
Mir Henglin
8Institute for Medical Biometry and Bioinformatics, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
4Center for Digital Medicine, Heinrich Heine University, Düsseldorf, Germany
Katherine M. Munson
2Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
Keon Rabbani
12Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA
Chen-Shan Chin
13Foundation of Biological Data Sciences, Belmont, CA, USA
Bida Gu
12Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA
Hufsah Ashraf
8Institute for Medical Biometry and Bioinformatics, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
4Center for Digital Medicine, Heinrich Heine University, Düsseldorf, Germany
Olanrewaju Austine-Orimoloye
14European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom
Parithi Balachandran
5The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
Marc Jan Bonder
15Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; Oncode Institute, Utrecht, The Netherlands
16Division of Computational Genomics and Systems Genetics, German Cancer Research Center, Heidelberg, Germany
Haoyu Cheng
17Department of Biomedical Informatics and Data Science, Yale School of Medicine, New Haven, CT, USA
Zechen Chong
18Department of Biomedical Informatics and Data Science, Heersink School of Medicine, University of Alabama, Birmingham, AL, USA
Jonathan Crabtree
19Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
Mark Gerstein
20Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
21Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
Lisbeth A. Guethlein
22Department of Structural Biology, School of Medicine, Stanford University, Stanford, CA, USA
Patrick Hasenfeld
23European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany
Glenn Hickey
24UC Santa Cruz Genomics Institute, University of California, Santa Cruz, CA, USA
Kendra Hoekzema
2Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
Sarah E. Hunt
14European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom
Matthew Jensen
20Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
21Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
Yunzhe Jiang
20Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
21Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
Sergey Koren
25Genome Informatics Section, Center for Genomics and Data Science Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
Youngjun Kwon
2Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
Chong Li
26Temple University, Department of Computer and Information Sciences, College of Science and Technology, Philadelphia, PA, USA
27Temple University, Institute for Genomics and Evolutionary Medicine, Philadelphia, PA, USA
Heng Li
28Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
29Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
Jiaqi Li
20Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA
21Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA
Paul J. Norman
30Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO, USA
31Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA
Keisuke K. Oshima
1Perelman School of Medicine, University of Pennsylvania, Department of Genetics, Epigenetics Institute, Philadelphia, PA, USA
Benedict Paten
24UC Santa Cruz Genomics Institute, University of California, Santa Cruz, CA, USA
Adam M. Phillippy
25Genome Informatics Section, Center for Genomics and Data Science Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
Nicholas R Pollock
30Department of Biomedical Informatics, University of Colorado School of Medicine, Aurora, CO, USA
Tobias Rausch
23European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany
Mikko Rautiainen
32Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Stephan Scholz
33Institute of Medical Microbiology and Hospital Hygiene, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
Yuwei Song
18Department of Biomedical Informatics and Data Science, Heersink School of Medicine, University of Alabama, Birmingham, AL, USA
Arda Söylev
8Institute for Medical Biometry and Bioinformatics, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
4Center for Digital Medicine, Heinrich Heine University, Düsseldorf, Germany
Arvis Sulovari
2Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
Likhitha Surapaneni
14European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom
Vasiliki Tsapalou
23European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany
Weichen Zhou
34Department of Computational Medicine & Bioinformatics, University of Michigan, MI, USA
Ying Zhou
28Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA
29Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
Qihui Zhu
5The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
35Stanford Health Care, Palo Alto, CA, USA
Michael C. Zody
36New York Genome Center, New York, NY, USA
Ryan E. Mills
34Department of Computational Medicine & Bioinformatics, University of Michigan, MI, USA
Scott E. Devine
19Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
Xinghua Shi
26Temple University, Department of Computer and Information Sciences, College of Science and Technology, Philadelphia, PA, USA
27Temple University, Institute for Genomics and Evolutionary Medicine, Philadelphia, PA, USA
Mike E. Talkowski
9Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
10Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
37Department of Neurology, Harvard Medical School, Boston, MA, USA
Mark J.P. Chaisson
12Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA
Alexander T. Dilthey
4Center for Digital Medicine, Heinrich Heine University, Düsseldorf, Germany
33Institute of Medical Microbiology and Hospital Hygiene, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
Miriam K. Konkel
6Clemson University, Department of Genetics & Biochemistry, Clemson, SC, USA
7Center for Human Genetics, Clemson University, Greenwood, SC, USA
Jan O. Korbel
23European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Heidelberg, Germany
Charles Lee
5The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
Christine R. Beck
5The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
38The University of Connecticut Health Center, Farmington, CT, USA
Evan E. Eichler
2Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, USA
39Howard Hughes Medical Institute, University of Washington, Seattle, WA, USA
Tobias Marschall
8Institute for Medical Biometry and Bioinformatics, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
4Center for Digital Medicine, Heinrich Heine University, Düsseldorf, Germany
Abstract
Diverse sets of complete human genomes are required to construct a pangenome reference and to understand the extent of complex structural variation. Here, we sequence 65 diverse human genomes and build 130 haplotype-resolved assemblies (130 Mbp median continuity), closing 92% of all previous assembly gaps1,2 and reaching telomere-to-telomere (T2T) status for 39% of the chromosomes. We highlight complete sequence continuity of complex loci, including the major histocompatibility complex (MHC), SMN1/SMN2, NBPF8, and AMY1/AMY2, and fully resolve 1,852 complex structural variants (SVs). In addition, we completely assemble and validate 1,246 human centromeres. We find up to 30-fold variation in α-satellite high-order repeat (HOR) array length and characterize the pattern of mobile element insertions into α-satellite HOR arrays. While most centromeres predict a single site of kinetochore attachment, epigenetic analysis suggests the presence of two hypomethylated regions for 7% of centromeres. Combining our data with the draft pangenome reference1 significantly enhances genotyping accuracy from short-read data, enabling whole-genome inference3 to a median quality value (QV) of 45. Using this approach, 26,115 SVs per sample are detected, substantially increasing the number of SVs now amenable to downstream disease association studies.
Competing Interest Statement
E.E.E. is a scientific advisory board member of Variant Bio, Inc. C. Lee is a scientific advisory board member of Nabsys and Genome Insight. S.K. has received travel funds to speak at events hosted by Oxford Nanopore Technologies. The following authors have previously disclosed a patent application (No. EP19169090) relevant to Strand-seq: J.O.K., T.M., and D.P. The other authors declare no competing interests.
Copyright
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
Posted September 25, 2024.
Complex genetic variation in nearly complete human genomes
Glennis A. Logsdon, Peter Ebert, Peter A. Audano, Mark Loftus, David Porubsky, Jana Ebler, Feyza Yilmaz, Pille Hallast, Timofey Prodanov, DongAhn Yoo, Carolyn A. Paisie, William T. Harvey, Xuefang Zhao, Gianni V. Martino, Mir Henglin, Katherine M. Munson, Keon Rabbani, Chen-Shan Chin, Bida Gu, Hufsah Ashraf, Olanrewaju Austine-Orimoloye, Parithi Balachandran, Marc Jan Bonder, Haoyu Cheng, Zechen Chong, Jonathan Crabtree, Mark Gerstein, Lisbeth A. Guethlein, Patrick Hasenfeld, Glenn Hickey, Kendra Hoekzema, Sarah E. Hunt, Matthew Jensen, Yunzhe Jiang, Sergey Koren, Youngjun Kwon, Chong Li, Heng Li, Jiaqi Li, Paul J. Norman, Keisuke K. Oshima, Benedict Paten, Adam M. Phillippy, Nicholas R Pollock, Tobias Rausch, Mikko Rautiainen, Stephan Scholz, Yuwei Song, Arda Söylev, Arvis Sulovari, Likhitha Surapaneni, Vasiliki Tsapalou, Weichen Zhou, Ying Zhou, Qihui Zhu, Michael C. Zody, Ryan E. Mills, Scott E. Devine, Xinghua Shi, Mike E. Talkowski, Mark J.P. Chaisson, Alexander T. Dilthey, Miriam K. Konkel, Jan O. Korbel, Charles Lee, Christine R. Beck, Evan E. Eichler, Tobias Marschall
bioRxiv 2024.09.24.614721; doi: https://doi.org/10.1101/2024.09.24.614721
Complex genetic variation in nearly complete human genomes
Glennis A. Logsdon, Peter Ebert, Peter A. Audano, Mark Loftus, David Porubsky, Jana Ebler, Feyza Yilmaz, Pille Hallast, Timofey Prodanov, DongAhn Yoo, Carolyn A. Paisie, William T. Harvey, Xuefang Zhao, Gianni V. Martino, Mir Henglin, Katherine M. Munson, Keon Rabbani, Chen-Shan Chin, Bida Gu, Hufsah Ashraf, Olanrewaju Austine-Orimoloye, Parithi Balachandran, Marc Jan Bonder, Haoyu Cheng, Zechen Chong, Jonathan Crabtree, Mark Gerstein, Lisbeth A. Guethlein, Patrick Hasenfeld, Glenn Hickey, Kendra Hoekzema, Sarah E. Hunt, Matthew Jensen, Yunzhe Jiang, Sergey Koren, Youngjun Kwon, Chong Li, Heng Li, Jiaqi Li, Paul J. Norman, Keisuke K. Oshima, Benedict Paten, Adam M. Phillippy, Nicholas R Pollock, Tobias Rausch, Mikko Rautiainen, Stephan Scholz, Yuwei Song, Arda Söylev, Arvis Sulovari, Likhitha Surapaneni, Vasiliki Tsapalou, Weichen Zhou, Ying Zhou, Qihui Zhu, Michael C. Zody, Ryan E. Mills, Scott E. Devine, Xinghua Shi, Mike E. Talkowski, Mark J.P. Chaisson, Alexander T. Dilthey, Miriam K. Konkel, Jan O. Korbel, Charles Lee, Christine R. Beck, Evan E. Eichler, Tobias Marschall
bioRxiv 2024.09.24.614721; doi: https://doi.org/10.1101/2024.09.24.614721
Subject Area
Subject Areas
- Biochemistry (13411)
- Bioengineering (10209)
- Bioinformatics (32648)
- Biophysics (16812)
- Cancer Biology (13880)
- Cell Biology (19716)
- Clinical Trials (138)
- Developmental Biology (10660)
- Ecology (15773)
- Epidemiology (2067)
- Evolutionary Biology (20084)
- Genetics (13258)
- Genomics (18403)
- Immunology (13502)
- Microbiology (31621)
- Molecular Biology (13177)
- Neuroscience (68884)
- Paleontology (512)
- Pathology (2137)
- Pharmacology and Toxicology (3686)
- Physiology (5750)
- Plant Biology (11829)
- Synthetic Biology (3316)
- Systems Biology (8053)
- Zoology (1821)