How giab fits in the rest of the world human genome structural variation consortium
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The document summarizes the work of the Human Structural Genomic Variation Consortium (HSGVC). The HSGVC sequenced 2504 samples from 26 populations to comprehensively discover structural variations using multiple platforms including PacBio, Illumina, and BioNano Genomics. They discovered over 10,000 structural variations per individual genome on average, with validations showing over 88% inheritance from parents and over 90% confirmation by other technologies. The HSGVC provides the most complete characterization of structural variation in human genomes to date.
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How giab fits in the rest of the world human genome structural variation consortium
- 1. Human Structural Genomic Variation Consortium Charles Lee, Ph.D., FACMG SCIENTIFIC DIRECTOR AND PROFESSOR The Jackson Laboratory for Genomic Medicine Farmington, Connecticut, USA March 28, 2019
- 2. Susan FairleyAli Bashir Steven McCarroll Scott Devine Ryan E. Mills Ken Chen Kai Ye Mark B. GersteinDianna Church Jonas Korlach Gabor Marth Jonathan Sebat Michael Talkowski Goo Jun Li Ding Sai Kit Lam Bing Ren Paul Flicek Pui-Yan Kwok Peter M. Lansdorp Xinghua Shi Tobias Marschall Jan KorbelEvan E. Eichler Chong Lek Koh HSGVC Principal Investigators PRINCIPAL FUNDER : National Human Genome Research Institute (NHGRI U41 grant U41HG007497)
- 3. 2504 Samples26 Populations Sequenced + Analyzed POPULATIONS: African American East Asian European South Asian 1000 Genomes Project
- 4. Structural Variations Deletion Insertion Duplication MEI (Mobile Element Insertion) Inversion
- 5. SV Discovery Over the Three Phases of the 1000 Genomes SV Type Phase I (no. sites) DELETIONS (biallelic) 14,232 DUPLICATIONS (biallelic) n/a mCNV (multi allelic copy number variation) n/a INVERSIONS n/a MEI (mobile element insertions) (Alu / L1 / SVA) n/a NUMT (nuclear mitochondrial insertion) n/a Phase II + III (no. sites) 42,279 6,025 2,929 786 16,631 (12,748 / 3,048 / 835) 168 All classes of variations found
- 6. Conclusion of the 1000G Project: Published September 30, 2015
- 7. No One Algorithm/Method is Comprehensive Mills et al. – Nature 470: 59, 2011 Read Pair Read Depth 6855 (63%) Split Read 486 303 4 3223 (80%) 1772 (33%) 3250
- 8. HGSV: Selected Trios GOAL: to utilize multiple platforms for comprehensive discovery of structural variations in selected individual genomes NA19240 HG00514 HG00733 NA19239 NA19238 Yoruban Han Chinese Puerto Rican HG00512 HG00513 HG00731 HG00732 (high genetic diversity) (low genetic diversity) (population admixture) Parents were previously sequenced in 1000G Children sequenced in HGSV to 223-fold combined coverage
- 9. HGSV: Strategy AVG Seq Coverage Pac Bio Illumina Short Insert Illumina liWGS Illumina 7kbp JMP 10X Chromium BioNano Genomics Tru-Seq SLR Strand-Seq Hi-C AVG Frag. Len. Physical Coverage 39.6 (child) 20.03 (parent) 19.49 74.5 3 1.1 82.4 N/A 3.47 N/A 8165 (child) 9619 (parent) 1.03E+07 694 3475 6973.2 90098 2.81E+05 4900 N/A 39.6 N/A 171 159 39.2 53.9 116.7 3.47 5.87
- 10. HGSV: Coverage NA19240 NA19239 NA19238 Yoruban (high genetic diversity) Pac Bio: 18.21X Illumina: 85.3X Jumping library: 154.3X TrueSeq: 4.02X Strand-seq: 6.08X Pac Bio: 37.67X Illumina: 85.9X Jumping library: 178.8X TrueSeq: 4.17X Pac Bio: 16.5X Illumina: 84.6X Jumping library: 153.7X TrueSeq: 2.69X Strand-seq: 7.73X
- 11. HGSV: Coverage HG00514 Han Chinese HG00512 HG00513 (low genetic diversity) Pac Bio: 17.39X Illumina: 85.5X Jumping library: 162.5X TrueSeq: 3.31X Strand-seq: 3.55X Pac Bio: 41.8X Illumina: 84.5X Jumping library: 138.1X TrueSeq: 1.44X Pac Bio: 22.04X Illumina: 86.5X Jumping library: 154.3X TrueSeq: 5.22X Strand-seq: 5.63X
- 12. HGSV: Coverage HG00733 Puerto Rican HG00731 HG00732 (population admixture) Pac Bio: 23.08X Illumina: 84.4X Jumping library: 142.7X TrueSeq: 2.97X Strand-seq: 5.27X Pac Bio: 39.43X Illumina: 85.1X Jumping library: 188.6X TrueSeq: 2.6X Pac Bio: 23.005X Illumina: 85.8X Jumping library: 156.2X TrueSeq: 4.81X Strand-seq: 7.31X
- 13. Indels and SVs 1-49 bp >50 bp Indels Structural Variation
- 14. Illumina Short reads 818,054 Indels/child PacBio Long reads 698,907 Indels/child GATK FreeBays Pindel Discovering Indels (1-49bp): Unified Callsets 345,281 Indels/child Phased-SV
- 15. Discovering SVs (>50bp): Unified Callsets Illumina Short reads 13 algorithms (Assemble/Map, Call Variants) 6,965 Deletions 2,654 Insertions 814 Duplications 10,884 SVs (avg/child) Increase: 13,941 SVs BNGPacBio Long reads Optical Mapping 2 algorithms (Assemble/Map, Call Variants) Haplotype-resolved Phased SV 9,488 Deletions 15,337 Insertions 24,825 SVs (avg/child)
- 16. Validation Experiments • INHERITANCE: We assessed transmission of the PB-SV calls in each child, by searching for evidence of each child’s SV in the long-read sequencing data of one of the two parents. 88% of the SVs showed read support from one of the two parents. • OXFORD NANOPORE: We have obtained 18.9 fold whole ONT genome sequence data for PUR child (HG00733) and searched for support for individual SV calls within the ONT reads. Requiring at least three reads to support an event gives a 91% (21,888 SVs) validation rate for SVs outside of tandem repeats, and 83% validation rate for SVs within tandem repeats. • BAC-BASED SEQUENCING: We independently sequenced 57 BACs to assess the base pair accuracy of our de novo assemblies. We searched specifically for SVs contained within the sequenced BAC insert that overlapped with our union SV callset. There were 27 homozygous calls that overlapped with the regions sequenced by BACs, of which 25 (92%) were confirmed in the BACs.
- 17. NA19240 Unified Callset for SV (INSERTIONS) 1344 3 435 121 1365 2939 1073 87 PacBio (n=17542 ) Illumina (n=4512) BioNan o (n=1716)
- 18. Discovering Inversions BNGIllumina PacBio Short reads, WGS Long read Optical Mapping Illumina Jumping Library (liWGS) Strand Seq 126 91 118 28 170 308 Inversions (across all 9 individuals, average 156 per genome, ~23 Mb of DNA) 156 Inversions (average/genome) Various algorithms (Assemble/Map , Call Variants)
- 19. Inversion Calls in Trios, Based on Technologies Smallest: 263 bp (ch1:187497343-187497605) Largest: 1.28Mb (chr8: 8230468-12095842) Technology Illumina Jumping PacBio Strand-seq Bionano
- 20. Recent updates Paper from hell! • Deposited to bioRxiv on September 23, 2017 • Revised version on bioRxiv on June 13, 2018 • In Press, Nature Communications U24 grant received a fundable score (I think) 1000 Genomes individuals – 30x Illumina sequencing Genome in a bottle samples
- 21. PRINCIPAL INVESTIGATORS: Susan FairleyAli Bashir Steven McCarroll Scott Devine Ryan E. Mills Ken Chen Kai Ye Mark B. GersteinDianna Church Jonas Korlach Gabor Marth Jonathan Sebat Michael Talkowski Goo Jun Li Ding Sai Kit Lam Bing Ren Paul Flicek Pui-Yan Kwok Peter M. Lansdorp Xinghua Shi Tobias Marschall Jan KorbelEvan E. Eichler Chong Lek Koh Acknowledgments PRINCIPAL FUNDER : National Human Genome Research Institute (NHGRI U41 grant U41HG007497)
Editor's Notes
- NOTE: The math doesn’t add up on Short Read Illumina totals, but these numbers are in paper.. A: Probably because it doesn’t include inversions, and other categories predicted by Svelter