Whole genome sequencing in the UK Biobank

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Whole genome sequencing in the UK Biobank Part of the UK Government s Industrial Strategy Challenge Fund (ISCF) for the Data to Early Diagnosis and Precision Medicine initiative Aim to produce deep

1 Whole genome sequencing in the UK Biobank Part of the UK Government s Industrial Strategy Challenge Fund (ISCF) for the Data to Early Diagnosis and Precision Medicine initiative Aim to produce deep characterisation of whole-genome sequences for the entire UK Biobank 5 year landscape for sequence data generation Two phases: Pilot phase ( Vanguard ): first 50,000 participants Main phase: remaining 450,000 participants

2 UK Biobank WGS: Vanguard Phase 30M MRC funding 50,000 participants 30x whole genome sequences, >85 Gb/genome Illumina short-read technology NovaSeq 6000 with S4 flow-cells 151-bp PE, PCR free libraries Sequencing start Aug 2018, at Sanger Institute 18 months turnaround for sequencing 4.5 petabases of sequence Innovation pilots inform Phase 2

3 Sequence variant discovery Variant discovery vs standard exome capture Variant discovery vs UK10K GP3 imputation Access to remaining 98% of the human genome Access to hard-toimpute fraction of human variants Empirical evaluation dataset: WES (50x) WGS (18x) Imputation (UK10K GP3)

4 Insights into rare variant associations from GWAS UK10K+1000GP3 imputation N=178,480 individuals MAF 0.1% 36 phenotypes 2,706 independent variants 210 low frequency (1-5% MAF) 130 rare (<1% MAF) Astle et al. Cell 2016

5 Insights into rare variant associations from GWAS Rare and low frequency Common Rare non-coding variants have comparable effect size distribution to coding variants Similar finding for chromatin segmentation states Astle et al. Cell 2016

6 DNMs are only enriched in undiagnosed DDD probands in ultra-conserved elements active in foetal brain p = 0.04 p = p = 9.8x10-4 Observed Expected (95% CI) Short et al, Nature (2018)

7 Tests aggregating rare variants over functional domains Tests aggregating over coding domains Test window 1 Test window 2 Tests aggregating over regulatory units Mutation rates, demography, purifying/ positive selection Regulatory annotation Large-scale experimental datasets Test window 1 Test window 2

8 Power to discover associations by aggregated rare variants Power Vanguard (n=50,000) Near perfect power to discover associations for variants with a cumulative beta greater than 0.6 SD and frequency of 6 : 1,000 Cumulative effect size (SD) Full dataset (n=500,000) Near perfect power to discover associations for variants with a cumulative beta greater than 0.6 SD and frequency of 4 : 10,000 Cumulative effect size (SD) Alex Sazonovs Cumulative allele frequency Cumulative allele frequency

Inversions (INV) Mobile Element Insertions

9 Phenotypic consequences of structural variation Read Pairs (RP) sample reference No SV Read Depth (RD) sample reads reference Duplication Deletion Mobile element (MEI) insertion MEI Deletion Tandem duplication Classes of structural variants Deletions (DEL) multiple Copy Number Variation (mcnv) Duplications (DUP) Inversions (INV) Mobile Element Insertions (MEI) Mitocondrial Insertions (NUMT) Split Reads (SR) Assembly (AS) reference Deletion reference Small Deletions Slide courtesy of 1000 Genomes Project

associated with quantification from Southern blot (mtrf) Ding et al.

10 Telomere length, health and aging Mean telomere length is under genetic control Page and has 25 been associated with human biology and disease Estimation of mean telomere length from WGS robustly associated with quantification from Southern blot (mtrf) Ding et al. NAR (2013) Europe PMC Funders Author Ma Codd et al. Nature Genetics (2013) The Telomeres Mendelian Randomization Collaboration. JAMA Oncology (2017)

transport chain) 22 trnas and 2 rrnas (translation of

11 Mitochondrial DNA (mtdna) variation and human traits 16,569 bp in humans 13 protein coding genes (electron transport chain) 22 trnas and 2 rrnas (translation of mt-encoded proteins) Wallace et al. J Clin Invest (2013)

Fine maps of mtdna sequence variation mtdna in UK Biobank from array capture known frequencies of major haplogroups Whole-genome sequencing can

12 Fine maps of mtdna sequence variation mtdna in UK Biobank from array capture known frequencies of major haplogroups Whole-genome sequencing can capture nearly totally of mtdna variants: sub-haplogroup resolution and fine-mapping of causal variants for disease Wallace et al.. J Clin Invest (2013)

Phenotypic consequences of mtdna copy number WGS yields ~100x-fold higher coverage on the mtdna than autosomes mtdna copy number is under genetic control by the

13 Phenotypic consequences of mtdna copy number WGS yields ~100x-fold higher coverage on the mtdna than autosomes mtdna copy number is under genetic control by the nuclear genome. Variation in mtdna levels correlates to tissuespecific stress, is associated with clinical endpoints (e.g. major depression) Cai et al. Current Biology 2015

14 Conclusions Technological innovation Broad explorations of genomic variation Rare coding and regulatory variation Structural variation, telomere length, mitochondrial DNA Genome structure tools Enhanced imputation reference panels Broad range of biological questions addressed Contribution of rare sequence variants to complex traits, and applications Understanding of rare regulatory variation Landscape of evolutionary and mutational constraints Phenotypic changes associated with human evolutionary processes Empowering UK and worldwide science based on UK Biobank

SEQUENCING. M Ataei, PhD. Feb 2016

SEQUENCING. M Ataei, PhD. Feb 2016 CLINICAL NEXT GENERATION SEQUENCING M Ataei, PhD Tehran Medical Genetics Laboratory Feb 2016 Overview 2 Background NGS in non-invasive prenatal diagnosis (NIPD) 3 Background Background 4 In the 1970s,