The Hong Kong genome project: building genome sequencing capacity and capability for advancing genomic science in Hong Kong

Abstract

Aim: The Hong Kong Genome Project (HKGP) is the first large-scale genome sequencing (GS) project in the Hong Kong Special Administrative Region. The Hong Kong Genome Institute (HKGI) is entrusted with the task of implementing the HKGP. With the aim to sequence 45,000-50,000 genomes in five years, it is the project’s goal to provide participants with more precise diagnosis and personalised treatment, and to drive the application and integration of genomic medicine into routine clinical care.

Methods: The HKGI Laboratory’s hardware and software components were customised to tailor to the needs of the project. Sample handling and storage protocol, DNA extraction, and PCR-free GS workflow were developed and optimised. Quality control indicators and metrics for assessing the quality of samples, sequencing libraries and sequencing data were established.

Results: The Laboratory is designed to facilitate a unidirectional GS workflow to minimise the risk of contamination. The Sample Manager system handles laboratory data generated from the HKGP samples and biobank. The Laboratory handles and analyses approximately 350-500 samples per week, the majority of which are whole blood. During the first 24 months since the launch of the HKGP, 12,937 participants and their family members (6,680 genomes) have been recruited and sequenced. The sequencing capacity of the Laboratory has been further enhanced to include the latest technologies, such as long-read sequencing and multi-omics in order to meet the target of the HKGP.

Conclusion: HKGI Laboratory established a robust GS workflow for the HKGP. The clinical utility of GS will bring precision medicine into routine clinical practice.

Keywords

Hong Kong Genome Project (HKGP) / genome sequencing / genomic medicine / precision health / laboratory establishment

References

[1] NurkS,RhieA.The complete sequence of a human genome.Science2022;376:44-53

[2] BeckT,ShorterT.GWAS central: an expanding resource for finding and visualising genotype and phenotype data from genome-wide association studies.Nucleic Acids Res2023;51:D986-93 PMCID:PMC9825503

[3] LandrumMJ,BensonM.ClinVar: improving access to variant interpretations and supporting evidence.Nucleic Acids Res2018;46:D1062-7 PMCID:PMC5753237

[4] GreenED.Charting a course for genomic medicine from base pairs to bedside.Nature2011;470:204-13

[5] HuT,MonosD.Next-generation sequencing technologies: an overview.Hum Immunol2021;82:801-11

[6] The cost of sequencing a human genome. 2020. Available from: https://www.genome.gov/about-genomics/fact-sheets/Sequencing-Human-Genome-cost [Last accessed on 23 Oct 2023]

[7] ChuATW,TongAHY.Potentials and challenges of launching the pilot phase of Hong Kong genome project.J Transl Genet Genom2022;6:290-303

[8] LiuJ,SongL.Precision cardiovascular medicine in China.J Geriatr Cardiol2020;17:638-41

[9] Japan Agency for Medical Research and Development. GA4HG. 2022. Available from: https://www.amed.go.jp/en/aboutus/collaboration/ga4gh_gem_japan.html [Last accessed on 23 Oct 2023]

[10] Global Alliance for Genomics & Health. GEM Japan releases largest-ever open-access Japanese variant frequency panel. 2022. Available from: https://www.ga4gh.org/news_item/gem-japan-releases-largest-ever-open-access-japanese-variant-frequency-panel/ [Last accessed on 23 Oct 2023]

[11] Genomics Thailand. Available from: https://genomicsthailand.com/Genomic/home [Last accessed on 23 Oct 2023]

[12] A twisted ladder to prosperity. Available from: https://www.nature.com/articles/d42473-020-00211-y [Last accessed on 23 Oct 2023]

[13] Aviesan. Genomic medicine France 2025. 2022. Available from: https://solidarites-sante.gouv.fr/IMG/pdf/genomic_medicine_france_2025.pdf [Last accessed on 23 Oct 2023]

[14] Genomics England. The 100,000 genomes project by numbers. Available from: https://www.genomicsengland.co.uk/news/the-100000-genomes-project-by-numbers [Last accessed on 23 Oct 2023]

[15] SmedleyD,MartinA.100,000 Genomes pilot on rare-disease diagnosis in health care - preliminary report.N Engl J Med2021;385:1868-80 PMCID:PMC7613219

[16] Cookies on our future health. Available from: https://ourfuturehealth.org.uk/research-programme/ [Last accessed on 23 Oct 2023]

[17] Genome UK: 2021 to 2022 implementation plan. Available from: https://www.gov.uk/government/publications/genome-uk-2021-to-2022-implementation-plan/genome-uk-2021-to-2022-implementation-plan [Last accessed on 23 Oct 2023]

[18] Danish ministry of health. Personalised medicine for the benefit of the patients. 2022. Available from: https://eng.ngc.dk/Media/637614364621421665/Danish%20Strategy%20for%20personalised%20medicine%202021%202022.pdf [Last accessed on 23 Oct 2023]

[19] Australian genomics. Available from: https://www.australiangenomics.org.au/our-history/ [Last accessed on 23 Oct 2023]

[20] StarkZ,PhillipsP.Australian genomics: a federated model for integrating genomics into healthcare.Am J Hum Genet2019;105:7-14 PMCID:PMC6612707

[21] Department of health and aged care, australian government. Genomics health futures mission. Available from: https://www.health.gov.au/initiatives-and-programs/genomics-health-futures-mission [Last accessed on 23 Oct 2023]

[22] Genome Canada. Available from: https://genomecanada.ca/challenge-areas/all-for-one/ [Last accessed on 23 Oct 2023]

[23] National human genome research institute. The undiagnosed diseases program. Available from: https://www.genome.gov/Current-NHGRI-Clinical-Studies/Undiagnosed-Diseases-Program-UDN [Last accessed on 23 Oct 2023]

[24] Saudi genome program. Available from: https://www.vision2030.gov.sa/en/projects/saudi-genome-program/ [Last accessed on 23 Oct 2023]

[25] BBMRI-ERIC. Turkish genome project launched. Available from: https://www.bbmri-eric.eu/news-events/turkish-genome-project-launched/ [Last accessed on 23 Oct 2023]

[26] ÖzçelikT.Medical genetics and genomic medicine in Turkey: a bright future at a new era in life sciences.Mol Genet Genomic Med2017;5:466-72 PMCID:PMC5606892

[27] ChungCCY,ChuATW.Rare disease emerging as a global public health priority.Front Public Health2022;10:1028545 PMCID:PMC9632971

[28] ChungBHY,WongGK.Rare versus common diseases: a false dichotomy in precision medicine.NPJ Genom Med2021;6:19 PMCID:PMC7904920

[29] PoseyJE,ChongJX.Insights into genetics, human biology and disease gleaned from family based genomic studies.Genet Med2019;21:798-812

[30] KarczewskiKJ,TiaoG.The mutational constraint spectrum quantified from variation in 141,456 humans.Nature2020;581:434-43

[31] Census and statistics department, Hong Kong special administrative region. Table 150-11001: projected mid-year population by sex and age group. Available from: https://www.censtatd.gov.hk/en/web_table.html?id=150-11001 [Last accessed on 23 Oct 2023]

[32] Census and statistics department, Hong Kong special administrative region. 2016 population by-census: summary results. Available from: https://www.bycensus2016.gov.hk/data/16bc-summary-results.pdf [Last accessed on 23 Oct 2023]

[33] The steering committee of genomic medicine, Hong Kong special administrative region. Strategic development of genomic medicine in Hong Kong. 2022. Available from: https://www.healthbureau.gov.hk/download/press_and_publications/otherinfo/200300_genomic/SCGM_report_en.pdf [Last accessed on 23 Oct 2023]

[34] Hong Kong genome institute. strategic plan 2022-25. Available from: https://hkgp.org/ebook/HKGI-Strategic-Plan/ [Last accessed on 23 Oct 2023]

[35] Van der Auwera G, O’Connor B. Genomics in the cloud: using docker, GATK, and WDL in Terra, 1st edition. Sebastopol, CA: O'Reilly Media 2020.

[36] LiH. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. 2013. Available from: https://ui.adsabs.harvard.edu/abs/2013arXiv1303.3997L/abstract [Last accessed on 23 Oct 2023]

[37] Picard tools. Version 2.17.8. Broad institute, GitHub repository. Available from: http://broadinstitute.github.io/picard/ [Last accessed on 23 Oct 2023]

[38] McLarenW,HuntSE.The ensembl variant effect predictor.Genome Biol2016;17:122 PMCID:PMC4893825

[39] DanecekP,LiddleJ.Twelve years of SAMtools and BCFtools.Gigascience2021;10:giab008 PMCID:PMC7931819

[40] SmedleyD,JägerM.Next-generation diagnostics and disease-gene discovery with the Exomiser.Nat Protoc2015;10:2004-15 PMCID:PMC5467691

[41] MartinAR,FoulgerRE.PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels.Nat Genet2019;51:1560-5

[42] RichardsS,BaleS.Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology.Genet Med2015;17:405-24 PMCID:PMC4544753

[43] HallL,BernardK. Establishing molecular testing in clinical laboratory environments; Proposed guideline. 2011. Available from: https://clsi.org/media/1474/mm19a_sample.pdf [Last accessed on 23 Oct 2023]

[44] AysalA,EkmekciS.How to set up a molecular pathology lab: a guide for pathologists.Turk Patoloji Derg2020;36:179-87 PMCID:PMC10510618

[45] MarshallCR,TaftRJ.Best practices for the analytical validation of clinical whole-genome sequencing intended for the diagnosis of germline disease.NPJ Genom Med2020;5:47 PMCID:PMC7585436

[46] AzizN,BryL.College of American pathologists’ laboratory standards for next-generation sequencing clinical tests.Arch Pathol Amp Lab Med2015;139:481-93

[47] BogdanovaN,GerkeV,HorstJ.Homologues to the first gene for autosomal dominant polycystic kidney disease are pseudogenes.Genomics2001;74:333-41

[48] HübschmannD.Evaluation of whole genome sequencing data.Methods Mol Biol Clifton N J2019;1956:321-36

[49] RibarskaT,SundaramAYM.Optimization of enzymatic fragmentation is crucial to maximize genome coverage: a comparison of library preparation methods for Illumina sequencing.BMC Genom2022;23:92 PMCID:PMC8805253

[50] KozarewaI,QuailMA,BerrimanM.Amplification-free Illumina sequencing-library preparation facilitates improved mapping and assembly of (G+C)-biased genomes.Nat Methods2009;6:291-5 PMCID:PMC2664327

[51] QuailMA,TurnerDJ.Improved protocols for the illumina genome analyzer sequencing system.Curr Protoc Hum Genet2009;62:18.2.1-27

[52] RehmHL,SmithL.GA4GH: international policies and standards for data sharing across genomic research and healthcare.Cell Genom2021;1:100029

[53] RettererK,ChoMT.Clinical application of whole-exome sequencing across clinical indications.Genet Med2016;18:696-704

[54] LeeH,DorraniN.Clinical exome sequencing for genetic identification of rare Mendelian disorders.JAMA2014;312:1880-7 PMCID:PMC4278636

[55] ChungCCY,NgNYT,ChuATW.Meta-analysis of the diagnostic and clinical utility of exome and genome sequencing in pediatric and adult patients with rare diseases across diverse populations.Genet Med2023;25:100896

[56] ScocchiaA,Masser-FryeD.Clinical whole genome sequencing as a first-tier test at a resource-limited dysmorphology clinic in Mexico.NPJ Genom Med2019;4:5 PMCID:PMC6375919

[57] MarxV.Method of the year: long-read sequencing.Nat Methods2023;20:6-11

[58] XingL,WeiX.Long-read Oxford nanopore sequencing reveals a de novo case of complex chromosomal rearrangement involving chromosomes 2, 7, and 13.Mol Genet Genom Med2022;10:e2011

[59] RobertsHE,PagnamentaAT.Short and long-read genome sequencing methodologies for somatic variant detection; genomic analysis of a patient with diffuse large B-cell lymphoma.Sci Rep2021;11:6408 PMCID:PMC7979876

[60] ChungBHY,ChanKYK.Analytical validity and clinical utility of whole-genome sequencing for cytogenetically balanced chromosomal abnormalities in prenatal diagnosis: abridged secondary publication.Hong Kong Med J2022;28:4-7

[61] GaraldeDR,JachimowiczD.Highly parallel direct RNA sequencing on an array of nanopores.Nat Methods2018;15:201-6

[62] SakamotoY,SuzukiA.A new era of long-read sequencing for cancer genomics.J Hum Genet2020;65:3-10 PMCID:PMC6892365

[63] TurnerH. Clinical long-read sequencing. WYNG foundation briefing. 2022. Available from: https://www.phgfoundation.org/briefing/clinical-long-read-sequencing [Last accessed on 23 Oct 2023]

[64] TurnerH. Long-read sequencing: clinical applications and implementation. WYNG foundation briefing. 2022. Available from: https://www.phgfoundation.org/briefing/lrs-clinical-applications-and-implementation [Last accessed on 23 Oct 2023]

[65] SanfordKobayashi E,WengerAM.Approaches to long-read sequencing in a clinical setting to improve diagnostic rate.Sci Rep2022;12:16945 PMCID:PMC9548499

[66] RoodJE,HupalowskaA,RegevA.Impact of the human cell atlas on medicine.Nat Med2022;28:2486-96

[67] AlfaroJA,DaiM.The emerging landscape of single-molecule protein sequencing technologies.Nat Methods2021;18:604-17 PMCID:PMC8223677

[68] TangX,LeiJ,ZhuX.The single-cell sequencing: new developments and medical applications.Cell Biosci2019;9:53 PMCID:PMC6595701

[69] NomuraS.Single-cell genomics to understand disease pathogenesis.J Hum Genet2021;66:75-84 PMCID:PMC7728598

[70] CuomoASE,RaychaudhuriS,PowellJE.Single-cell genomics meets human genetics.Nat Rev Genet2023;24:535-49

[71] SreenivasanVKA,SpielmannM.The role of single-cell genomics in human genetics.J Med Genet2022;59:827-39 PMCID:PMC9411920

[72] LeiY,XuJ.Applications of single-cell sequencing in cancer research: progress and perspectives.J Hematol Oncol2021;14:91 PMCID:PMC8190846

[73] LiuJ,JinY,ZhangY.Progress and clinical application of single-cell transcriptional sequencing technology in cancer research.Front Oncol2020;10:593085 PMCID:PMC7886993