The hidden heritability of immune-related diseases
A greater understanding of human genetics and disease-related research has fueled the search for a connection between heritability and immune-related diseases. The well-documented association of the human major histocompatibility complex (MHC) and killer immune receptor (KIR) with many immune-related diseases has spurred large investments in a variety of advanced sequencing tools and large cohort studies. Despite these efforts, the fine mapping of causal variants within MHC or KIR remains difficult, limiting our understanding of the mechanisms leading to immune disease1.
The inherent complexity of the immune sub-genomic regions may be why linking associated variants to immune diseases has been challenging. The MHC and KIR gene complex contain large copy number variants (CNVs), a high density of genes, hyper-polymorphic gene alleles, and conserved extended haplotypes (CEH) with enormous linkage disequilibrium (LDs). This level of complexity makes it difficult to de novo assemble or align these haplotypes correctly using next-generation sequencing methods2.
Discover how SMRT Sequencing impacts your immuno-genomic research
Single Molecule, Real-Time (SMRT) Sequencing delivers the long reads, uniform coverage, and high accuracy needed to comprehensively and confidently phase-resolve the complete range of sequence variants observed in complex immune regions.
- Access the full spectrum of polymorphisms across entire HLA genes
- Characterize conserved extended MHC haplotypes
- Simultaneously genotype and haplotype KIR gene complexes
- Profile full-length immunoglobulin repertoire diversity
Featured research: Explore genetic variation in complex immune loci such as KIR genes
Scientists used long-read sequencing to generate unambiguous KIR genotypes in a well-characterized population of Cynomolgus macaques. They identified nine novel allele variants which aided the refinement of Mafa-KIR haplotype organization model (shown above)3.
Explore this research further.
References
- Trowsdale J. and Knight JC., (2013) Major histocompatibility complex genomics and human disease. Annual Review Genomics Human Genetics. 14, 301-323.
- Brandt, D. Y. C., et al., (2015) Mapping bias overestimates reference allele frequencies at the HLA genes in the 1000 Genomes Project phase I data. 5(5), 931-941.
- Prall, T. M., et al., (2017) Improved full-length killer cell immunoglobulin-like receptor transcript discovery in Mauritian cynomolgus macaques. Immunogenetics doi:10.1007/s00251-017-0977-7.
Selected Resources
- Suzuki, Shingo et al. (2018) Reference grade characterization of polymorphisms in full-length HLA class I and II genes with short-read sequencing on the Ion PGM system and long-reads generated by Single Molecule, Real-time Sequencing on the PacBio platform Frontiers in immunology
- Sutton, Jolene et al. (2018) A high-quality, long-read de novo genome assembly to aid conservation of Hawaii’s last remaining crow species Genes
- Kumari, Romika et al. (2018) PausePred and Rfeet: webtools for inferring ribosome pauses and visualizing footprint density from ribosome profiling data. RNA
- Breaux, Breanna et al. (2018) The Florida manatee (Trichechus manatus latirostris) T cell receptor loci exhibit V subgroup synteny and chain-specific evolution. Developmental and comparative immunology
- Bultitude, W P et al. (2018) KIR2DL1 allele sequence extensions and discovery of 2DL1*0010102 and 2DL1*0010103 alleles by DNA sequencing. HLA
- Hosoya, Tomonori et al. (2018) High throughput single cell sequencing of both T-cell-receptor-beta alleles BioRxiv
- Cousin, Margot A et al. (2018) Utility of DNA, RNA, protein, and functional approaches to solve cryptic immunodeficiencies. Journal of clinical immunology
- Han, Seung Yub et al. (2018) Coupling of single molecule, long read sequencing with IMGT/HighV-QUEST analysis expedites identification of SIV gp140-specific antibodies from scFv phage display libraries. Frontiers in immunology
- Bruijnesteijn, Jesse et al. (2018) Human and rhesus macaque KIR haplotypes defined by their transcriptomes. Journal of immunology
- Cheng, Yuanyuan et al. (2018) Characterisation of MHC class I genes in the koala. Immunogenetics
- Ardui, Simon et al. (2018) Single molecule real-time (SMRT) sequencing comes of age: applications and utilities for medical diagnostics. Nucleic acids research
- Turner, T R et al. (2018) Single molecule real-time (SMRT®) DNA sequencing of HLA genes at ultra-high resolution from 126 International HLA and Immunogenetics Workshop cell lines. HLA
- Hemadou, Audrey et al. (2017) Pacific Biosciences sequencing and IMGT/HighV-QUEST analysis of full-length single chain fragment variable from an in vivo selected phage-display combinatorial Library. Frontiers in immunology
- Deiss, Thaddeus C et al. (2017) Immunogenetic factors driving formation of ultralong VH CDR3 in Bos taurus antibodies. Cellular & molecular immunology
- Semler, Matthew R et al. (2017) Novel full-length major histocompatibility complex class I allele discovery and haplotype definition in pig-tailed macaques. Immunogenetics
- Pei, Weike et al. (2017) Polylox barcoding reveals haematopoietic stem cell fates realized in vivo. Nature
- Chen, Shi-Yi et al. (2017) A transcriptome atlas of rabbit revealed by PacBio single-molecule long-read sequencing. Scientific reports
- Albrecht, V et al. (2017) Dual redundant sequencing strategy: Full-length gene characterisation of 1056 novel and confirmatory HLA alleles. HLA
- Ries, Moritz et al. (2017) KIR3DL01 upregulation on gut natural killer cells in response to SIV infection of KIR- and MHC class I-defined rhesus macaques. PLoS pathogens
- Novák, Karel et al. (2017) Diversity of the TLR4 immunity receptor in Czech native cattle breeds revealed using the Pacific Biosciences sequencing platform. Animal biotechnology
- Giudicelli, Véronique et al. (2017) IG and TR single chain fragment variable (scFv) sequence analysis: a new advanced functionality of IMGT/V-QUEST and IMGT/HighV-QUEST. BMC immunology
- Roe, D. et al. (2017) Revealing complete complex KIR haplotypes phased by long-read sequencing technology Genes and immunity
- Bassano, Irene et al. (2017) Accurate characterization of the IFITM locus using MiSeq and PacBio sequencing shows genetic variation in Galliformes. BMC genomics
- Prall, Trent M et al. (2017) Improved full-length killer cell immunoglobulin-like receptor transcript discovery in Mauritian cynomolgus macaques. Immunogenetics
- Karl, Julie A et al. (2017) Major histocompatibility complex haplotyping and long-amplicon allele discovery in cynomolgus macaques from Chinese breeding facilities. Immunogenetics
- Viluma, Agnese et al. (2017) Genomic structure of the horse major histocompatibility complex class II region resolved using PacBio long-read sequencing technology. Scientific reports
- Hans, Jörg B et al. (2017) Gorilla MHC class I gene and sequence variation in a comparative context. Immunogenetics
- van Bergen, Cornelis A M et al. (2017) Selective graft-versus-leukemia depends on magnitude and diversity of the alloreactive T cell response. The Journal of clinical investigation
- Breaux, Breanna et al. (2017) The Florida manatee (Trichechus manatus latirostris) immunoglobulin heavy chain suggests the importance of clan III variable segments in repertoire diversity. Developmental and comparative immunology
- Koenig, Patrick et al. (2017) Mutational landscape of antibody variable domains reveals a switch modulating the interdomain conformational dynamics and antigen binding. Proceedings of the National Academy of Sciences of the United States of America
- Warren, Wesley C et al. (2017) A new chicken genome assembly provides insight into avian genome structure. G3
- Seo, Jieun et al. (2016) Tofacitinib relieves symptoms of stimulator of interferon genes (STING)-associated vasculopathy with onset in infancy caused by 2 de novo variants in TMEM173. The Journal of allergy and clinical immunology
- Oren, Matan et al. (2016) Short tandem repeats, segmental duplications, gene deletion, and genomic instability in a rapidly diversified immune gene family. BMC genomics
- Ashley, Euan A et al. (2016) Towards precision medicine. Nature reviews. Genetics
- Palmer, William H et al. (2016) Variation and evolution in the glutamine-rich repeat region of Drosophila argonaute-2. G3
- Poster: Ranade, S. et al. (2018) High-throughput SMRT Sequencing of clinically relevant targets
- Poster: McLaughlin, I., et al. (2017) Targeted sequencing using a long-read sequencing technology
- Poster: Oh, Steve et al. (2017) T-cell receptor profiling using PacBio sequencing of SMARTer libraries
- Poster: Watson, C. T. et al. (2016) Characterizing haplotype diversity at the immunoglobulin heavy chain locus across human populations using novel long-read sequencing and assembly approaches
- Poster: Pollard, M. O. et al. (2016) The MHC Diversity in Africa Project (MDAP) pilot – 125 African high resolution HLA types from 5 populations
- Poster: Cereb, N et al. (2016) Whole gene sequencing of KIR-3DL1 with SMRT Sequencing and the distribution of allelic variants in different ethnic groups
- Poster: Jenny Gu, Kevin Eng, Anand Sethuraman, Steve Kujawa et al. (2016) Multiplex target enrichment using barcoded multi-kilobase fragments and probe-based capture technologies
- Poster: Ekholm, JM et al. (2016) Resolving KIR genotypes and haplotypes simultaneously using Single Molecule, Real-Time Sequencing
- Poster: Baybayan, Primo et al. (2016) Application specific barcoding strategies for SMRT Sequencing
- Poster: Ranade, Swati et al. (2016) Immune regions are no longer incomprehensible with SMRT Sequencing
- Korlach, Jonas (2018) Webinar: New PacBio Solutions for High-Resolution Microbiology & Immunology Analysis
- Jacob, Howard (2017) Podcast: Huh? 30 million Americans have a rare disease? Howard Jacob on the state of clinical sequencing
- Korlach, Jonas (2017) ASHG PacBio Workshop: PacBio applications updates & future roadmap
- Ranade, Swati (2017) Webinar: A paradigm shift in HLA sequencing: from exons to high-resolution allele-level HLA yyping
- Cereb, Nezih (2017) AGBT PacBio Workshop: High-throughput HLA class I whole gene and HLA class II long range typing on PacBio RSII and Sequel Platforms
- Laird Smith, Melissa (2016) ASHG PacBio Workshop: SMRT Sequencing as a translational research tool to investigate germline, somatic and infectious diseases
- Pollard, Martin (2016) ASHG Virtual Poster: The MHC Diversity in Africa Project (MDAP) pilot – 125 African high resolution HLA types from 5 populations
- Wenger, Aaron (2016) Video: Using the Integrative Genomics Viewer (IGV) to visualize PacBio long-read SMRT Sequencing data
- Laird Smith, Melissa (2016) Nature Webinar: Using long-read sequencing to characterize population diversity at the immunoglobulin heavy chain locus
- Hill, Christopher (2016) AGBT Conference: Long-read sequence of the gorilla genome
- Ranade, Swati (2016) AGBT Virtual Poster: Immune regions are no longer incomprehensible with SMRT Sequencing
- Seetin, Matthew (2016) AGBT Virtual Poster: Long-read assembly of the Aedes aegypti Aag2 cell line genome resolves ancient endogenous viral elements
- Ryder, Oliver (2016) PAG PacBio Workshop: Conservation genomics of a critically endangered Hawaiian bird: A high quality genome assembly of the ‘alala will assist in population management and reintroduction
- PacBio Certified Service Providers (2018)
- Application Brief: Long-read RNA sequencing – Best Practices (2018)
- SMRT Sequencing Brochure: Revolutionize genomics with SMRT Sequencing (2018)
- Application Brochure: No-Amp targeted sequencing. (2018)
- Infographic: Structural variants and disease (2017)
- Case Study: SMRT sequencing brings clarity to HIV vaccine and transplant research at the Wisconsin national primate research center. (2017)
- Case Study: Improving precision medicine studies in Asia using ethnicity-specific human reference genomes and PacBio long-read sequencing (2017)
- Application Note: Multiplex target enrichment using barcoded multi-kilobase fragments and probe-based capture technologies (2016)