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
- 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
- Karl, Julie A et al. (2016) Major histocompatibility complex haplotyping and long-amplicon allele discovery in cynomolgus macaques from Chinese breeding facilities bioRxiv
- Ashley, Euan A et al. (2016) Towards precision medicine. Nature Reviews. Genetics
- Koning, Marvyn T et al. (2016) ARTISAN PCR: rapid identification of full-length immunoglobulin rearrangements without primer binding bias. British Journal of Haematology
- Dahal-Koirala, S et al. (2016) TCR sequencing of single cells reactive to DQ2.5-glia-a2 and DQ2.5-glia-?2 reveals clonal expansion and epitope-specific V-gene usage. Mucosal Immunology
- Vij, Shubha et al. (2016) Chromosomal-level assembly of the Asian seabass genome using long sequence reads and multi-layered scaffolding. PLoS Genetics
- Huddleston, John et al. (2016) An incomplete understanding of human genetic variation. Genetics
- Gordon, David et al. (2016) Long-read sequence assembly of the gorilla genome. Science
- Gowda, Malali et al. (2016) Comparative analyses of low, medium and high-resolution HLA typing technologies for human populations Journal of Clinical & Cellular Immunology
- 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
- 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
- Ashley, Euan (2016) AGBT Roche and PacBio Workshop: Towards precision medicine
- Ranade, Swati (2016) AGBT Virtual Poster: Immune regions are no longer incomprehensible with SMRT Sequencing
- 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 (2017)
- Human Biomedical Research Brochure: The most comprehensive view of the human genome (2017)
- Case Study: Improving precision medicine studies in Asia using ethnicity-specific human reference genomes and PacBio long-read sequencing (2017)
- Application Brief: Long-read RNA sequencing – Best Practices (2017)
- SMRT Sequencing Brochure: Revolutionize genomics with SMRT Sequencing (2017)
- SV Application Brochure: Track the full extent of structural variation in a genome (2016)
- Isoform Sequencing Application Brochure: Read full-length transcripts – no assembly required (2016)
- Application Note: Multiplex target enrichment using barcoded multi-kilobase fragments and probe-based capture technologies (2016)