Long-range multilocus haplotype phasing of the MHC

Guo, Zhen; Hood, Leroy; Malkki, Mari; Petersdorf, Effie W.

doi:10.1073/pnas.0602286103

Cited by 40 publications

(33 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Thus, accurate phase information allows identification of donor-recipient matches at high risk for life-threatening transplant complications and, in addition, the detection of novel genetic factors related to GvHD. However, long range phasing of the MHC presents a particular challenge due to abundant sequence variability, structural complexity, and large distances between the HLA genes (Guo et al 2006). In a first step, we aimed to demonstrate validity of our extended MHC sequences phased in MP1.…”

Section: Extended Phase In the Mhc Region Resolves Haplotypes Of Key mentioning

confidence: 99%

A comprehensively molecular haplotype-resolved genome of a European individual

Suk

McEwen

Duitama³

et al. 2011

Genome Res.

111

View full text Add to dashboard Cite

Independent determination of both haplotype sequences of an individual genome is essential to relate genetic variation to genome function, phenotype, and disease. To address the importance of phase, we have generated the most complete haplotype-resolved genome to date, “Max Planck One” (MP1), by fosmid pool-based next generation sequencing. Virtually all SNPs (>99%) and 80,000 indels were phased into haploid sequences of up to 6.3 Mb (N50 ∼1 Mb). The completeness of phasing allowed determination of the concrete molecular haplotype pairs for the vast majority of genes (81%) including potential regulatory sequences, of which >90% were found to be constituted by two different molecular forms. A subset of 159 genes with potentially severe mutations in either cis or trans configurations exemplified in particular the role of phase for gene function, disease, and clinical interpretation of personal genomes (e.g., BRCA1). Extended genomic regions harboring manifold combinations of physically and/or functionally related genes and regulatory elements were resolved into their underlying “haploid landscapes,” which may define the functional genome. Moreover, the majority of genes and functional sequences were found to contain individual or rare SNPs, which cannot be phased from population data alone, emphasizing the importance of molecular phasing for characterizing a genome in its molecular individuality. Our work provides the foundation to understand that the distinction of molecular haplotypes is essential to resolve the (inherently individual) biology of genes, genomes, and disease, establishing a reference point for “phase-sensitive” personal genomics. MP1's annotated haploid genomes are available as a public resource.

show abstract

Section: Extended Phase In the Mhc Region Resolves Haplotypes Of Key mentioning

confidence: 99%

A comprehensively molecular haplotype-resolved genome of a European individual

Suk

McEwen

Duitama³

et al. 2011

Genome Res.

111

View full text Add to dashboard Cite

show abstract

“…14,16 However, HLA-identical pairs might be unique for genomic interpretation because these would not be complicated by the noise of MHC-linked immune response polymorphisms (i.e., polymorphic responsiveness against disparate donor HLA antigens being eliminated). 17,18 In this respect, no (early) tolerance correlation occurred with individual A, B, C, DR, DQ, or DP HLA loci.…”

mentioning

confidence: 99%

Genomic Biomarkers Correlate with HLA-Identical Renal Transplant Tolerance

Leventhal

Mathew

Salomon

et al. 2013

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

The ability to achieve immunologic tolerance after transplantation is a therapeutic goal. Here, we report interim results from an ongoing trial of tolerance in HLAidentical sibling renal transplantation. The immunosuppressive regimen included alemtuzumab induction, donor hematopoietic stem cells, tacrolimus/mycophenolate immunosuppression converted to sirolimus, and complete drug withdrawal by 24 months post-transplantation. Recipients were considered tolerant if they had normal biopsies and renal function after an additional 12 months without immunosuppression. Of the 20 recipients enrolled, 10 had at least 36 months of follow-up after transplantation. Five of these 10 recipients had immunosuppression successfully withdrawn for 16-36 months (tolerant), 2 had disease recurrence, and 3 had subclinical rejection in protocol biopsies (nontolerant). Microchimerism disappeared after 1 year, and CD4 + CD25 high CD127 2 FOXP3 + regulatory T cells and CD19 + IgD/M + CD27 2 B cells were increased through 5 years post-transplantation in both tolerant and nontolerant recipients. Immune/inflammatory gene expression pathways in the peripheral blood and urine, however, were differentially downregulated between tolerant and nontolerant recipients. In summary, interim results from this trial of tolerance in HLA-identical renal transplantation suggest that predictive genomic biomarkers, but not immunoregulatory phenotyping, may be able to discriminate tolerant from nontolerant patients.

show abstract

“…This group developed a ‘phasing’ method for analysing genes contained within HLA haplotypes48 and applied this technique retrospectively to a series of 246 HSCT recipients and their HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1-matched unrelated donors. MHC haplotype mismatching was associated with an increased risk of severe GvHD with lower risk of disease recurrence.…”

Section: Future Directionsmentioning

confidence: 99%

My approach to the immunogenetics of haematopoietic stem cell transplant matching: Figure 1

Sage

2010

J Clin Pathol

View full text Add to dashboard Cite

Haematopoietic stem cell transplantation (HSCT) is now viewed as an effective treatment modality for a wide and varied number of diseases including both malignant and non-malignant haematological diseases, bone marrow failures, inherited immunodeficiencies and congenital metabolic disorders. This review will discuss the immunogenetic factors that play an influential role in the successful outcome of HSCT, most importantly the human leucocyte antigens (HLAs). Advances in HLA typing techniques enabling the definition of HLA types at the allele level have made it possible to investigate the impact of mismatching at individual HLA loci on HSCT outcome. Such studies have informed the strategy used for selection of both related and unrelated donors. This strategy, including the histocompatibility and immunogenetics laboratory testing required, is discussed in the context of published data, guidelines and recommendations. THE HLA SYSTEMThe HLA system has long been implicated as central to the successful outcome of haematopoietic stem cell transplantation (HSCT). The importance of matching patient and donor for HLA class I (A and B) and class II (DR) has long been established. 1e4 The advent of the molecular era has allowed H&I scientists to further elucidate and reveal the complexity and extent of the polymorphism found in HLA genes. These advances have posed an ever increasing challenge to the histocompatibility and immunogenetics (H&I) laboratory to find the optimal donor for a patient requiring HSCT.

show abstract

Long-range multilocus haplotype phasing of the MHC

Cited by 40 publications

References 49 publications

A comprehensively molecular haplotype-resolved genome of a European individual

A comprehensively molecular haplotype-resolved genome of a European individual

Genomic Biomarkers Correlate with HLA-Identical Renal Transplant Tolerance

My approach to the immunogenetics of haematopoietic stem cell transplant matching: Figure 1

Contact Info

Product

Resources

About