Novel transcriptional activity and extensive allelic imbalance in the human MHC region

Gensterblum, Elizabeth; Wu, Weisheng; Sawalha, Amr H.

doi:10.1101/186809

Cited by 5 publications

(5 citation statements)

References 40 publications

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“…Using the expression data at the HLA-allele level we found a low level of asymmetry in expression, with 77% of the heterozygotes having ASE between 0.4 and 0.5, with Class II genes showing a distribution with a larger variance (Allele-specific expression (ASE) was defined as the proportion of the gene expression attributed to the less expressed HLA allele, Figure 7), and we see no instances of extreme imbalance as recently reported for SNPs in HLA genes [54]. Therefore, the extreme imbalance seen at the SNP level does not hold at the HLA allele resolution.…”

Section: Hla Allele-level Analysissupporting

confidence: 75%

Expression estimation and eQTL mapping for HLA genes with a personalized pipeline

Aguiar

Cesar

Delaneau

et al. 2018

Preprint

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The HLA (Human Leukocyte Antigens) genes are well-documented targets of balancing selection, and variation at these loci is associated with many disease phenotypes. Variation in expression levels also influences disease susceptibility and resistance, but little information exists about the regulation and population-level patterns of expression due to the difficulty in mapping short reads to these highly polymorphic loci, and in accounting for the existence of several paralogues. We developed a computational pipeline to accurately estimate expression for HLA genes based on RNA-seq, improving both locus-level and allele-level estimates. First, reads are aligned to all known HLA sequences in order to infer HLA genotypes, then quantification of expression is carried out using a personalized index. We use simulations to show that expression estimates are not biased due to divergence from the reference genome. We applied our pipeline to GEUVADIS dataset, and compared the quantifications to those obtained with reference transcriptome, and found that a substantial portion of the variation captured by the HLA-personalized index in not captured by the standard index (23%). We describe the impact of the HLA-personalized approach on downstream analyses for seven HLA loci (HLA-A, HLA-B, HLA-C, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRB1 ). Although the influence of the HLA-personalized approach is modest for eQTL mapping, the p-values and the causality of the eQTLs obtained are better than when the reference transcriptome is used. Finally, we integrate information on HLA-allele level expression with the eQTL findings to show 2 . CC-BY 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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Section: Hla Allele-level Analysissupporting

confidence: 75%

Expression estimation and eQTL mapping for HLA genes with a personalized pipeline

Aguiar

Cesar

Delaneau

et al. 2018

Preprint

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“…In addition to genetic variants, functional analyses of other complex genomic regions can also benefit greatly from our unbiased approach to constructing haplotype-resolved assemblies of targeted regions. For regions with high polymorphisms, such as the MHC, the conventional strategy of mapping short-read sequencing data to a single reference genome (e.g., hg19 or hg38) is known to yield biased alignments, leading towards inaccurate quantifications 41,42 . This has prompted recent attempts to replace a single reference genome with the computationally inferred personal genotypes as the reference, all of which showed improved accuracies of quantifications compared to the standard approach 36,[43][44][45][46] .…”

Section: Discussionmentioning

confidence: 99%

CRISPR-based targeted haplotype-resolved assembly of a megabase region

Zhang

et al. 2023

Nat Commun

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Constructing high-quality haplotype-resolved genome assemblies has substantially improved the ability to detect and characterize genetic variants. A targeted approach providing readily access to the rich information from haplotype-resolved genome assemblies will be appealing to groups of basic researchers and medical scientists focused on specific genomic regions. Here, using the 4.5 megabase, notoriously difficult-to-assemble major histocompatibility complex (MHC) region as an example, we demonstrated an approach to construct haplotype-resolved assembly of the targeted genomic region with the CRISPR-based enrichment. Compared to the results from haplotype-resolved genome assembly, our targeted approach achieved comparable completeness and accuracy with reduced computing complexity, sequencing cost, as well as the amount of starting materials. Moreover, using the targeted assembled personal MHC haplotypes as the reference both improves the quantification accuracy for sequencing data and enables allele-specific functional genomics analyses of the MHC region. Given its highly efficient use of resources, our approach can greatly facilitate population genetic studies of targeted regions, and may pave a new way to elucidate the molecular mechanisms in disease etiology.

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“…In addition to genetic variants, functional analyses of any genomic regions can also benefit greatly from our unbiased approach of constructing haplotype-resolved assemblies of targeted regions. For regions with high polymorphisms, such as the MHC, the conventional strategy of mapping short-read sequencing data to a single reference genome (e.g., hg19 or hg38) is known to yield biased alignments, leading towards inaccurate quantifications 36,37 . This has prompted recent attempts to replace a single reference genome with the computationally inferred personal genotypes as the reference, all of which showed improved accuracies of quantifications compared to the standard approach 33,[38][39][40][41] .…”

Section: Discussionmentioning

confidence: 99%

CRISPR-based targeted haplotype-resolved assemblies of a megabase region

Zhang

et al. 2022

Preprint

View full text Add to dashboard Cite

Constructing high-quality haplotype-resolved genome assemblies has substantially improved the ability to detect and characterize genetic variants. A targeted approach providing readily access to the rich information from haplotype-resolved genome assemblies will be appealing to groups of basic researchers and medical scientists focused on specific genomic regions. Here, using the 4.5 megabase, notoriously difficult-to-assemble major histocompatibility complex (MHC) region as an example, we demonstrated an approach to construct haplotype-resolved de novo assemblies of targeted genomic regions with the CRISPR-based enrichment. Compared to the results from haplotype-resolved genome assemblies, our targeted approach achieved comparable completeness and accuracy with greatly reduced computing complexity, sequencing cost, as well as the amount of starting materials. Moreover, using the targeted assembled personal haplotypes as the reference both improves the quantification accuracy for sequencing data and enables allele-specific functional genomics analyses. Given its highly efficient use of resources, our approach can greatly facilitate population genetic studies of targeted regions, and may pave a new way to elucidate the molecular mechanisms in disease etiology.

show abstract

Novel transcriptional activity and extensive allelic imbalance in the human MHC region

Cited by 5 publications

References 40 publications

Expression estimation and eQTL mapping for HLA genes with a personalized pipeline

Expression estimation and eQTL mapping for HLA genes with a personalized pipeline

CRISPR-based targeted haplotype-resolved assembly of a megabase region

CRISPR-based targeted haplotype-resolved assemblies of a megabase region

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