Systematic genetic analysis of the MHC region reveals mechanistic underpinnings of HLA type associations with disease

D’Antonio, Matteo; Reyna, Joaquin; Jakubosky, David; Donovan, Maureen D.; Bonder, Marc Jan; Matsui, Hiroko; Stegle, Oliver; Nariai, Naoki; D’Antonio‐Chronowska, Agnieszka; Frazer, Kelly A.

doi:10.7554/elife.48476

Cited by 44 publications

(37 citation statements)

References 77 publications

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“…However, the extent to which quantitative regulation of gene expression is functionally important to pathogen defense and thus the target of selection is unclear. Alternatively, these regulatory variants may be hitchhiking with functionally important and tightly linked coding variants under strong positive or balancing selection ( D'Antonio et al, 2019 ; Meyer et al, 2018 ; Shiina et al, 2009 ). If non-coding trans-species polymorphisms are targets of long lived balancing selection on gene regulation ( Johnsen et al, 2009 ; Leffler et al, 2013 ), we expect these polymorphisms to display similar eQTL effects in both species.…”

Section: Discussionmentioning

confidence: 99%

Gene expression variability in human and chimpanzee populations share common determinants

Fair

Blake

Sarkar

et al. 2020

eLife

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Inter-individual variation in gene expression has been shown to be heritable and is often associated with differences in disease susceptibility between individuals. Many studies focused on mapping associations between genetic and gene regulatory variation, yet much less attention has been paid to the evolutionary processes that shape the observed differences in gene regulation between individuals in humans or any other primate. To begin addressing this gap, we performed a comparative analysis of gene expression variability and expression quantitative trait loci (eQTLs) in humans and chimpanzees, using gene expression data from primary heart samples. We found that expression variability in both species is often determined by non-genetic sources, such as cell-type heterogeneity. However, we also provide evidence that inter-individual variation in gene regulation can be genetically controlled, and that the degree of such variability is generally conserved in humans and chimpanzees. In particular, we found a significant overlap of orthologous genes associated with eQTLs in both species. We conclude that gene expression variability in humans and chimpanzees often evolves under similar evolutionary pressures.

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Section: Discussionmentioning

confidence: 99%

Gene expression variability in human and chimpanzee populations share common determinants

Fair

Blake

Sarkar

et al. 2020

eLife

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“…rs3101018 is located in the Human Leukocyte Antigen (HLA) region of the genome. While many genetic variants at this locus alter amino acid usage in major histocompatibility complex molecules and affect antigen presentation, non-coding genetic variants across the HLA region have also been demonstrated to affect gene expression independently of HLA-type [63][64][65] . Additionally, the SLE risk locus encoding SYNGR1 was recently identified in a high-density genotyping study of subjects with Asian ancestry 42 and also increases disease risk for schizophrenia 66 In this study, we used MPRA to uncover specific genetic variants within the risk haplotypes of a complex disease in specific cell types.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide discovery of SLE genetic risk variant allelic enhancer activity

Lü

Forney

et al. 2020

Preprint

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Genome-wide association studies of Systemic Lupus Erythematosus (SLE) nominate 3,073 genetic variants at 91 risk loci. To systematically screen these variants for allelic transcriptional enhancer activity, we constructed a massively parallel reporter assay (MPRA) library comprising 12,396 DNA oligonucleotides containing the genomic context around every allele of each SLE variant. Transfection into EBV-infected B cells revealed 482 variants with enhancer activity, with 51 variants showing genotype-dependent (allelic) enhancer activity at 27 risk loci. In-depth analysis of allelic transcription factor (TF) binding at and around these 51 variants identified one class of TFs whose DNA-binding motif tends to be directly altered by the risk variant and a second, larger class of TFs that also bind allelically but do not have their motifs directly altered by the variant. Collectively, our approach provides a blueprint for the discovery of allelic gene regulation at risk loci for any disease and offers insight into the transcriptional regulatory mechanisms underlying SLE.

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“…While the exact reasons for this apparent discrepancy are still unclear, it is known that allelic variations on other non-CFTR genes (modifier genes) can impact disease severity. [55][56][57]…”

Section: Precision Medicinementioning

confidence: 99%

Cystic Fibrosis and Genotype-Dependent Therapy: Is There a Need for a Sex-Specific Therapy?

Bradbury

2020

Gender and the Genome

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Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulation (CFTR) anion channel. Loss of CFTR protein and/or function disrupts chloride, bicarbonate, and fluid transport and also impacts epithelial sodium transport. Such altered ion and fluid transport produces mucus obstruction, inflammation, pulmonary infection, and damage to multiple organs. Although an autosomal disease, it is apparent that gender differences in life expectancy and quality of life do exist. Conventionally established therapies have treated the downstream sequelae of CFTR dysfunction and have led to a steady increase in life expectancy. Physicians now have access to medications that treat the basic defect in CF, in the form of CFTR modulators. These drugs target the trafficking and/or function of CFTR to improve clinical outcomes for patients. This review summarizes the science behind CFTR modulators and shows how these drugs have dramatically changed how patients with CF are treated. Surprisingly, although the drug target(s) are identical in males and females, CF females seem to display a greater improvement than their male counterparts.

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Systematic genetic analysis of the MHC region reveals mechanistic underpinnings of HLA type associations with disease

Cited by 44 publications

References 77 publications

Gene expression variability in human and chimpanzee populations share common determinants

Gene expression variability in human and chimpanzee populations share common determinants

Genome-wide discovery of SLE genetic risk variant allelic enhancer activity

Cystic Fibrosis and Genotype-Dependent Therapy: Is There a Need for a Sex-Specific Therapy?

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