Polymorphisme génétique | EPFL Graph Search

Le polymorphisme génétique (du grec « poly » plusieurs et « morphê » forme) est la coexistence de plusieurs allèles pour un gène ou locus donné, dans une population animale, végétale, fongique, bactérienne. Il explique qu'une espèce présente des individus aux caractères phénotypiques différents (appelés morphotypes) au sein d'une même population. C'est un des éléments, intraspécifique, de la diversité génétique qui est considéré comme facilitant l'adaptation des populations à leur environnement plus ou moins changeant. Il explique notamment des motifs variables (ex : dessins de pelages ou de certaines coquilles d'escargot), ou diverses spécificités (groupes sanguins humains, etc.). Histoire des sciences L'expression a été utilisée pour la première fois pour décrire des différences visibles telle que la couleur du pelage, mais on l'utilise aujourd'hui pour toutes les espèces et tous les types de phénotypes (dont les groupes sanguins). Types de polymorphisme Le

Host genetic predictors of the kynurenine pathway of tryptophan catabolism among treated HIV-infected Ugandans

Yunfei Huang

Objective: Plasma kynurenine/tryptophan ratio, a biomarker of indoleamine 2,3-dioxygenase-1 (IDO) activity, is a strong independent predictor of mortality in HIV-infected Ugandans initiating antiretroviral therapy (ART) and may play a key role in HIV pathogenesis. We performed a genome-wide study to identify potential host genetic determinants of kynurenine/tryptophan ratio in HIV-infected ART-suppressed Ugandans. Design/methods: We performed genome-wide and exome array genotyping and measured plasma kynurenine/tryptophan ratio during the initial 6-12 months of suppressive ART in Ugandans. We evaluated more than 16 million single nucleotide polymorphisms in association with log(10) kynurenine/tryptophan ratio using linear mixed models adjusted for cohort, sex, pregnancy, and ancestry. Results: Among 597 Ugandans, 62% were woman, median age was 35, median baseline CD4(+) cell count was 135 cells/mu l, and median baseline HIV-1 RNA was 5.1 log(10) copies/ml. Several polymorphisms in candidate genes TNF, IFNGR1, and TLR4 were associated with log(10) kynurenine/tryptophan ratio (P < 5.0 x 10(-5)). An intergenic polymorphism between CSPG5 and ELP6 was genome-wide significant, whereas several others exhibited suggestive associations (P < 5.0 x 10(-7)), including genes encoding protein tyrosine phosphatases (PTPRM and PTPRN2) and the vitamin D metabolism gene, CYP24A1. Several of these single nucleotide polymorphisms were associated with markers of inflammation, coagulation, and monocyte activation, but did not replicate in a small US cohort (N = 262; 33% African-American). Conclusion: Our findings highlight a potentially important role of IFN-gamma, TNF-alpha, and Toll-like receptor signaling in determining IDO activity and subsequent mortality risk in HIV-infected ART-suppressed Ugandans. These results also identify potential novel pathways involved in IDO immunoregulation. Further studies are needed to confirm these findings in treated HIV-infected populations. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

Lippincott Williams & Wilkins2016

A Baseline Cellular Antiviral State Is Maintained by cGAS and Its Most Frequent Naturally Occurring Variant rs610913

Jacques Fellay, Christian Axel Wandall Thorball, Shuting Xu

Upon recognition of aberrantly located DNA, the innate immune sensor cyclic GMP-AMP synthase (cGAS) activates stimulator of IFN genes (STING)/IFN regulatory factor (IRF)3-driven antiviral responses. In this study, we characterized the ability of a specific variant of the human cGAS-encoding gene MB21D1, rs610913, to alter cGAS-mediated DNA sensing and viral infection. rs610913 is a frequent G>T polymorphism resulting in a P261H exchange in the cGAS protein. Data from the International Collaboration for the Genomics of HIV suggested that rs610913 nominally associates with HIV-1 acquisition in vivo. Molecular modeling of cGAS(P261H) hinted toward the possibility for an additional binding site for a potential cellular cofactor in cGAS dimers. However, cGAS(wild-type [WT]) or cGAS(P261H)-reconstituted THP-1 cGAS knockout cells shared steady-state expression of IFN-stimulated genes, as opposed to cells expressing the enzymatically inactive cGAS(G212A/S(213)A). Accordingly, cGAS(WT) and cGAS(P261H) cells were less susceptible to lentiviral transduction and infection with HIV-1, HSV-1, and Chikungunya virus as compared with cGAS knockout or cGAS(G212A/S(213)A) cells. Upon DNA challenge, innate immune activation appeared to be mildly reduced upon expression of cGAS(P261H) compared with cGAS(WT). Finally, DNA challenge of PBMCs from donors homozygously expressing rs610913 provoked a trend toward a slightly reduced type I IFN response as compared with PBMCs from GG donors. Taken together, the steady-state activity of cGAS maintains a baseline antiviral state rendering cells more refractory to IFN-stimulated gene-sensitive viral infections. rs610913 failed to grossly differ phenotypically from the WT gene, suggesting that cGAS(P261H) and WT cGAS share a similar ability to sense viral infections in vivo.

AMER ASSOC IMMUNOLOGISTS2022

The evolution of gene expression and binding specificity of the largest transcription factor family in primates

Jeffrey David Jensen, Adamantia Kapopoulou, Lisha Mathew, Didier Trono

The KRAB-containing zinc finger (KRAB-ZF) proteins represent the largest family of transcription factors (TFs) in humans, yet for the great majority, their function and specific genomic target remain unknown. However, it has been shown that a large fraction of these genes arose from segmental duplications, and that they have expanded in gene and zinc finger number throughout vertebrate evolution. To determine whether this expansion is linked to selective pressures acting on different domains, we have manually curated all KRAB-ZF genes present in the human genome together with their orthologous genes in three closely related species and assessed the evolutionary forces acting at the sequence level as well as on their expression profiles. We provide evidence that KRAB-ZFs can be separated into two categories according to the polymorphism present in their DNA-contacting residues. Those carrying a nonsynonymous single nucleotide polymorphism (SNP) in their DNA-contacting amino acids exhibit significantly reduced expression in all tissues, have emerged in a recent lineage, and seem to be less strongly constrained evolutionarily than those without such a polymorphism. This work provides evidence for a link between age of the TF, as well as polymorphism in their DNA-contacting residues and expression levels-both of which may be jointly affected by selection.

Wiley-Blackwell2016