Impact Of Haplotypes Research Articles

AlphaFold2 Reveals Structural Patterns of Seasonal Haplotype Diversification in SARS-CoV-2 Spike Protein Variants.

The slow experimental acquisition of high-quality atomic structures of the rapidly changing proteins of the COVID-19 virus challenges vaccine and therapeutic drug development efforts. Fortunately, deep learning tools such as AlphaFold2 can quickly generate reliable models of atomic structure at experimental resolution. Current modeling studies have focused solely on definitions of mutant constellations of Variants of Concern (VOCs), leaving out the impact of haplotypes on protein structure. Here, we conduct a thorough comparative structural analysis of S-proteins belonging to major VOCs and corresponding latitude-delimited haplotypes that affect viral seasonal behavior. Our approach identified molecular regions of importance as well as patterns of structural recruitment. The S1 subunit hosted the majority of structural changes, especially those involving the N-terminal domain (NTD) and the receptor-binding domain (RBD). In particular, structural changes in the NTD were much greater than just translations in three-dimensional space, altering the sub-structures to greater extents. We also revealed a notable pattern of structural recruitment with the early VOCs Alpha and Delta behaving antagonistically by suppressing regions of structural change introduced by their corresponding haplotypes, and the current VOC Omicron behaving synergistically by amplifying or collecting structural change. Remarkably, haplotypes altering the galectin-like structure of the NTD were major contributors to seasonal behavior, supporting its putative environmental-sensing role. Our results provide an extensive view of the evolutionary landscape of the S-protein across the COVID-19 pandemic. This view will help predict important regions of structural change in future variants and haplotypes for more efficient vaccine and drug development.

High-resolution HLA phased haplotype frequencies to predict the success of unrelated donor searches and clinical outcome following hematopoietic stem cell transplantation

HLA matching is a critical factor for successful allogeneic hematopoietic stem cell transplantation. For unrelated donor searches, matching is usually based on high-resolution typing at five HLA loci, looking for a 10/10 match. Some studies have proposed that further matching at the haplotype level could be beneficial for clinical outcome. In this study, we determined the phased haplotypes of 291 patients using family members and segregation analysis. The sum of ranks of the haplotypes carried by patients was used as a surrogate predictor of a successful unrelated donor search. The putative impact of haplotypes was then analyzed in a cohort of 211 recipients transplanted with 10/10 matched unrelated donors. A logistic regression analysis showed a highly significant effect of the haplotypes in the outcome of a search, but we did not find any significant effect on overall survival, graft versus host disease or relapse/progression following HSCT. This study provides useful data for the optimization of unrelated bone marrow donor searches, but does not confirm previous reports that matching at the haplotype level has a clinical impact following HSCT. Due to the extreme polymorphism of HLA genes, further studies are warranted to better understand the many factors at play.

Variants in C-reactive protein and IL-6 genes and susceptibility to obstructive sleep apnea in children: a candidate-gene association study in European American and Southeast European populations

BackgroundPreliminary evidence indicates that variants of the C-reactive protein (CRP) and IL-6 genes might be associated with the presence of obstructive sleep apnea (OSA) in childhood. Thus a candidate-gene association study was conducted to investigate the association of four variants of the CRP gene (1444C/T, −717T/C, 1861C/T, and 1919A/T) and two variants of the IL-6 gene (−174G/C and 597G/A) with OSA in a cohort of European American and Greek children. MethodsThe genetic risk effects were estimated based on the odds ratio (OR) of the allele contrast and the generalized odds ratio (ORG), which is a model-free approach. The mode of inheritance was assessed using the degree of dominance index. The impact of haplotypes was also examined. ResultsIn the American population, the allele contrast and the model-free approach produced significant ORs for the CRP 1444C/T variant (OR, 3.82 [95% confidence interval {CI}, 1.91–7.63] and ORG, 4.37 [95% CI, 1.96–9.76]), respectively, and the mode of inheritance was recessiveness of allele T. Significance was also shown for the CRP 1919A/T variant (OR, 2.45 [95% CI, 1.23–4.85] and ORG, 2.76 [95% CI, 1.26–6.03]) with the mode of inheritance being nondominance of allele T. For the IL-6-174G/C variant, there was an indication of recessiveness of allele C. Finally, the IL-6-174C/IL-6 597A haplotype was associated with OSA. In the Greek population, no association was detected for any variant or haplotype. ConclusionsGenetic variation in the IL-6/CRP pathway was associated with increased risk for OSA in European American children and may account for the higher CRP levels in the context of pediatric OSA compared to Greek children.

Polymorphisms and haplotypes in TLR9 and MYD88 are associated with the development of Hodgkin's lymphoma: a candidate–gene association study

Toll-like receptors (TLRs) and myeloid differentiation primary response protein 88 (MYD88) gene polymorphisms may be involved in the pathogenesis of Hodgkin's lymphoma (HL) through altered immunoregulatory and inflammatory responses. A candidate-gene association study was conducted to investigate the association between TLR9 -1237T>C, TLR9 2848A>G, MYD88 -938C>A and MYD88 1944C>G gene polymorphisms and the risk for HL. The impact of haplotypes was also examined. The study showed that carriership for -1237C and 2848A was associated with an increased risk for HL (odds ratio (OR)=2.53 (1.36-4.71) and OR=6.20 (1.3-28.8)). The MYD88 polymorphisms produced nonsignificant results. The estimated frequencies of the TLR9/1237C-2848A and MYD88/938C-1944G haplotypes were also significantly different between HL and controls (P<0.01). In addition, a significant difference between HL and controls was observed for the TLR9/1237C-TLR9/2848A-MYD88/938C-MYD88/1944C haplotypes (P<0.01). In conclusion, our study showed that TLR polymorphisms, and TLR9 and MYD88 haplotypes are related to the development of HL.