scholarly journals Population variation of miRNAs and isomiRs and their impact on human immunity to infection

2020 ◽  
Author(s):  
Maxime Rotival ◽  
Katherine J Siddle ◽  
Martin Silvert ◽  
Julien Pothlichet ◽  
Hélène Quach ◽  
...  
Keyword(s):  
Mirna Expression ◽  
Influenza A ◽  
Population Level ◽  
Population Variation ◽  
European Ancestry ◽  
Population Differences ◽  
Rich Cluster ◽  
Protein Coding ◽  
Expression Variability ◽  
A Minor

ABSTRACTMicroRNAs (miRNAs) are key epigenetic regulators of the immune system, yet their variation and contribution to intra- and inter-population differences in immune responses is poorly characterized. Here, we generated 977 miRNA-sequencing profiles from primary monocytes, from individuals of African and European ancestry, following activation of three TLR pathways (TLR4, TLR1/2 and TLR7/8) or infection with Influenza A virus. We find that immune activation leads to important modifications in the miRNA and isomiR repertoire, particularly in response to viral challenges. These changes are, however, much weaker than those observed for protein-coding genes, suggesting stronger selective constraints on the miRNA response to stimulation. This is supported by the limited genetic control of miRNA expression variability (miR-QTLs) — and the lower occurrence of G×E interactions — in stark contrast with eQTLs that are largely context-dependent. We also detect marked differences in miRNA expression between populations, which are mostly driven by non-genetic factors. Yet, on average, miR-QTLs explain ~60% of population differences in expression of their cognate miRNAs, and, in some cases, evolve adaptively, as shown in Europeans for a miRNA-rich cluster on chromosome 14. Finally, integrating miRNA and mRNA data from the same individuals, we provide evidence that the canonical model of miRNA-driven transcript degradation has a minor impact on miRNA-mRNA correlations, which are, in our setting, mainly driven by co-transcription. Together, our results shed new light onto the factors driving miRNA and isomiR diversity at the population level, and constitute a useful resource for evaluating their role in host differences of immunity to infection.

scholarly journals MITOMIX, an Algorithm to Reconstruct Population Admixture Histories Indicates Ancient European Ancestry of Modern Hungarians

2018 ◽  
Author(s):  
Zoltán Maróti ◽  
Tibor Török ◽  
Endre Neparáczki ◽  
István Raskó ◽  
István Nagy ◽  
...  
Keyword(s):  
Bronze Age ◽  
Population Level ◽  
European Ancestry ◽  
Human Populations ◽  
Population Admixture ◽  
Genetic Composition ◽  
Depth Analysis ◽  
A Minor ◽  
Past Population ◽  
Shed Light

AbstractBy making use of the increasing number of available mitogenomes we propose a novel population genetic distance metric, named Shared Haplogroup Distance (SHD). Unlike FST, SHD is a true mathematical distance that complies with all metric axioms, which enables our new algorithm (MITOMIX) to detect population-level admixture based on SHD minimum optimization. In order to demonstrate the effectiveness of our methodology we analyzed the relation of 62 modern and 25 ancient Eurasian human populations, and compared our results with the most widely used FST calculation. We also sequenced and performed an in-depth analysis of 272 modern Hungarian mtDNA genomes to shed light on the genetic composition of modern Hungarians. MITOMIX analysis showed that in general admixture occurred between neighboring populations, but in some cases it also indicated admixture with migrating populations. SHD and MITOMIX analysis comply with known genetic data and shows that in case of closely related and/or admixing populations, SHD gives more realistic results and provides better resolution than FST. Our results suggest that the majority of modern Hungarian maternal lineages have Late Neolith/Bronze Age European origins (partially shared also with modern Danish, Belgian/Dutch and Basque populations), and a smaller fraction originates from surrounding (Serbian, Croatian, Slovakian, Romanian) populations. However only a minor genetic contribution (<3%) was identified from the IXth Hungarian Conquerors whom are deemed to have brought Hungarians to the Carpathian Basin. Our analysis shows that SHD and MITOMIX can augment previous methods by providing novel insights into past population processes.

scholarly journals Survival dynamical systems: individual-level survival analysis from population-level epidemic models

2019 ◽  
Vol 10 (1) ◽  
pp. 20190048 ◽  
Author(s):  
Wasiur R. KhudaBukhsh ◽  
Boseung Choi ◽  
Eben Kenah ◽  
Grzegorz A. Rempała
Keyword(s):  
Influenza A ◽  
Large Population ◽  
Synthetic Data ◽  
Population Level ◽  
Epidemic Models ◽  
Hazard Functions ◽  
Individual Level ◽  
Washington State University ◽  
Influenza A H1n1 ◽  
The Individual

In this paper, we show that solutions to ordinary differential equations describing the large-population limits of Markovian stochastic epidemic models can be interpreted as survival or cumulative hazard functions when analysing data on individuals sampled from the population. We refer to the individual-level survival and hazard functions derived from population-level equations as a survival dynamical system (SDS). To illustrate how population-level dynamics imply probability laws for individual-level infection and recovery times that can be used for statistical inference, we show numerical examples based on synthetic data. In these examples, we show that an SDS analysis compares favourably with a complete-data maximum-likelihood analysis. Finally, we use the SDS approach to analyse data from a 2009 influenza A(H1N1) outbreak at Washington State University.

scholarly journals IGHV1-69 polymorphism modulates anti-influenza antibody repertoires, correlates with IGHV utilization shifts and varies by ethnicity

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Yuval Avnir ◽  
Corey T. Watson ◽  
Jacob Glanville ◽  
Eric C. Peterson ◽  
Aimee S. Tallarico ◽  
...  
Keyword(s):  
B Cell ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Cell Function ◽  
Somatic Hypermutation ◽  
Population Level ◽  
Humoral Immune ◽  
Humoral Immune System ◽  
The Individual ◽  
Universal Influenza Vaccine

Abstract IGHV polymorphism provides a rich source of humoral immune system diversity. One important example is the IGHV1-69 germline gene where the biased use of alleles that encode the critical CDR-H2 Phe54 (F-alleles) to make broadly neutralizing antibodies (HV1-69-sBnAb) to the influenza A hemagglutinin stem domain has been clearly established. However, whether IGHV1-69 polymorphism can also modulate B cell function and Ab repertoire expression through promoter and copy number (CN) variations has not been reported, nor has whether IGHV1-69 allelic distribution is impacted by ethnicity. Here we studied a cohort of NIH H5N1 vaccinees and demonstrate for the first time the influence of IGHV1-69 polymorphism on V-segment usage, somatic hypermutation and B cell expansion that elucidates the dominance of F-alleles in HV1-69-sBnAbs. We provide evidence that Phe54/Leu54 (F/L) polymorphism correlates with shifted repertoire usage of other IGHV germline genes. In addition, we analyzed ethnically diverse individuals within the 1000 genomes project and discovered marked variations in F- and L- genotypes and CN among the various ethnic groups that may impact HV1-69-sBnAb responses. These results have immediate implications for understanding HV1-69-sBnAb responses at the individual and population level and for the design and implementation of “universal” influenza vaccine.

scholarly journals Population-Level Antibody Estimates to Novel Influenza A/H7N9

2013 ◽  
Vol 208 (4) ◽  
pp. 554-558 ◽  
Author(s):  
Maciej F. Boni ◽  
Nguyen Van Vinh Chau ◽  
Nguyen Dong ◽  
Stacy Todd ◽  
Nguyen Thi Duy Nhat ◽  
...  
Keyword(s):  
Influenza A ◽  
Population Level ◽  
Novel Influenza A

scholarly journals Genetics of Type 2 Diabetes

2011 ◽  
Vol 57 (2) ◽  
pp. 241-254 ◽  
Author(s):  
Emma Ahlqvist ◽  
Tarunveer Singh Ahluwalia ◽  
Leif Groop
Keyword(s):  
Type 2 Diabetes ◽  
Rare Variants ◽  
Disease Risk ◽  
Association Studies ◽  
Population Level ◽  
Great Effort ◽  
Disease Pathogenesis ◽  
Disease Etiology ◽  
A Minor

BACKGROUND Type 2 diabetes (T2D) is a complex disorder that is affected by multiple genetic and environmental factors. Extensive efforts have been made to identify the disease-affecting genes to better understand the disease pathogenesis, find new targets for clinical therapy, and allow prediction of disease. CONTENT Our knowledge about the genes involved in disease pathogenesis has increased substantially in recent years, thanks to genomewide association studies and international collaborations joining efforts to collect the huge numbers of individuals needed to study complex diseases on a population level. We have summarized what we have learned so far about the genes that affect T2D risk and their functions. Although more than 40 loci associated with T2D or glycemic traits have been reported and reproduced, only a minor part of the genetic component of the disease has been explained, and the causative variants and affected genes are unknown for many of the loci. SUMMARY Great advances have recently occurred in our understanding of the genetics of T2D, but much remains to be learned about the disease etiology. The genetics of T2D has so far been driven by technology, and we now hope that next-generation sequencing will provide important information on rare variants with stronger effects. Even when variants are known, however, great effort will be required to discover how they affect disease risk.

MYC stimulates EZH2 expression by repression of its negative regulator miR-26a

Blood ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 4202-4212 ◽  
Author(s):  
Sandrine Sander ◽  
Lars Bullinger ◽  
Kay Klapproth ◽  
Katja Fiedler ◽  
Hans A. Kestler ◽  
...  
Keyword(s):  
Mirna Expression ◽  
Cell Cycle Progression ◽  
Ectopic Expression ◽  
Negative Regulator ◽  
Protein Coding ◽  
Myc Oncogene ◽  
Polycomb Protein ◽  
Ezh2 Expression ◽  
Mirna Expression Profiling ◽  
The Impact

Abstract The MYC oncogene, which is commonly mutated/amplified in tumors, represents an important regulator of cell growth because of its ability to induce both proliferation and apoptosis. Recent evidence links MYC to altered miRNA expression, thereby suggesting that MYC-regulated miRNAs might contribute to tumorigenesis. To further analyze the impact of MYC-regulated miRNAs, we investigated a murine lymphoma model harboring the MYC transgene in a Tet-off system to control its expression. Microarray-based miRNA expression profiling revealed both known and novel MYC targets. Among the miRNAs repressed by MYC, we identified the potential tumor suppressor miR-26a, which possessed the ability to attenuate proliferation in MYC-dependent cells. Interestingly, miR-26a was also found to be deregulated in primary human Burkitt lymphoma samples, thereby probably being of clinical relevance. Although today only few miRNA targets have been identified in human disease, we could show that ectopic expression of miR-26a influenced cell cycle progression by targeting the bona fide oncogene EZH2, a Polycomb protein and global regulator of gene expression yet unknown to be regulated by miRNAs. Thus, in addition to directly targeting protein-coding genes, MYC modulates genes important to oncogenesis via deregulation of miRNAs, thereby vitally contributing to MYC-induced lymphomagenesis.

scholarly journals Influenza "A": Account of a Minor Epidemic

BMJ ◽  
1944 ◽  
Vol 1 (4331) ◽  
pp. 42-43 ◽  
Author(s):  
T. H. Donnelly ◽  
H. P. Hughes ◽  
D. Robertson ◽  
E. Philipp
Keyword(s):  
Influenza A ◽  
A Minor

scholarly journals A review of mathematical models of influenza A infections within a host or cell culture: lessons learned and challenges ahead

2021 ◽  
Author(s):  
Catherine A. A. Beauchemin ◽  
Andreas Handel
Keyword(s):  
Public Health ◽  
Cell Culture ◽  
Mathematical Models ◽  
Influenza A ◽  
Influenza Infection ◽  
Population Level ◽  
Host Population ◽  
Lessons Learned ◽  
Infection Dynamics ◽  
Individual Host

Most mathematical models used to study the dynamics of influenza A have thus far focused on the between-host population level, with the aim to inform public health decisions regarding issues such as drug and social distancing intervention strategies, antiviral stockpiling or vaccine distribution. Here, we investigate mathematical modeling of influenza infection spread at a different scale; namely that occurring within an individual host or a cell culture. We review the models that have been developed in the last decades and discuss their contributions to our understanding of the dynamics of influenza infections. We review kinetic parameters (e.g., viral clearance rate, lifespan of infected cells) and values obtained through fitting mathematical models, and contrast them with values obtained directly from experiments. We explore the symbiotic role of mathematical models and experimental assays in improving our quantitative understanding of influenza infection dynamics. We also discuss the challenges in developing better, more comprehensive models for the course of influenza infections within a host or cell culture. Finally, we explain the contributions of such modeling efforts to important public health issues, and suggest future modeling studies that can help to address additional questions relevant to public health.

scholarly journals Single-Cell and Bulk RNA-Sequencing Reveal Differences in Monocyte Susceptibility to Influenza A Virus Infection Between Africans and Europeans

2021 ◽  
Vol 12 ◽  
Author(s):  
Mary B. O’Neill ◽  
Hélène Quach ◽  
Julien Pothlichet ◽  
Yann Aquino ◽  
Aurélie Bisiaux ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Single Cell ◽  
Rna Sequencing ◽  
Influenza A Virus ◽  
Influenza A ◽  
Type I Interferon ◽  
African Ancestry ◽  
Cellular Heterogeneity ◽  
European Ancestry ◽  
Type I

There is considerable inter-individual and inter-population variability in response to viruses. The potential of monocytes to elicit type-I interferon responses has attracted attention to their role in viral infections. Here, we use single-cell RNA-sequencing to characterize the role of cellular heterogeneity in human variation of monocyte responses to influenza A virus (IAV) exposure. We show widespread inter-individual variability in the percentage of IAV-infected monocytes. Notably, individuals with high cellular susceptibility to IAV are characterized by a lower activation at basal state of an IRF/STAT-induced transcriptional network, which includes antiviral genes such as IFITM3, MX1 and OAS3. Upon IAV challenge, we find that cells escaping viral infection display increased mRNA expression of type-I interferon stimulated genes and decreased expression of ribosomal genes, relative to both infected cells and those never exposed to IAV. We also uncover a stronger resistance of CD16+ monocytes to IAV infection, together with CD16+-specific mRNA expression of IL6 and TNF in response to IAV. Finally, using flow cytometry and bulk RNA-sequencing across 200 individuals of African and European ancestry, we observe a higher number of CD16+ monocytes and lower susceptibility to IAV infection among monocytes from individuals of African-descent. Based on these data, we hypothesize that higher basal monocyte activation, driven by environmental factors and/or weak-effect genetic variants, underlies the lower cellular susceptibility to IAV infection of individuals of African ancestry relative to those of European ancestry. Further studies are now required to investigate how such cellular differences in IAV susceptibility translate into population differences in clinical outcomes and susceptibility to severe influenza.

Influenza A Virus Subpopulations and Their Implication in Pathogenesis and Vaccine Development

2020 ◽  
Vol 8 (1) ◽  
pp. 247-267 ◽  
Author(s):  
Amir Ghorbani ◽  
John M. Ngunjiri ◽  
Chang-Won Lee
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Vaccine Development ◽  
Current Knowledge ◽  
Genomic Diversity ◽  
Biologically Active ◽  
Virus Particles ◽  
Live Attenuated Influenza Vaccine ◽  
Minor Portion ◽  
A Minor

The concept of influenza A virus (IAV) subpopulations emerged approximately 75 years ago, when Preben von Magnus described “incomplete” virus particles that interfere with the replication of infectious virus. It is now widely accepted that infectious particles constitute only a minor portion of biologically active IAV subpopulations. The IAV quasispecies is an extremely diverse swarm of biologically and genetically heterogeneous particle subpopulations that collectively influence the evolutionary fitness of the virus. This review summarizes the current knowledge of IAV subpopulations, focusing on their biologic and genomic diversity. It also discusses the potential roles IAV subpopulations play in virus pathogenesis and live attenuated influenza vaccine development.

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