scholarly journals Human P2X7 Pore Function Predicts Allele Linkage Disequilibrium

2006 ◽  
Vol 52 (6) ◽  
pp. 995-1004 ◽  
Author(s):  
Loren C Denlinger ◽  
Douglas B Coursin ◽  
Kathleen Schell ◽  
Giuditta Angelini ◽  
Dawn N Green ◽  
...  
Keyword(s):  
Linkage Disequilibrium ◽  
Linkage Analysis ◽  
Whole Blood ◽  
Interleukin 10 ◽  
Genomic Variation ◽  
Loss Of Function ◽  
Roc Curve Analysis ◽  
Activity Data ◽  
Diagnostic Threshold ◽  
Sequence Variations

Abstract Background: Innate immune response amplification is achieved by leukocyte expression of the purinergic nucleotide receptor P2X7, an extracellular nucleotide-gated pore. Previously, low P2X7 pore activity in whole blood was associated with loss-of-function genotypes in correlation with a decreased ratio of lipopolysaccharide-stimulated tumor necrosis factor-α to interleukin-10, of relevance to a variety of infectious and inflammatory disorders. We hypothesized that evaluation of participants with discordance between the P2X7 genotype and pore status would disclose additional alleles, linkage disequilibrium, and novel functional correlates of genotype to phenotype. Methods: Comparison of whole-blood pore results with restriction fragment length polymorphism data for known loss-of-function genotypes from 200 healthy participants optimized the diagnostic threshold for low pore activity by ROC curve analysis. We identified novel alleles and inferred haplotypes by sequencing outlier genomic templates and by linkage analysis. Results: With a refined threshold of low activity, a normal pore result had only a 2% probability of association with known loss-of-function variants. By contrast, the positive predictive value of low pore activity was 59% for identifying known alleles. DNA samples from this discordant group contained 28 P2X7 sequence variations. Linkage analysis demonstrated that A1513C, T1729A, and G946A are inherited independently from one another, although these loss-of-function variants are in disequilibrium with other alleles. When we segregated pore activity data according to genotypes, nonsynonymous sequence variations (G474A and A1405G) appeared to exhibit modulatory effects on P2X7 pore activity. Conclusions: Direct analysis of pore activity demonstrates functional interactions between P2X7 alleles. The performance characteristics of the whole-blood pore assay enables correlation of genomic variation with concomitant investigation of functional performance in clinical studies.

scholarly journals Genomic Variation in IbA10G2 and Other Patient-Derived Cryptosporidium hominis Subtypes

2016 ◽  
Vol 55 (3) ◽  
pp. 844-858 ◽  
Author(s):  
Per Sikora ◽  
Sofia Andersson ◽  
Jadwiga Winiecka-Krusnell ◽  
Björn Hallström ◽  
Cecilia Alsmark ◽  
...  
Keyword(s):  
Parasite Burden ◽  
Genomic Variation ◽  
Loss Of Function ◽  
Oocyst Wall ◽  
Gene Encoding ◽  
Cryptosporidium Hominis ◽  
Content Type ◽  
Successful Isolation ◽  
Target Dna ◽  
Stool Samples

ABSTRACTIn order to improve genotyping and epidemiological analysis ofCryptosporidiumspp., genomic data need to be generated directly from a broad range of clinical specimens. Utilizing a robust method that we developed for the purification and generation of amplified target DNA, we present its application for the successful isolation and whole-genome sequencing of 14 differentCryptosporidium hominispatient specimens. Six isolates of subtype IbA10G2 were analyzed together with a single representative each of 8 other subtypes: IaA20R3, IaA23R3, IbA9G3, IbA13G3, IdA14, IeA11G3T3, IfA12G1, and IkA18G1. Parasite burden was measured over a range of more than 2 orders of magnitude for all samples, while the genomes were sequenced to mean depths of between 17× and 490× coverage. Sequence homology-based functional annotation identified several genes of interest, including the gene encodingCryptosporidiumoocyst wall protein 9 (COWP9), which presented a predicted loss-of-function mutation in all the sequence subtypes, except for that seen with IbA10G2, which has a sequence identical to theCryptosporidium parvumreference Iowa II sequence. Furthermore, phylogenetic analysis showed that all the IbA10G2 genomes form a monophyletic clade in theC. hoministree as expected and yet display some heterogeneity within the IbA10G2 subtype. The current report validates the aforementioned method for isolating and sequencingCryptosporidiumdirectly from clinical stool samples. In addition, the analysis demonstrates the potential in mining data generated from sequencing multiple whole genomes ofCryptosporidiumfrom human fecal samples, while alluding to the potential for a higher degree of genotyping withinCryptosporidiumepidemiology.

Joint Linkage and Linkage Disequilibrium Mapping of Quantitative Trait Loci in Natural Populations

Genetics ◽  
2002 ◽  
Vol 160 (2) ◽  
pp. 779-792 ◽  
Author(s):  
Rongling Wu ◽  
Chang-Xing Ma ◽  
George Casella
Keyword(s):  
Linkage Disequilibrium ◽  
Quantitative Trait Loci ◽  
Linkage Analysis ◽  
Quantitative Trait ◽  
Genome Mapping ◽  
Linkage Disequilibrium Mapping ◽  
Allelic Association ◽  
Mapping Strategy ◽  
Trait Loci ◽  
New Strategy

AbstractLinkage analysis and allelic association (also referred to as linkage disequilibrium) studies are two major approaches for mapping genes that control simple or complex traits in plants, animals, and humans. But these two approaches have limited utility when used alone, because they use only part of the information that is available for a mapping population. More recently, a new mapping strategy has been designed to integrate the advantages of linkage analysis and linkage disequilibrium analysis for genome mapping in outcrossing populations. The new strategy makes use of a random sample from a panmictic population and the open-pollinated progeny of the sample. In this article, we extend the new strategy to map quantitative trait loci (QTL), using molecular markers within the EM-implemented maximum-likelihood framework. The most significant advantage of this extension is that both linkage and linkage disequilibrium between a marker and QTL can be estimated simultaneously, thus increasing the efficiency and effectiveness of genome mapping for recalcitrant outcrossing species. Simulation studies are performed to test the statistical properties of the MLEs of genetic and genomic parameters including QTL allele frequency, QTL effects, QTL position, and the linkage disequilibrium of the QTL and a marker. The potential utility of our mapping strategy is discussed.

scholarly journals Examining the effect of linkage disequilibrium on multipoint linkage analysis

BMC Genetics ◽  
2005 ◽  
Vol 6 (Suppl 1) ◽  
pp. S83 ◽  
Author(s):  
Qiqing Huang ◽  
Sanjay Shete ◽  
Michael Swartz ◽  
Christopher I Amos
Keyword(s):  
Linkage Disequilibrium ◽  
Linkage Analysis ◽  
Multipoint Linkage Analysis ◽  
Multipoint Linkage

scholarly journals Aberrant Concentrations of Liver-Derived Plasma Albumin mRNA in Liver Pathologies

2010 ◽  
Vol 56 (1) ◽  
pp. 82-89 ◽  
Author(s):  
Rebecca WY Chan ◽  
John Wong ◽  
Henry LY Chan ◽  
Tony SK Mok ◽  
Wyatt YW Lo ◽  
...  
Keyword(s):  
Whole Blood ◽  
Marrow Transplant ◽  
Polymorphism Analysis ◽  
Transplant Recipients ◽  
Pcr Assay ◽  
Roc Curve Analysis ◽  
Single Nucleotide ◽  
Tissue Compartments ◽  
Albumin Mrna ◽  
Liver Cell Death

Abstract Background: We hypothesized that liver-derived mRNA, such as ALB (albumin) mRNA, would be released into human plasma with liver cell death. Methods: We genotyped ALB mRNA molecules in samples of plasma and whole blood from liver and bone marrow transplant recipients by RNA single-nucleotide polymorphism analysis. Plasma and whole blood ALB mRNA genotypes were compared with the DNA genotypes of the recipients and donors. A reverse-transcription quantitative real-time PCR assay was used to measure plasma ALB mRNA concentrations in 107 patients [hepatocellular carcinoma (HCC), cirrhosis, or chronic hepatitis B (CHB)] and 207 healthy controls. Results: The RNA genotype data revealed ALB mRNA in plasma to be liver derived, whereas tissue compartments other than the liver also contributed to the ALB mRNA detected in whole blood. Statistically significant increases in plasma ALB mRNA concentrations were observed for HCC, cirrhosis, and active CHB, compared with controls. A cutoff of 835 copies/mL of plasma ALB mRNA identified by ROC curve analysis showed 85.5% diagnostic sensitivity and 92.8% diagnostic specificity for the detection of liver pathologies. Only 21.5% of patients with liver pathologies had increased alanine aminotransferase (ALT) activities, whereas 73.8% had increased plasma ALB mRNA concentrations. Only 48.6% of the HCC patients had increased serum α-fetoprotein concentrations, whereas 91.4% had increased plasma ALB mRNA concentrations. Conclusions: ALB mRNA is liver specific in plasma, but not in whole blood. Plasma ALB mRNA is increased in some liver pathologies and may be more diagnostically sensitive than α-fetoprotein and ALT.

Linkage disequilibrium and linkage analysis of the glucose-6-phosphatase gene

1998 ◽  
Vol 103 (2) ◽  
pp. 199-203 ◽  
Author(s):  
L.-J. C. Wong ◽  
Min-Hui Liang ◽  
Wuh-Liang Hwu ◽  
Ching-Wan Lam
Keyword(s):  
Linkage Disequilibrium ◽  
Linkage Analysis
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