MalHaploFreq: A computer programme for estimating malaria haplotype frequencies from blood samples

<p>Abstract</p> <p>Background</p> <p>Molecular markers, particularly those associated with drug resistance, are important surveillance tools that can inform policy choice. People infected with <it>falciparum </it>malaria often contain several genetically-distinct clones of the parasite; genotyping the patients' blood reveals whether or not the marker is present (i.e. its prevalence), but does not reveal its frequency. For example a person with four malaria clones may contain both mutant and wildtype forms of a marker but it is not possible to distinguish the relative frequencies of the mutant and wildtypes i.e. 1:3, 2:2 or 3:1.</p> <p>Methods</p> <p>An appropriate method for obtaining frequencies from prevalence data is by Maximum Likelihood analysis. A computer programme has been developed that allows the frequency of markers, and haplotypes defined by up to three codons, to be estimated from blood phenotype data.</p> <p>Results</p> <p>The programme has been fully documented [see Additional File <supplr sid="S1">1</supplr>] and provided with a user-friendly interface suitable for large scale analyses. It returns accurate frequencies and 95% confidence intervals from simulated dataset sets and has been extensively tested on field data sets.</p> <suppl id="S1"> <title> <p>Additional File 1</p> </title> <text> <p>User manual for MalHaploFreq.</p> </text> <file name="1475-2875-7-130-S1.pdf"> <p>Click here for file</p> </file> </suppl> <p>Conclusion</p> <p>The programme is included [see Additional File <supplr sid="S2">2</supplr>] and/or may be freely downloaded from <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>. It can then be used to extract molecular marker and haplotype frequencies from their prevalence in human blood samples. This should enhance the use of frequency data to inform antimalarial drug policy choice.</p> <suppl id="S2"> <title> <p>Additional File 2</p> </title> <text> <p>executable programme compiled for use on DOS or windows</p> </text> <file name="1475-2875-7-130-S2.exe"> <p>Click here for file</p> </file> </suppl

Somatic mosaicism and common genetic variation contribute to the risk of very-early-onset inflammatory bowel disease

Abstract: Very-early-onset inflammatory bowel disease (VEO-IBD) is a heterogeneous phenotype associated with a spectrum of rare Mendelian disorders. Here, we perform whole-exome-sequencing and genome-wide genotyping in 145 patients (median age-at-diagnosis of 3.5 years), in whom no Mendelian disorders were clinically suspected. In five patients we detect a primary immunodeficiency or enteropathy, with clinical consequences (XIAP, CYBA, SH2D1A, PCSK1). We also present a case study of a VEO-IBD patient with a mosaic de novo, pathogenic allele in CYBB. The mutation is present in ~70% of phagocytes and sufficient to result in defective bacterial handling but not life-threatening infections. Finally, we show that VEO-IBD patients have, on average, higher IBD polygenic risk scores than population controls (99 patients and 18,780 controls; P < 4 × 10−10), and replicate this finding in an independent cohort of VEO-IBD cases and controls (117 patients and 2,603 controls; P < 5 × 10−10). This discovery indicates that a polygenic component operates in VEO-IBD pathogenesis

Expression of a GRM3 splice variant is increased in the dorsolateral prefrontal cortex of individuals carrying a schizophrenia risk SNP.

Genetic variation in the metabotropic glutamate receptor 3 (GRM3, mGluR3) has been associated with schizophrenia, but the mechanism by which it confers risk is unknown. Previously, we reported the existence of a splice variant, GRM3Delta4, which has an exon 4 deletion and encodes a truncated form of the receptor that is expressed in brain. The aim of the present study was to determine whether expression of this splice variant is altered in individuals with schizophrenia and is affected by a risk genotype. We measured GRM3 and GRM3Delta4 transcripts in human dorsolateral prefrontal cortex (DLPFC) and hippocampus of the CBDB/NIMH collection ( approximately 70 controls, approximately 30 schizophrenia patients) and in the DLPFC of the Stanley Array Collection. Expression data of GRM3 mRNA in the DLPFC were inconsistent: GRM3 was increased in schizophrenia patients in the CBDB/NIMH collection, but not in the Stanley Array Collection. GRM3 expression did not change in the frontal cortex of rats treated chronically with haloperidol or clozapine. An exon 3 SNP previously associated with schizophrenia (rs2228595) predicted increased expression of the GRM3Delta4 splice variant. Our results suggest that rs2228595, or a neighboring SNP in linkage disequilibrium with it, may contribute to risk for schizophrenia by modulating GRM3 splicing