Identifying Tmem59 related gene regulatory network of mouse neural stem cell from a compendium of expression profiles

<p>Abstract</p> <p>Background</p> <p>Neural stem cells offer potential treatment for neurodegenerative disorders, such like Alzheimer's disease (AD). While much progress has been made in understanding neural stem cell function, a precise description of the molecular mechanisms regulating neural stem cells is not yet established. This lack of knowledge is a major barrier holding back the discovery of therapeutic uses of neural stem cells. In this paper, the regulatory mechanism of mouse neural stem cell (NSC) differentiation by <it>tmem59 </it>is explored on the genome-level.</p> <p>Results</p> <p>We identified regulators of <it>tmem59 </it>during the differentiation of mouse NSCs from a compendium of expression profiles. Based on the microarray experiment, we developed the parallelized SWNI algorithm to reconstruct gene regulatory networks of mouse neural stem cells. From the inferred <it>tmem59 </it>related gene network including 36 genes, <it>pou6f1 </it>was identified to regulate <it>tmem59 </it>significantly and might play an important role in the differentiation of NSCs in mouse brain. There are four pathways shown in the gene network, indicating that <it>tmem59 </it>locates in the downstream of the signalling pathway. The real-time RT-PCR results shown that the over-expression of <it>pou6f1 </it>could significantly up-regulate <it>tmem59 </it>expression in C17.2 NSC line. 16 out of 36 predicted genes in our constructed network have been reported to be AD-related, including <it>Ace</it>, <it>aqp1</it>, <it>arrdc3</it>, <it>cd14</it>, <it>cd59a</it>, <it>cds1</it>, <it>cldn1</it>, <it>cox8b</it>, <it>defb11</it>, <it>folr1</it>, <it>gdi2</it>, <it>mmp3</it>, <it>mgp</it>, <it>myrip</it>, <it>Ripk4</it>, <it>rnd3</it>, and <it>sncg</it>. The localization of <it>tmem59 </it>related genes and functional-related gene groups based on the Gene Ontology (GO) annotation was also identified.</p> <p>Conclusions</p> <p>Our findings suggest that the expression of <it>tmem59 </it>is an important factor contributing to AD. The parallelized SWNI algorithm increased the efficiency of network reconstruction significantly. This study enables us to highlight novel genes that may be involved in NSC differentiation and provides a shortcut to identifying genes for AD.</p

Reduced purine biosynthesis in humans after their divergence from Neandertals

We analyze the metabolomes of humans, chimpanzees, and macaques in muscle, kidney and three different regions of the brain. Although several compounds in amino acid metabolism occur at either higher or lower concentrations in humans than in the other primates, metabolites downstream of adenylosuccinate lyase, which catalyzes two reactions in purine synthesis, occur at lower concentrations in humans. This enzyme carries an amino acid substitution that is present in all humans today but absent in Neandertals. By introducing the modern human substitution into the genomes of mice, as well as the ancestral, Neandertal-like substitution into the genomes of human cells, we show that this amino acid substitution contributes to much or all of the reduction of de novo synthesis of purines in humans

Identification of Sequence Variants in Genetic Disease-Causing Genes Using Targeted Next-Generation Sequencing

Identification of gene variants plays an important role in research on and diagnosis of genetic diseases. A combination of enrichment of targeted genes and next-generation sequencing (targeted DNA-HiSeq) results in both high efficiency and low cost for targeted sequencing of genes of interest.To identify mutations associated with genetic diseases, we designed an array-based gene chip to capture all of the exons of 193 genes involved in 103 genetic diseases. To evaluate this technology, we selected 7 samples from seven patients with six different genetic diseases resulting from six disease-causing genes and 100 samples from normal human adults as controls. The data obtained showed that on average, 99.14% of 3,382 exons with more than 30-fold coverage were successfully detected using Targeted DNA-HiSeq technology, and we found six known variants in four disease-causing genes and two novel mutations in two other disease-causing genes (the STS gene for XLI and the FBN1 gene for MFS) as well as one exon deletion mutation in the DMD gene. These results were confirmed in their entirety using either the Sanger sequencing method or real-time PCR.Targeted DNA-HiSeq combines next-generation sequencing with the capture of sequences from a relevant subset of high-interest genes. This method was tested by capturing sequences from a DNA library through hybridization to oligonucleotide probes specific for genetic disorder-related genes and was found to show high selectivity, improve the detection of mutations, enabling the discovery of novel variants, and provide additional indel data. Thus, targeted DNA-HiSeq can be used to analyze the gene variant profiles of monogenic diseases with high sensitivity, fidelity, throughput and speed