Breakpoint Associated with a novel 2.3 Mb deletion in the VCFS region of 22q11 and the role of Alu (SINE) in recurring microdeletions

BACKGROUND: Chromosome 22q11.2 region is highly susceptible to rearrangement, specifically deletions that give rise to a variety of genomic disorders including velocardiofacial or DiGeorge syndrome. Individuals with this 22q11 microdeletion syndrome are at a greatly increased risk to develop schizophrenia. METHODS: Genotype analysis was carried out on the DNA from a patient with the 22q11 microdeletion using genetic markers and custom primer sets to define the deletion. Bioinformatic analysis was performed for molecular characterization of the deletion breakpoint sequences in this patient. RESULTS: This 22q11 deletion patient was established to have a novel 2.3 Mb deletion with a proximal breakpoint located between genetic markers RH48663 and RH48348 and a distal breakpoint between markers D22S1138 and SHGC-145314. Molecular characterization of the sequences at the breakpoints revealed a 270 bp shared sequence of the breakpoint regions (SSBR) common to both ends that share >90% sequence similarity to each other and also to short interspersed nuclear elements/Alu elements. CONCLUSION: This Alu sequence like SSBR is commonly in the proximity of all known deletion breakpoints of 22q11 region and also in the low copy repeat regions (LCRs). This sequence may represent a preferred sequence in the breakpoint regions or LCRs for intra-chromosomal homologous recombination mechanisms resulting in common 22q11 deletion

Hippocampal Gene Expression Meta-Analysis Identifies Aging and Age-Associated Spatial Learning Impairment (ASLI) Genes and Pathways

<div><p>A number of gene expression microarray studies have been carried out in the past, which studied aging and age-associated spatial learning impairment (ASLI) in the hippocampus in animal models, with varying results. Data from such studies were never integrated to identify the most significant ASLI genes and to understand their effect. In this study we integrated these data involving rats using meta-analysis. Our results show that proper removal of batch effects from microarray data generated from different laboratories is necessary before integrating them for meta-analysis. Our meta-analysis has identified a number of significant differentially expressed genes across age or across ASLI. These genes affect many key functions in the aged compared to the young rats, which include viability of neurons, cell-to-cell signalling and interaction, migration of cells, neuronal growth, and synaptic plasticity. These functional changes due to the altered gene expression may manifest into various neurodegenerative diseases and disorders, some of which leading into syndromic memory impairments. While other aging related molecular changes can result into altered synaptic plasticity simply causing normal aging related non-syndromic learning or spatial learning impairments such as ASLI.</p></div

Top canonical pathways in the IU comparison.

<p>Top canonical pathways in the IU comparison.</p

Top ten most up- and down-regulated genes (based on ES) in the IU comparison.

<p>Top genes identified by IPA are indicated by an asterisk (*). Legends: ES, effect size; pBH, p-value with Benjamini and Hochberg correction; FC, fold change; DE, differentially expressed.</p

Top canonical pathways in the AY comparison.

<p>Top canonical pathways in the AY comparison.</p

Hierarchical clustering of RMA normalized R7 data.

<p>Each color represents a batch of arrays, which were hybridized and processed at the same time. Batch effects are evident even after normalization and before batch adjustment (A) as arrays are mostly clustered in batches. However, following Empirical Bayes adjustment arrays are clustered based on aged and young phenotypes irrespective of batches (B). Leaf labels: A, aged; Y, young; I, impaired; U, unimpaired; c, control.</p

Top ten most up- and down-regulated genes (based on ES) in the AY comparison.

<p>Top genes identified by IPA are indicated by an asterisk (*). Legends: ES, effect size; pBH, p-value with Benjamini and Hochberg correction; FC, fold change; DE, differentially expressed.</p

Data selection process.

<p>Search in the public microarray data repositories identified 38 microarray datasets involving cognitive impairments. We excluded 19 datasets that were either not relevant to our study or were not associated with any publication. We excluded 14 more studies as they involved different learning paradigms, test conditions, and outcomes in mice. We finally selected five studies that dealt with hippocampus dependent age-associated spatial learning in rats.</p

Forest plots of four representative significant genes.

<p>For the selected probe-set for each gene the individual study specific standardized mean differences (SMD) and their 95% confidence intervals (CI) are plotted and shown on each row. The effect size results are shown at the bottom of each plot. <i>C3</i> is up-regulated (A) and <i>Tubb2b</i> is down-regulated in the aged rats. <i>Arc</i> is down-regulated (C) and <i>Marcks</i> is up-regulated (D) in the aged-impaired rats.</p

Major functions associated with the top five networks in the AY comparison.

<p>Major functions associated with the top five networks in the AY comparison.</p