Quantitative Analysis of Single Nucleotide Polymorphisms within Copy Number Variation

Background Single nucleotide polymorphisms (SNPs) have been used extensively in genetics and epidemiology studies. Traditionally, SNPs that did not pass the Hardy-Weinberg equilibrium (HWE) test were excluded from these analyses. Many investigators have addressed possible causes for departure from HWE, including genotyping errors, population admixture and segmental duplication. Recent large-scale surveys have revealed abundant structural variations in the human genome, including copy number variations (CNVs). This suggests that a significant number of SNPs must be within these regions, which may cause deviation from HWE. Results We performed a Bayesian analysis on the potential effect of copy number variation, segmental duplication and genotyping errors on the behavior of SNPs. Our results suggest that copy number variation is a major factor of HWE violation for SNPs with a small minor allele frequency, when the sample size is large and the genotyping error rate is 0~1%. Conclusions Our study provides the posterior probability that a SNP falls in a CNV or a segmental duplication, given the observed allele frequency of the SNP, sample size and the significance level of HWE testing.

3'-UTR SIRF: A database for identifying clusters of short interspersed repeats in 3' untranslated regions

BACKGROUND:Short (~5 nucleotides) interspersed repeats regulate several aspects of post-transcriptional gene expression. Previously we developed an algorithm (REPFIND) that assigns P-values to all repeated motifs in a given nucleic acid sequence and reliably identifies clusters of short CAC-containing motifs required for mRNA localization in Xenopus oocytes.DESCRIPTION:In order to facilitate the identification of genes possessing clusters of repeats that regulate post-transcriptional aspects of gene expression in mammalian genes, we used REPFIND to create a database of all repeated motifs in the 3' untranslated regions (UTR) of genes from the Mammalian Gene Collection (MGC). The MGC database includes seven vertebrate species: human, cow, rat, mouse and three non-mammalian vertebrate species. A web-based application was developed to search this database of repeated motifs to generate species-specific lists of genes containing specific classes of repeats in their 3'-UTRs. This computational tool is called 3'-UTR SIRF (Short Interspersed Repeat Finder), and it reveals that hundreds of human genes contain an abundance of short CAC-rich and CAG-rich repeats in their 3'-UTRs that are similar to those found in mRNAs localized to the neurites of neurons. We tested four candidate mRNAs for localization in rat hippocampal neurons by in situ hybridization. Our results show that two candidate CAC-rich (Syntaxin 1B and Tubulin beta4) and two candidate CAG-rich (Sec61alpha and Syntaxin 1A) mRNAs are localized to distal neurites, whereas two control mRNAs lacking repeated motifs in their 3'-UTR remain primarily in the cell body.CONCLUSION:Computational data generated with 3'-UTR SIRF indicate that hundreds of mammalian genes have an abundance of short CA-containing motifs that may direct mRNA localization in neurons. In situ hybridization shows that four candidate mRNAs are localized to distal neurites of cultured hippocampal neurons. These data suggest that short CA-containing motifs may be part of a widely utilized genetic code that regulates mRNA localization in vertebrate cells. The use of 3'-UTR SIRF to search for new classes of motifs that regulate other aspects of gene expression should yield important information in future studies addressing cis-regulatory information located in 3'-UTRs.

Statistic Rate Monotonic Scheduling

In this paper we present Statistical Rate Monotonic Scheduling (SRMS), a generalization of the classical RMS results of Liu and Layland that allows scheduling periodic tasks with highly variable execution times and statistical QoS requirements. Similar to RMS, SRMS has two components: a feasibility test and a scheduling algorithm. The feasibility test for SRMS ensures that using SRMS' scheduling algorithms, it is possible for a given periodic task set to share a given resource (e.g. a processor, communication medium, switching device, etc.) in such a way that such sharing does not result in the violation of any of the periodic tasks QoS constraints. The SRMS scheduling algorithm incorporates a number of unique features. First, it allows for fixed priority scheduling that keeps the tasks' value (or importance) independent of their periods. Second, it allows for job admission control, which allows the rejection of jobs that are not guaranteed to finish by their deadlines as soon as they are released, thus enabling the system to take necessary compensating actions. Also, admission control allows the preservation of resources since no time is spent on jobs that will miss their deadlines anyway. Third, SRMS integrates reservation-based and best-effort resource scheduling seamlessly. Reservation-based scheduling ensures the delivery of the minimal requested QoS; best-effort scheduling ensures that unused, reserved bandwidth is not wasted, but rather used to improve QoS further. Fourth, SRMS allows a system to deal gracefully with overload conditions by ensuring a fair deterioration in QoS across all tasks---as opposed to penalizing tasks with longer periods, for example. Finally, SRMS has the added advantage that its schedulability test is simple and its scheduling algorithm has a constant overhead in the sense that the complexity of the scheduler is not dependent on the number of the tasks in the system. We have evaluated SRMS against a number of alternative scheduling algorithms suggested in the literature (e.g. RMS and slack stealing), as well as refinements thereof, which we describe in this paper. Consistently throughout our experiments, SRMS provided the best performance. In addition, to evaluate the optimality of SRMS, we have compared it to an inefficient, yet optimal scheduler for task sets with harmonic periods.