This work presents the first known multiple DNA sequence alignment benchmarks that are (1) comprised of protein-coding portions of DNA (2) based on biological features such as the tertiary structure of encoded proteins. These reference DNA databases contain a total of 3545 alignments, comprising of 68 581 sequences. Two versions of the database are available: mdsa_100s and mdsa_all. The mdsa_100s version contains the alignments of the data sets that TBLASTN found 100% sequence identity for each sequence. The mdsa_all version includes all hits with an E-value score above the threshold of 0.001. A primary use of these databases is to benchmark the performance of MSA applications on DNA data sets. The first such case study is included in the Supplementary Material.
BackgroundMetabolism of energy nutrients by the mitochondrial electron transport chain (ETC) is implicated in the aging process. Polymorphisms in core ETC proteins may have an effect on longevity. Here we investigate the cytochrome b (cytb) polymorphism at amino acid 7 (cytbI7T) that distinguishes human mitochondrial haplogroup H from haplogroup U.Principal FindingsWe compared longevity of individuals in these two haplogroups during historical extremes of caloric intake. Haplogroup H exhibits significantly increased longevity during historical caloric restriction compared to haplogroup U (p = 0.02) while during caloric abundance they are not different. The historical effects of natural selection on the cytb protein were estimated with the software TreeSAAP using a phylogenetic reconstruction for 107 mammal taxa from all major mammalian lineages using 13 complete protein-coding mitochondrial gene sequences. With this framework, we compared the biochemical shifts produced by cytbI7T with historical evolutionary pressure on and near this polymorphic site throughout mammalian evolution to characterize the role cytbI7T had on the ETC during times of restricted caloric intake.SignificanceOur results suggest the relationship between caloric restriction and increased longevity in human mitochondrial haplogroup H is determined by cytbI7T which likely enhances the ability of water to replenish the Qi binding site and decreases the time ubisemiquinone is at the Qo site, resulting in a decrease in the average production rate of radical oxygen species (ROS).
Abstract:We investigated three single nucleotide polymorphisms (SNPs) in the mitochondrial sub-haplogroups of the Pima Indians to determine the effect of selection on each SNP and on metabolic efficiency. The SNPs are within genes encoding proteins in electron transport and oxidative phosphorylation, and may affect the efficiency of energy metabolism, including resting metabolic rate (RMR) and respiratory quotient (RQ). They may be adaptations toward an energy-efficient metabolism when this population migrated to the desert and adopted a restricted caloric intake, and they may currently contribute to obesity. We found that two of the three recent SNPs affect RMR and/or RQ. Using the analytical software TreeSAAP, we inspected selection throughout mammalian evolution in 107 species, and characterized the biochemical shift produced by the amino acid substitutions. Our results suggest that two SNPs were affected by selection during mammalian evolution in a manner consistent with the effects on metabolic efficiency in Pima Indian SNP's. Therefore, evolutionary selection favors the recent Pima Indian mutations that result in amino acid substitutions consistent with increased efficiency of energy metabolism, with consequent effects on RMR and RQ.
Genome-wide analysis of single nucleotide polymorphism (SNP) markers is an extremely efficient means for genetic mapping of mutations or traits in mice. However, this approach often defines a relatively large recombinant interval. To facilitate the refinement of this interval, we developed the program SNP2RFLP. This program can be used to identify region-specific SNPs in which the polymorphic nucleotide creates a restriction fragment length polymorphism (RFLP) that can be readily assayed at the benchtop using restriction enzyme digestion of SNP-containing PCR products. The program permits user-defined queries that maximize the informative markers for a particular application. This facilitates fine-mapping in a region containing a mutation of interest, which should prove valuable to the mouse genetics community. SNP2RFLP and further details are publicly available at http://genetics.bwh.harvard.edu/snp2rflp/
The CYP2D6 gene is responsible for metabolising a large portion of the commonly prescribed drugs. Because of its importance, various approaches have been taken to analyse CYP2D6 and Single Nucleotide Polymorphisms (SNPs) throughout its sequence. This study introduces a novel method to analyse the effects of SNPs on encoded protein complexes by focusing on the biochemical properties of each non-synonymous substitution using the program TreeSAAP. Our results show four SNPs in CYP2D6 that exhibit radical changes in amino acid properties which may cause a lack of functionality in the CYP2D6 gene and contribute to a person's inability to metabolise specific drugs.
Neuroblastoma is the most common extracranial solid tumour in children. It accounts for 7-10% of malignancies in patients younger than 15 years and 15% of childhood oncology deaths. Each year, there are about 650 new cases of neuroblastoma occurring in the US. The survival rate is 70 - 95 % for low stage (stage 1, 2, 3) tumors. Unfortunately more than 50% of the patients present with advanced stage and the overall survival rate is less than 40% (less than 30% of the children over 1 year old) despite current aggressive multimodal therapies. We have reached the maximal tolerated dosage for most of the chemotherapeutic agents currently used to treat neuroblastoma. Therefore, better targeted therapeutic agents are required to reduce the toxicity related to the therapies. To identify specific targeting agents for neuroblastoma cells, we have undertaken nucleic acid based approach, known as aptamers. Aptamers are short single stranded nucleic acid ligands which can bind specifically to target protein or small molecules because of their unique 3D structures. Low or no immunogenicity together with high specificity makes aptamers potential candidates for therapeutic agents. In our study we have applied Systematic Evolution of Ligands by EXponential Enrichment (SELEX) to isolate RNA aptamers that target neuroblastoma. A modified RNA pool containing a theoretical 109 unique molecules was generated from a synthetic combinatorial library of nucleic acids, by using 2′-F pyrimidine and 2′-OH purine nucleotides in order to increase the stability toward nucleases. We performed 13 rounds of selection against one of the aggressive stage 4 neuroblastoma cell lines, SK-NA-S. After preliminary analysis we have identified 15 modified RNA sequences and performed binding affinity studies by labeling those sequences with 33P. The apparent dissociation constant (Kd) values are in nanomolar range. The aptamers with the lowest Kd values are chosen for further study in order to visualize the site of binding as well as to identify the target protein they are binding to. Once a neuroblastoma specific aptamer is verified, it will be evaluated for targeted therapeutics in neroblastoma by conjugating it with the polymerized liposomal nanoparticles containing small molecule drugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5486.
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