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/
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