Conflict between Translation Initiation and Elongation in Vertebrate Mitochondrial Genomes

The strand-biased mutation spectrum in vertebrate mitochondrial genomes results in an AC-rich L-strand and a GT-rich H-strand. Because the L-strand is the sense strand of 12 protein-coding genes out of the 13, the third codon position is overall strongly AC-biased. The wobble site of the anticodon of the 22 mitochondrial tRNAs is either U or G to pair with the most abundant synonymous codon, with only one exception. The wobble site of Met-tRNA is C instead of U, forming the Watson-Crick match with AUG instead of AUA, the latter being much more frequent than the former. This has been attributed to a compromise between translation initiation and elongation; i.e., AUG is not only a methionine codon, but also an initiation codon, and an anticodon matching AUG will increase the initiation rate. However, such an anticodon would impose selection against the use of AUA codons because AUA needs to be wobble-translated. According to this translation conflict hypothesis, AUA should be used relatively less frequently compared to UUA in the UUR codon family. A comprehensive analysis of mitochondrial genomes from a variety of vertebrate species revealed a general deficiency of AUA codons relative to UUA codons. In contrast, urochordate mitochondrial genomes with two tRNA(Met) genes with CAU and UAU anticodons exhibit increased AUA codon usage. Furthermore, six bivalve mitochondrial genomes with both of their tRNA-Met genes with a CAU anticodon have reduced AUA usage relative to three other bivalve mitochondrial genomes with one of their two tRNA-Met genes having a CAU anticodon and the other having a UAU anticodon. We conclude that the translation conflict hypothesis is empirically supported, and our results highlight the fine details of selection in shaping molecular evolution

An Extensive Study of Mutation and Selection on the Wobble Nucleotide in tRNA Anticodons in Fungal Mitochondrial Genomes

Abstract Two alternative hypotheses aim to predict the wobble nucleotide of tRNA anticodons in mitochondrion. The codon-anticodon adaptation hypothesis predicts that the wobble nucleotide of tRNA anticodon should evolve toward maximizing the Watson-Crick base pairing with the most frequently used codon within each synonymous codon family. In contrast, the wobble versatility hypothesis argues that the nucleotide at the wobble site should be occupied by a nucleotide most versatile in wobble pairing, i.e., the wobble site of the tRNA anticodon should be G for NNY codon families and U for NNR and NNN codon families (where Y stands for C or U, R for A or G, and N for any nucleotide). We examined codon usage and anticodon wobble sites in 36 fungal genomes to evaluate these two alternative hypotheses and identify exceptional cases that deserve new explanations. While the wobble versatility hypothesis is generally supported, there are interesting exceptions involving tRNA Arg translating the CGN codon family, tRNA Trp translating the UGR codon family, and tRNA Met translating the AUR codon family. Our results suggest that the potential to suppress stop codons, the historical inertia, and the conflict between translation initiation and elongation can all contribute to determining the wobble nucleotide of tRNA anticodons

The effect of anticodons (AC) of the two tRNA-Met genes in bivalve mitochondrial genomes on P_UUA and P_AUA.

<p>Those with only CAU-tRNA^Met genes have reduced AUA usage than those with both CAU-tRNA^Met and UAU-tRNA-^Met genes.</p

Results from the 13 CDSs from the four urochordate species, <i>Halocynthia roretzi, Ciona intestinalis, Ciona savignyi</i>, and <i>Doliolum nationalis</i>, whose mitochondrial genomes each have a UAU-tRNA^Met gene in addition to a CAU-tRNA^Met gene.

<p>Results from the 13 CDSs from the four urochordate species, <i>Halocynthia roretzi, Ciona intestinalis, Ciona savignyi</i>, and <i>Doliolum nationalis</i>, whose mitochondrial genomes each have a UAU-tRNA^Met gene in addition to a CAU-tRNA^Met gene.</p

LIFEHOUSE\u27s Functional Nutrition Examination (Physical Exam, Anthropometrics, and Selected Biomarkers) Informs Personalized Wellness Interventions.

Each individual has a unique and interacting set of genetic, lifestyle, and environmental factors that are reflected in their physical exam and laboratory biomarkers and significantly impact their experience of health. Patterns of nutrient deficiency signs and biomarker levels below health-promoting thresholds have been identified in national nutrition surveys. However, identifying these patterns remains a challenge in clinical medicine for many reasons, including clinician training and education, clinical time restraints, and the belief that these signs are both rare and recognizable only in cases of severe nutritional deficiencies. With an increased interest in prevention and limited resources for comprehensive diagnostic evaluations, a functional nutrition evaluation may augment patient-centered screening evaluations and personalized wellness programs. During LIFEHOUSE, we have documented physical exam, anthropometric, and biomarker findings that may increase the recognition of these wellness-challenging patterns in a population of 369 adult employees working in two occupational areas: administrative/sales and manufacturing/warehouse. Distinct and significant physical exam differences and constellations of biomarker abnormalities were identified. We present these patterns of physical exam findings, anthropometrics, and advanced biomarkers to assist clinicians in diagnostic and therapeutic interventions that may stem the loss of function that precedes the development of the non-communicable chronic diseases of aging

Personalized Lifestyle Intervention and Functional Evaluation Health Outcomes SurvEy: Presentation of the LIFEHOUSE Study Using N-of-One Tent&ndash;Umbrella&ndash;Bucket Design

The working definition of health is often the simple absence of diagnosed disease. This common standard is limiting given that changes in functional health status represent early warning signs of impending health declines. Longitudinal assessment of functional health status may foster prevention of disease occurrence and modify disease progression. The LIFEHOUSE (Lifestyle Intervention and Functional Evaluation-Health Outcomes SurvEy) longitudinal research project explores the impact of personalized lifestyle medicine approaches on functional health determinants. Utilizing an adaptive tent&ndash;umbrella&ndash;bucket design, the LIFEHOUSE study follows the functional health outcomes of adult participants recruited from a self-insured employee population. Participants were each allocated to the tent of an all-inclusive N-of-one case series. After assessing medical history, nutritional physical exam, baseline functional status (utilizing validated tools to measure metabolic, physical, cognitive, emotional and behavioral functional capacity), serum biomarkers, and genomic and microbiome markers, participants were assigned to applicable umbrellas and buckets. Personalized health programs were developed and implemented using systems biology formalism and functional medicine clinical approaches. The comprehensive database (currently 369 analyzable participants) will yield novel interdisciplinary big-health data and facilitate topological analyses focusing on the interactome among each participant&rsquo;s genomics, microbiome, diet, lifestyle and environment