Stops making sense: translational trade-offs and stop codon reassignment

Background Efficient gene expression involves a trade-off between (i) premature termination of protein synthesis; and (ii) readthrough, where the ribosome fails to dissociate at the terminal stop. Sense codons that are similar in sequence to stop codons are more susceptible to nonsense mutation, and are also likely to be more susceptible to transcriptional or translational errors causing premature termination. We therefore expect this trade-off to be influenced by the number of stop codons in the genetic code. Although genetic codes are highly constrained, stop codon number appears to be their most volatile feature. Results In the human genome, codons readily mutable to stops are underrepresented in coding sequences. We construct a simple mathematical model based on the relative likelihoods of premature termination and readthrough. When readthrough occurs, the resultant protein has a tail of amino acid residues incorrectly added to the C-terminus. Our results depend strongly on the number of stop codons in the genetic code. When the code has more stop codons, premature termination is relatively more likely, particularly for longer genes. When the code has fewer stop codons, the length of the tail added by readthrough will, on average, be longer, and thus more deleterious. Comparative analysis of taxa with a range of stop codon numbers suggests that genomes whose code includes more stop codons have shorter coding sequences. Conclusions We suggest that the differing trade-offs presented by alternative genetic codes may result in differences in genome structure. More speculatively, multiple stop codons may mitigate readthrough, counteracting the disadvantage of a higher rate of nonsense mutation. This could help explain the puzzling overrepresentation of stop codons in the canonical genetic code and most variants

Electronic structure and the minimum conductance of a graphene layer on SiO2 from density-functional methods.

The effect of the SiO$_2$ substrate on a graphene film is investigated using realistic but computationally convenient energy-optimized models of the substrate supporting a layer of graphene. The electronic bands are calculated using density-functional methods for several model substrates. This provides an estimate of the substrate-charge effects on the behaviour of the bands near $E_F$, as well as a variation of the equilibrium distance of the graphene sheet. A model of a wavy graphene layer is examined as a possible candidate for understanding the nature of the minimally conducting states in graphene.Comment: 6 pages, 5 figure

Are self-report of disability pension and long-term sickness absence accurate? Comparisons of self-reported interview data with national register data in a Swedish twin cohort

<p>Abstract</p> <p>Background</p> <p>Self-reported disability pension (DP) and sickness absence are commonly used in epidemiological and other studies as a measure of exposure or even as an outcome. The aims were (1) to compare such self-reports with national register information in order to evaluate the validity of self-reported DP and sickness absence, and (2) to estimate the concordance of reporting behaviour in different twin zygosity groups, also by sex.</p> <p>Methods</p> <p>All Swedish twins born 1933-1958 who participated in the Screening Across the Lifespan Twin study (SALT) 1998-2003, were included (31,122 individuals). The self-reported DP and long-term sickness absence (LTSA) at the time of interview was compared to the corresponding register information retrieved from the National Social Insurance Agency by calculating the proportions of agreements, kappa, sensitivity, specificity, concordance rates, and chi-square test, to evaluate construct validity.</p> <p>Results</p> <p>The proportions of overall agreement were 96% and specificity 99% for both DP and LTSA, while the sensitivity was 70% for DP and 45% for LTSA. Kappa estimates were 0.76 for DP, and 0.58 for LTSA. The proportions of positive agreement were 64% for DP and 42% for LTSA. No difference in response style was found between zygosity groups among complete twin pairs for DP and LTSA. Results were similar for women and men and across age. Kappa estimates for DP differed somewhat depending on years of education, 0.68 (college/university) vs. 0.77 (less than 13 years in school) but not for LTSA.</p> <p>Conclusions</p> <p>Self-reported DP data may be very useful in studies when register information is not available, however, register data is preferred especially for LTSA. The same degree of twin similarity was found for truthful self-report of DP and LTSA in both monozygotic and dizygotic twin pairs. Thus, the response style was not influenced by genetic factors. One consequence of this would be that when estimating the relative importance of genetic and environmental effects from twin models, heritability estimates would not be biased.</p

Patterns and rates of exonic de novo mutations in autism spectrum disorders

Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified1,2. To identify further genetic risk factors, we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n= 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant and the overall rate of mutation is only modestly higher than the expected rate. In contrast, there is significantly enriched connectivity among the proteins encoded by genes harboring de novo missense or nonsense mutations, and excess connectivity to prior ASD genes of major effect, suggesting a subset of observed events are relevant to ASD risk. The small increase in rate of de novo events, when taken together with the connections among the proteins themselves and to ASD, are consistent with an important but limited role for de novo point mutations, similar to that documented for de novo copy number variants. Genetic models incorporating these data suggest that the majority of observed de novo events are unconnected to ASD, those that do confer risk are distributed across many genes and are incompletely penetrant (i.e., not necessarily causal). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5 to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favor of CHD8 and KATNAL2 as genuine autism risk factors

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

Stops making sense: translational trade-offs and stop codon reassignment BMC Evolutionary Biology Stops making sense: translational trade-offs and stop codon reassignment

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