Substitution Bias Research Articles

Substitution bias and evolutionary rate of mitochondrial protein-encoding genes in four species of Cecidomyiidae.

Five mitochondrial protein-encoding genes (COX1, COX2, CytB, ND4 and ND5) from the wheat midge, Sitodiplosis mosellana (Diptera: Cecidomyiidae), were sequenced and compared with those of 3 other Cecidoidae species, Mayetiola destructor, Rhopalomyia pomum and Asphondylia rosetta. These genes shared similar AT content (74.0-80.1%) and base substitution bias in favour of transversions (68.87-79.72%) over transitions (20.28-37.04%). Substitution saturation analyses indicated fast saturation of transitional substitutions in COX2, CytB, ND4 and ND5, especially at the 3rd codon positions. Analysis of interspecific divergence among the 4 species showed that the sequence divergence rates (evolutionary rates) were in the order of ND4 = CytB > COX2 = ND5 > COX1. Intraspecific genetic polymorphism analysis within the field populations of S. mosellana indicated that ND4 had the highest genetic polymorphism and COX1 the lowest. Genetic variation patterns suggested that COX1 could be used as a molecular marker for phylogenetic analysis across a relatively wide taxonomic range in Cecidomyiidae, while COX2 and ND5 may be useful for estimating relationships at a subgenus level or among closely related species. With its high genetic polymorphism, ND4 was the molecular market most suitable for population genetics studies. These findings will be valuable for our further understanding and studies in evolutionary biology and population genetics for S. mosellana and other Cecidomyiidae insects.

Introduction of Chain-Weighted Method and GDP Fluctuations

The Bank of Korea changed its method of GDP estimation from a fixed-weighted to a chain-weighted measure in 2009. The fixed-weighted method had had problems such as substitution bias and the rewriting of economic history. As a result of the change, annual growth rates calculated using the chain-weighted method from 1970 through 2008 turned out to be 0.8%p higher on average than the existing rates. The quarterly average chain-weighted growth rates were 0.19%p higher than the fixed-weighted ones, but they changed in the same directions. In this paper we analyze whether the differences in rates between the two calculation methods would bring about a difference in the cyclical characteristics of GDP. We conclude that although there were differences in growth rates after introduction of the chain-weighted method, there was no difference in the cyclical fluctuation.

Substitution Bias and External Validity: Why an Innovative Anti-Poverty Program Showed No Net Impact

The net impact of development interventions can depend on the availability of close substitutes to the intervention. We analyze a randomized trial of an innovative anti-poverty program in South India which provides “ultra-poor” households with inputs to create a new, sustainable livelihood. We find no statistically significant evidence of lasting net impact on consumption, income or asset accumulation. Instead, income from the new livelihood substituted for earnings from wage labor. A very similar intervention made a large difference elsewhere in South Asia, however, where wage labor alternatives were less compelling. The analysis highlights the roles of substitution bias and dropout bias in shaping evaluation results and delimiting external validity.

A Comprehensive Survey of Ras Mutations in Cancer

All mammalian cells express 3 closely related Ras proteins, termed H-Ras, K-Ras, and N-Ras, that promote oncogenesis when they are mutationally activated at codon 12, 13, or 61. Although there is a high degree of similarity among the isoforms, K-Ras mutations are far more frequently observed in cancer, and each isoform displays preferential coupling to particular cancer types. We examined the mutational spectra of Ras isoforms curated from large-scale tumor profiling and found that each isoform exhibits surprisingly distinctive codon mutation and amino-acid substitution biases. These findings were unexpected given that these mutations occur in regions that share 100% amino-acid sequence identity among the 3 isoforms. Of importance, many of these mutational biases were not due to differences in exposure to mutagens, because the patterns were still evident when compared within specific cancer types. We discuss potential genetic and epigenetic mechanisms, as well as isoform-specific differences in protein structure and signaling, that may promote these distinct mutation patterns and differential coupling to specific cancers.

Protein Conformational Diversity Modulates Sequence Divergence

It is well established that the conservation of protein structure during evolution constrains sequence divergence. The conservation of certain physicochemical environments to preserve protein folds and then the biological function originates a site-specific structurally constrained substitution pattern. However, protein native structure is not unique. It is known that the native state is better described by an ensemble of conformers in a dynamic equilibrium. In this work, we studied the influence of conformational diversity in sequence divergence and protein evolution. For this purpose, we derived a set of 900 proteins with different degrees of conformational diversity from the PCDB database, a conformer database. With the aid of a structurally constrained protein evolutionary model, we explored the influence of the different conformations on sequence divergence. We found that the presence of conformational diversity strongly modulates the substitution pattern. Although the conformers share several of the structurally constrained sites, 30% of them are conformer specific. Also, we found that in 76% of the proteins studied, a single conformer outperforms the others in the prediction of sequence divergence. It is interesting to note that this conformer is usually the one that binds ligands participating in the biological function of the protein. The existence of a conformer-specific site-substitution pattern indicates that conformational diversity could play a central role in modulating protein evolution. Furthermore, our findings suggest that new evolutionary models and bioinformatics tools should be developed taking into account this substitution bias.

Substitution bias and the construction of a spatial cost of living index

AbstractWe estimate the spatial substitution bias based on the difference between a price index (PI) and the true cost of living (COL). This bias is computed at three geographical scales, using several fixed baskets and across different expenditures quartiles. Our results show a significant substitution bias for small geographical units. The choice of the base basket is also relevant for the bias estimation. Finally, the spatial substitution bias is larger for upper side of the expenditure distribution due to the heterogeneity in the consumption basket. This exercise shows that the spatial dimension affects the construction of a price index and that the approach of fixed baskets should be carefully considered in the estimation of spatial price differentials.

Mat á efra stigs staðgöngubjaga í verðbólgumælingum á Íslandi

Staðgöngubjagi stafar af því að neysluhegðun breytist frá þeim tíma sem líður frá því að vogir neyslukörfu eru metnar og fram að notkun hennar við verðbólgumælingu. Neyslukannanir sem liggja til grundvallar mati á vogum 2/3 hluta neyslukörfunnar eru að meðaltali 3¼ ára gamlar við mælingu verðbólgu. Stafar aldur þeirra að mestu leyti af sofnunar- og úrvinnslutíma gagna, en vogir neyslukörfunnar eru uppfærðar árlega. Í þessari rannsókn er bjagi metinn fyrir þann hluta neyslukörfunnar sem byggir á neyslukönnunum. Með sögulegum gögnum berum við saman verðbólgutölur Hagstofunnar við verðbólgutölur sem fást með notkun einfaldrar útfærslu af Marshall-Edgeworth-vísitölunni sem er að meðaltali samtímamæld. Okkar mat á staðgöngubjaga í verðbólgumælingum á Íslandi er 0,3% á ári (0,45% í 2/3 af neysluvísitölunni). Matið á bjaganum er hærra en fengist hefur í sambærilegum rannsóknum erlendis. Mat á verðbólgu með árlegri uppfærslu voga reyndist svipað og mat á verðbólgu með vogum sem uppfærðar voru á fimm ára fresti.

Offshoring Bias in U.S. Manufacturing

In this paper, we show that the substitution of imported for domestically produced goods and services—often known as offshoring—can lead to overestimates of U.S. productivity growth and value added. We explore how the measurement of productivity and value added in manufacturing has been affected by the dramatic rise in imports of manufactured goods, which more than doubled from 1997 to 2007. We argue that, analogous to the widely discussed problem of outlet substitution bias in the literature on the Consumer Price Index, the price declines associated with the shift to low-cost foreign suppliers are generally not captured in existing price indexes. Just as the CPI fails to capture fully the lower prices for consumers due to the entry and expansion of big-box retailers like Wal-Mart, import price indexes and the intermediate input price indexes based on them do not capture the price drops associated with a shift to new low-cost suppliers in China and other developing countries. As a result, the real growth of imported inputs has been understated. And if input growth is understated, it follows that the growth in multifactor productivity and real value added in the manufacturing sector have been overstated. We estimate that average annual multifactor productivity growth in manufacturing was overstated by 0.1 to 0.2 percentage points and real value added growth by 0.2 to 0.5 percentage points from 1997 to 2007. Moreover, this bias may have accounted for a fifth to a half of the growth in real value added in manufacturing output excluding the computer and electronics industry.

Substitution Patterns Are GC-Biased in Divergent Sequences across the Metazoans

The fastest-evolving regions in the human and chimpanzee genomes show a remarkable excess of weak (A,T) to strong (G,C) nucleotide substitutions since divergence from their common ancestor. We investigated the phylogenetic extent and possible causes of this weak to strong (W→S) bias in divergent sequences (BDS) using recently sequenced genomes and recombination maps from eight trios of eukaryotic species. To quantify evidence for BDS, we inferred substitution histories using an efficient maximum likelihood approach with a context-dependent evolutionary model. We then annotated all lineage-specific substitutions in terms of W→S bias and density on the chromosomes. Finally, we used the inferred substitutions to calculate a BDS score—a log odds ratio between substitution type and density—and assessed its statistical significance with Fisher's exact test. Applying this approach, we found significant BDS in the coding and noncoding sequence of human, mouse, dog, stickleback, fruit fly, and worm. We also observed a significant lack of W→S BDS in chicken and yeast. The BDS score varies between species and across the chromosomes within each species. It is most strongly correlated with different genomic features in different species, but a strong correlation with recombination rates is found in several species. Our results demonstrate that a W→S substitution bias in fast-evolving sequences is a widespread phenomenon. The patterns of BDS observed suggest that a recombination-associated process, such as GC-biased gene conversion, is involved in the production of the bias in many species, but the strength of the BDS likely depends on many factors, including genome stability, variability in recombination rate over time and across the genome, the frequency of meiosis, and the amount of outcrossing in each species.

Lowe and Cobb-Douglas Consumer Price Indices and their Substitution Bias

Summary Catching the effect of substitution behaviour in a Consumer Price Index (CPI) as good as possible is a goal pursued by statistical agencies throughout the world. The difference between a CPI and a certain target cost-of-living index is called substitution bias. Balk and Diewert (2003) considered the substitution bias of a Lowe Consumer Price Index; see also CPI Manual (2004: Chapter 17). The present paper considers the substitution bias of a Cobb-Douglas (or Geometric Young) CPI, and compares the two price indices with respect to their substitution bias. It appears difficult to draw a clear-cut conclusion.

CodonTest: Modeling Amino Acid Substitution Preferences in Coding Sequences

Codon models of evolution have facilitated the interpretation of selective forces operating on genomes. These models, however, assume a single rate of non-synonymous substitution irrespective of the nature of amino acids being exchanged. Recent developments have shown that models which allow for amino acid pairs to have independent rates of substitution offer improved fit over single rate models. However, these approaches have been limited by the necessity for large alignments in their estimation. An alternative approach is to assume that substitution rates between amino acid pairs can be subdivided into rate classes, dependent on the information content of the alignment. However, given the combinatorially large number of such models, an efficient model search strategy is needed. Here we develop a Genetic Algorithm (GA) method for the estimation of such models. A GA is used to assign amino acid substitution pairs to a series of rate classes, where is estimated from the alignment. Other parameters of the phylogenetic Markov model, including substitution rates, character frequencies and branch lengths are estimated using standard maximum likelihood optimization procedures. We apply the GA to empirical alignments and show improved model fit over existing models of codon evolution. Our results suggest that current models are poor approximations of protein evolution and thus gene and organism specific multi-rate models that incorporate amino acid substitution biases are preferred. We further anticipate that the clustering of amino acid substitution rates into classes will be biologically informative, such that genes with similar functions exhibit similar clustering, and hence this clustering will be useful for the evolutionary fingerprinting of genes.

Host Dependent Evolutionary Patterns and the Origin of 2009 H1N1 Pandemic Influenza

The origin of H1N1pdm constitutes an unresolved mystery, as its most recently observed ancestors were isolated in pigs nearly a decade before it emerged in humans. One theory suggests imperfect surveillance of swine viruses caused the virus to be missed in swine herds. Other hypotheses point to the possibility of laboratory error or an avian intermediary. We show substitution bias classification identifies the host where a virus has been evolving. Comparing the evolution of H1N1pdm ancestors with other influenza viruses, we show the evolutionary history in unsampled years is similar to the evolution of other swine viruses, presenting evidence it emerged from unsampled herds.

Benchmarking Multi-Rate Codon Models

The single rate codon model of non-synonymous substitution is ubiquitous in phylogenetic modeling. Indeed, the use of a non-synonymous to synonymous substitution rate ratio parameter has facilitated the interpretation of selection pressure on genomes. Although the single rate model has achieved wide acceptance, we argue that the assumption of a single rate of non-synonymous substitution is biologically unreasonable, given observed differences in substitution rates evident from empirical amino acid models. Some have attempted to incorporate amino acid substitution biases into models of codon evolution and have shown improved model performance versus the single rate model. Here, we show that the single rate model of non-synonymous substitution is easily outperformed by a model with multiple non-synonymous rate classes, yet in which amino acid substitution pairs are assigned randomly to these classes. We argue that, since the single rate model is so easy to improve upon, new codon models should not be validated entirely on the basis of improved model fit over this model. Rather, we should strive to both improve on the single rate model and to approximate the general time-reversible model of codon substitution, with as few parameters as possible, so as to reduce model over-fitting. We hint at how this can be achieved with a Genetic Algorithm approach in which rate classes are assigned on the basis of sequence information content.

Accelerated Evolution of Fetuin-A ( FETUA, also AHSG) is Driven by Positive Darwinian Selection, not GC-Biased Gene Conversion

Human Fetuin-A (FETUA, also termed AHSG) is a serum protein composed of two cystatin-like domains D1 and D2 of together 235 amino acids ( aa) and an unrelated domain D3 of 114 aa. Though the protein plays a role in diverse physiological and pathological processes, comparably little is known about sequence evolution of FETUA. We therefore analyzed its molecular evolution on the basis of coding sequences of 16 primate species. Ratios of non-synonymous to synonymous substitution rates ( d n/ d s = ω) suggest that a previously reported acceleration of sequence evolution of exon 7, which encodes domain D3, is driven by positive selection instead of neutral evolution. Irrespective of the maximum likelihood model used, a remarkable 40% of codon sites is estimated to be positively selected in domain D3, with an average ω of 4.3. Analyses of GC/AT- and AT/GC-substitutions reveal that GC-biased gene conversion ( gBGC) cannot explain the observed pattern. We thus reject the extended null model of molecular evolution (neutral evolution and gBGC) and conclude that positive Darwinian selection contributes to the sequence evolution of FETUA domain D3. Remarkably, domain D3 of human FETUA is characterized by a significant accumulation of proteolytic cleavage sites. Though speculative at present, the accelerated evolution of domain D3 might be due to the evolution of differential cleavage site patterns across primates reflecting different paths to achieve one goal, the decomposition of FETUA under pathological conditions. Present analyses use a PERL-script ("Substitution Bias Indicator", SBI) for the extraction of the numbers of GC/AT- and AT/GC-substitutions from supplemental results files of PAML analyses. The script is available upon request and the presented approach of testing the extended null hypothesis of molecular evolution can be transferred to every other protein coding locus.

Large-scale evolutionary surveillance of the 2009 H1N1 influenza A virus using resequencing arrays

In April 2009, a new influenza A (H1N1 2009) virus emerged that rapidly spread around the world. While current variants of this virus have caused widespread disease, particularly in vulnerable groups, there remains the possibility that future variants may cause increased virulence, drug resistance or vaccine escape. Early detection of these virus variants may offer the chance for increased containment and potentially prevention of the virus spread. We have developed and field-tested a resequencing kit that is capable of interrogating all eight segments of the 2009 influenza A(H1N1) virus genome and its variants, with added focus on critical regions such as drug-binding sites, structural components and mutation hotspots. The accompanying base-calling software (EvolSTAR) introduces novel methods that utilize neighbourhood hybridization intensity profiles and substitution bias of probes on the microarray for mutation confirmation and recovery of ambiguous base queries. Our results demonstrate that EvolSTAR is highly accurate and has a much improved call rate. The high throughput and short turn-around time from sample to sequence and analysis results (30 h for 24 samples) makes this kit an efficient large-scale evolutionary biosurveillance tool.

A novel scoring function for discriminating hyperthermophilic and mesophilic proteins with application to predicting relative thermostability of protein mutants

BackgroundThe ability to design thermostable proteins is theoretically important and practically useful. Robust and accurate algorithms, however, remain elusive. One critical problem is the lack of reliable methods to estimate the relative thermostability of possible mutants.ResultsWe report a novel scoring function for discriminating hyperthermophilic and mesophilic proteins with application to predicting the relative thermostability of protein mutants. The scoring function was developed based on an elaborate analysis of a set of features calculated or predicted from 540 pairs of hyperthermophilic and mesophilic protein ortholog sequences. It was constructed by a linear combination of ten important features identified by a feature ranking procedure based on the random forest classification algorithm. The weights of these features in the scoring function were fitted by a hill-climbing algorithm. This scoring function has shown an excellent ability to discriminate hyperthermophilic from mesophilic sequences. The prediction accuracies reached 98.9% and 97.3% in discriminating orthologous pairs in training and the holdout testing datasets, respectively. Moreover, the scoring function can distinguish non-homologous sequences with an accuracy of 88.4%. Additional blind tests using two datasets of experimentally investigated mutations demonstrated that the scoring function can be used to predict the relative thermostability of proteins and their mutants at very high accuracies (92.9% and 94.4%). We also developed an amino acid substitution preference matrix between mesophilic and hyperthermophilic proteins, which may be useful in designing more thermostable proteins.ConclusionsWe have presented a novel scoring function which can distinguish not only HP/MP ortholog pairs, but also non-homologous pairs at high accuracies. Most importantly, it can be used to accurately predict the relative stability of proteins and their mutants, as demonstrated in two blind tests. In addition, the residue substitution preference matrix assembled in this study may reflect the thermal adaptation induced substitution biases. A web server implementing the scoring function and the dataset used in this study are freely available at http://www.abl.ku.edu/thermorank/.

Substitutability vs. Complementarity: Rethinking STI Composite Indicators Building with an Application of Sensitivity Analysis

The paper challenges the common view that the arithmetic mean aggregation's rule for building STI indicators is the fairest approach. We argue, on the contrary, that it hides a silent “substitution assumption” among the sub-indicators involved. According to this perspective Casadio and Palazzi (2004) provided a new composite indicator based on a “concave mean”. This approach overcomes the “substitution bias” generated by the arithmetic aggregation. As the concave mean is a highly non-linear formula, the paper provides a Sensitivity Analysis (as suggested by Saltelli et al., 2004) to detect sub-indexes importance in this special case. We perform an application to a specific STI indicator comparing results from the concave mean and other aggregation rules.

Relative mutation rates of each nucleotide for another estimated from allele frequency spectra at human gene loci

This study aims to comprehensively examine the mutation rates of one base for another in human gene loci. In contrast to most previous efforts based on divergence data from untranscribed regions, the present study employs the basic theory of the reversible recurrent mutation model using large-scale, high-quality re-sequencing data from public databases of gene loci. Population mutation parameters (4Nnu and 4Nmu) are obtained for each pair of base substitutions. The estimated parameters show good strand reversal symmetry, supporting the existence of mutation-drift equilibrium. Analysis of specific gene regions including mRNA, coding sequence (CDS), 5'-untranslated region (5'-UTRs), 3'-UTR and intron shows that there are clear differences in the mutation rates of each base for another depending on the location of the base in question. Results from analyses that take the adjacent bases into account exhibit excellent strand reversal symmetry, confirming that the identity of an adjacent base influences mutation rates. The CpG to TpG (or CpG to CpA) substitution is found at a rate approximately seven-fold higher than the reverse transition in intron regions due to cytosine deamination, but the effect is strongly reduced in mRNA regions and almost entirely lost in 5'-UTRs. However, from the overall increased transitions in sites other than CpGs and the proportion of CpGs in the total sequence, CpG methylation is not the main factor responsible for the increased rate of transitions as compared with transversions. In this report, after adjusting average mutation rates to the sequence compositions, no substitution bias is found between A+T and C+G, indicating base composition equilibrium in human gene loci. Population differences are also identified between groups of people of African and European descent, presumably due to past population histories. By applying the basic theory of population genetics to re-sequenced data, this study contributes new, detailed information regarding mutations in human gene regions.

Consumer Substitution, Cost of Living Measurement and Real Exchange Rate in Argentina - First Part: 1960-1995 (Long Version, in Spanish) (Sustitucion en el Consumo, Medición del Costo de Vida y Tipo de Cambio Real en la Argentina - Primera Parte: 1960-1995)

Ordinary consumer price indices customarily overstate increases in the cost of living because they do not allow for consumer substitution as relative prices change. This study looks for a more accurate measure of variations in the cost of living in Argentina over the years 1960 to 1995, taking account of consumer substitution, and for applying it to the question of estimating PPP exchange rates. A second paper will analyze the subsequent years 1996-2006. The main finding is that over 35 years (1960-95), the Consumer Price Index of Argentina overstated the rise in the true cost of living by 77% relative to the estimated cost of living index. Put in a different way, 44% of official inflation was avoided by consumers through substitution between goods, brands and outlets. The estimated cost of living index based in 1960 was in 1995 just 56% of the official index value. Concerning the value of Argentine currency, this study computes a purchasing-power-parity (PPP) exchange rate for 1960-95, based on a United Nations ECLA estimation of PPP exchange rates in various Latin American countries for the year 1960, updated with estimated cost of living indices for Argentina and the United States. For the US, studies by several authors are used to estimate a cost of living index controlling for the CPI's substitution bias, consistent with the index used for Argentina. The conclusions are that the exchange rate in Argentina was almost always above PPP during 1960-90, with the exception of 1979-81. It is also shown that the PPP rate was below the rate of one peso to the dollar when the latter was established by the so-called Convertibility Law in March 1991, but the PPP rate rapidly and smoothly converged to one peso per dollar during 1991-92, and remained in the close vicinity of the actual rate of exchange in subsequent years. A shorter English version is at http://ssrn.com/abstract=1437383.

Identifying novel constrained elements by exploiting biased substitution patterns

Motivation: Comparing the genomes from closely related species provides a powerful tool to identify functional elements in a reference genome. Many methods have been developed to identify conserved sequences across species; however, existing methods only model conservation as a decrease in the rate of mutation and have ignored selection acting on the pattern of mutations.Results: We present a new approach that takes advantage of deeply sequenced clades to identify evolutionary selection by uncovering not only signatures of rate-based conservation but also substitution patterns characteristic of sequence undergoing natural selection. We describe a new statistical method for modeling biased nucleotide substitutions, a learning algorithm for inferring site-specific substitution biases directly from sequence alignments and a hidden Markov model for detecting constrained elements characterized by biased substitutions. We show that the new approach can identify significantly more degenerate constrained sequences than rate-based methods. Applying it to the ENCODE regions, we identify as much as 10.2% of these regions are under selection.Availability: The algorithms are implemented in a Java software package, called SiPhy, freely available at http://www.broadinstitute.org/science/software/.Contact: xhx@ics.uci.eduSupplementary information: Supplementary data are available at Bioinformatics online.