Showing papers on "Mutation (genetic algorithm) published in 2008"
TL;DR: The current understanding of the ways in which natural selection participates in the creation and maintenance of codon bias is discussed and some ideas on how they can be addressed using a combination of computational and experimental analyses are offered.
Abstract: In a wide variety of organisms, synonymous codons are used with different frequencies, a phenomenon known as codon bias. Population genetic studies have shown that synonymous sites are under weak selection and that codon bias is maintained by a balance between selection, mutation, and genetic drift. It appears that the major cause for selection on codon bias is that certain preferred codons are translated more accurately and/or efficiently. However, additional and sometimes maybe even contradictory selective forces appear to affect codon usage as well. In this review, we discuss the current understanding of the ways in which natural selection participates in the creation and maintenance of codon bias. We also raise several open questions: (i ) Is natural selection weak independently of the level of codon bias? It is possible that selection for preferred codons is weak only when codon bias approaches equilibrium and may be quite strong on genes with codon bias levels that are much lower and/or above equilibrium. (ii ) What determines the identity of the major codons? (iii ) How do shifts in codon bias occur? (iv) What is the exact nature of selection on codon bias? We discuss these questions in depth and offer some ideas on how they can be addressed using a combination of computational and experimental analyses.
825 citations
TL;DR: The potential for rapid adaptation from standing genetic variation and from new mutations is reviewed, and four types of evolutionary change that might promote or constrain rapid adaptation during the invasion process are examined.
781 citations
TL;DR: The role of historical contingency in evolution of Escherichia coli has been much debated, but rarely tested as discussed by the authors, which suggests that historical contingency is especially important when it facilitates the evolution of key innovations that are not easily evolved by gradual, cumulative selection.
Abstract: The role of historical contingency in evolution has been much debated, but rarely tested. Twelve initially identical populations of Escherichia coli were founded in 1988 to investigate this issue. They have since evolved in a glucose-limited medium that also contains citrate, which E. coli cannot use as a carbon source under oxic conditions. No population evolved the capacity to exploit citrate for >30,000 generations, although each population tested billions of mutations. A citrate-using (Cit+) variant finally evolved in one population by 31,500 generations, causing an increase in population size and diversity. The long-delayed and unique evolution of this function might indicate the involvement of some extremely rare mutation. Alternately, it may involve an ordinary mutation, but one whose physical occurrence or phenotypic expression is contingent on prior mutations in that population. We tested these hypotheses in experiments that “replayed” evolution from different points in that population's history. We observed no Cit+ mutants among 8.4 × 1012 ancestral cells, nor among 9 × 1012 cells from 60 clones sampled in the first 15,000 generations. However, we observed a significantly greater tendency for later clones to evolve Cit+, indicating that some potentiating mutation arose by 20,000 generations. This potentiating change increased the mutation rate to Cit+ but did not cause generalized hypermutability. Thus, the evolution of this phenotype was contingent on the particular history of that population. More generally, we suggest that historical contingency is especially important when it facilitates the evolution of key innovations that are not easily evolved by gradual, cumulative selection.
764 citations
TL;DR: The discovery of a missense mutation in TDP‐43 in a family with dominantly inherited motor neuron disease provides evidence of a direct link between altered T DP‐43 function and neurodegeneration.
Abstract: To identify novel causes of familial neurodegenerative diseases, we extended our previous studies of TAR DNA-binding protein 43 (TDP-43) proteinopathies to investigate TDP-43 as a candidate gene in familial cases of motor neuron disease. Sequencing of the TDP-43 gene led to the identification of a novel missense mutation, Ala-315-Thr, which segregates with all affected members of an autosomal dominant motor neuron disease family. The mutation was not found in 1,505 healthy control subjects. The discovery of a missense mutation in TDP-43 in a family with dominantly inherited motor neuron disease provides evidence of a direct link between altered TDP-43 function and neurodegeneration.
612 citations
TL;DR: At least one in 200 healthy humans harbors a pathogenic mtDNA mutation that potentially causes disease in the offspring of female carriers, and the exclusive detection of m.14484T→C on haplogroup J implicates the background mtDNA haplotype in mutagenesis.
Abstract: Mitochondrial DNA (mtDNA) mutations are a major cause of genetic disease, but their prevalence in the general population is not known. We determined the frequency of ten mitochondrial point mutations in 3168 neonatal-cord-blood samples from sequential live births, analyzing matched maternal-blood samples to estimate the de novo mutation rate. mtDNA mutations were detected in 15 offspring (0.54%, 95% CI = 0.30-0.89%). Of these live births, 0.00107% (95% CI = 0.00087-0.0127) harbored a mutation not detected in the mother's blood, providing an estimate of the de novo mutation rate. The most common mutation was m.3243A-->G. m.14484T-->C was only found on sub-branches of mtDNA haplogroup J. In conclusion, at least one in 200 healthy humans harbors a pathogenic mtDNA mutation that potentially causes disease in the offspring of female carriers. The exclusive detection of m.14484T-->C on haplogroup J implicates the background mtDNA haplotype in mutagenesis. These findings emphasize the importance of developing new approaches to prevent transmission.
532 citations
TL;DR: PMS2 mutations contribute significantly to Lynch syndrome, but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes.
495 citations
TL;DR: An improved method for the accurate calculation of mutation rates based on the fluctuation assay is described and a definition for the effective target size of genes (the probability that a mutation inactivates the gene) is proposed that acknowledges that the mutation rate is nonuniform across the genome.
Abstract: Although mutation rates are a key determinant of the rate of evolution they are difficult to measure precisely and global mutations rates (mutations per genome per generation) are often extrapolated from the per-base-pair mutation rate assuming that mutation rate is uniform across the genome. Using budding yeast, we describe an improved method for the accurate calculation of mutation rates based on the fluctuation assay. Our analysis suggests that the per-base-pair mutation rates at two genes differ significantly (3.80 × 10−10 at URA3 and 6.44 × 10−10 at CAN1) and we propose a definition for the effective target size of genes (the probability that a mutation inactivates the gene) that acknowledges that the mutation rate is nonuniform across the genome.
340 citations
TL;DR: A likelihood ratio test is developed to examine the null hypothesis that codon usage is due to mutation bias alone, not influenced by natural selection, suggesting that natural selection may be a driving force in the evolution of synonymouscodon usage in mammals.
Abstract: Current models of codon substitution are formulated at the levels of nucleotide substitution and do not explicitly consider the separate effects of mutation and selection. They are thus incapable of inferring whether mutation or selection is responsible for evolution at silent sites. Here we implement a few population genetics models of codon substitution that explicitly consider mutation bias and natural selection at the DNA level. Selection on codon usage is modeled by introducing codon-fitness parameters, which together with mutation-bias parameters, predict optimal codon frequencies for the gene. The selective pressure may be for translational efficiency and accuracy or for fine-tuning translational kinetics to produce correct protein folding. We apply the models to compare mitochondrial and nuclear genes from several mammalian species. Model assumptions concerning codon usage are found to affect the estimation of sequence distances (such as the synonymous rate d(S), the nonsynonymous rate d(N), and the rate at the 4-fold degenerate sites d(4)), as found in previous studies, but the new models produced very similar estimates to some old ones. We also develop a likelihood ratio test to examine the null hypothesis that codon usage is due to mutation bias alone, not influenced by natural selection. Application of the test to the mammalian data led to rejection of the null hypothesis in most genes, suggesting that natural selection may be a driving force in the evolution of synonymous codon usage in mammals. Estimates of selection coefficients nevertheless suggest that selection on codon usage is weak and most mutations are nearly neutral. The sensitivity of the analysis on the assumed mutation model is discussed.
318 citations
TL;DR: It is suggested that wild-type HIF-2 alpha regulates erythropoietin production in adults and a family with erythrocytosis and a mutation in the HIF2A gene, which encodes the Hif-2alpha protein, is described.
Abstract: Hypoxia-inducible factor (HIF) α, which has three isoforms, is central to the continuous balancing of the supply and demand of oxygen throughout the body. HIF-α is a transcription factor that modulates a wide range of processes, including erythropoiesis, angiogenesis, and cellular metabolism. We describe a family with erythrocytosis and a mutation in the HIF2A gene, which encodes the HIF-2α protein. Our functional studies indicate that this mutation leads to stabilization of the HIF-2α protein and suggest that wild-type HIF-2α regulates erythropoietin production in adults.
308 citations
TL;DR: The development of four independent populations with considerable mutation density, together with an additional method for screening closely related targets, indicates that soybean is a suitable organism for high-throughput mutation discovery even with its extensively duplicated genome.
Abstract: Soybean (Glycine max L. Merr.) is an important nitrogen-fixing crop that provides much of the world's protein and oil. However, the available tools for investigation of soybean gene function are limited. Nevertheless, chemical mutagenesis can be applied to soybean followed by screening for mutations in a target of interest using a strategy known as Targeting Induced Local Lesions IN Genomes (TILLING). We have applied TILLING to four mutagenized soybean populations, three of which were treated with ethyl methanesulfonate (EMS) and one with N-nitroso-N-methylurea (NMU). We screened seven targets in each population and discovered a total of 116 induced mutations. The NMU-treated population and one EMS mutagenized population had similar mutation density (~1/140 kb), while another EMS population had a mutation density of ~1/250 kb. The remaining population had a mutation density of ~1/550 kb. Because of soybean's polyploid history, PCR amplification of multiple targets could impede mutation discovery. Indeed, one set of primers tested in this study amplified more than a single target and produced low quality data. To address this problem, we removed an extraneous target by pretreating genomic DNA with a restriction enzyme. Digestion of the template eliminated amplification of the extraneous target and allowed the identification of four additional mutant alleles compared to untreated template. The development of four independent populations with considerable mutation density, together with an additional method for screening closely related targets, indicates that soybean is a suitable organism for high-throughput mutation discovery even with its extensively duplicated genome.
289 citations
TL;DR: Strand-asymmetric mutation bias, coupled with selection to maintain specific nonsynonymous bases, therefore provides an explanation for the extreme base composition of the mitochondrial genome of Drosophila.
Abstract: Mitochondrial DNA (mtDNA) variants are widely used in evolutionary genetics as markers for population history and to estimate divergence times among taxa. Inferences of species history are generally based on phylogenetic comparisons, which assume that molecular evolution is clock-like. Between-species comparisons have also been used to estimate the mutation rate, using sites that are thought to evolve neutrally. We directly estimated the mtDNA mutation rate by scanning the mitochondrial genome of Drosophila melanogaster lines that had undergone approximately 200 generations of spontaneous mutation accumulation (MA). We detected a total of 28 point mutations and eight insertion-deletion (indel) mutations, yielding an estimate for the single-nucleotide mutation rate of 6.2 310 � 8 per site per fly generation. Most mutations were heteroplasmic within a line, and their frequency distribution suggests that the effective number of mitochondrial genomes transmitted per female per generation is about 30. We observed repeated occurrences of some indel mutations, suggesting that indel mutational hotspots are common. Among the point mutations, there is a large excess of G!A mutations on the major strand (the sense strand for the majority of mitochondrial genes). These mutations tend to occur at nonsynonymous sites of protein-coding genes, and they are expected to be deleterious, so do not become fixed between species. The overall mtDNA mutation rate per base pair per fly generation in Drosophila is estimated to be about 103 higher than the nuclear mutation rate, but the mitochondrial major strand G!A mutation rate is about 703higher than the nuclear rate. Silent sites are substantially more strongly biased towards A and T than nonsynonymous sites, consistent with the extreme mutation bias towards AþT. Strand-asymmetric mutation bias, coupled with selection to maintain specific nonsynonymous bases, therefore provides an explanation for the extreme base composition of the mitochondrial genome of Drosophila.
TL;DR: The results imply that the IG-DMR has an important cis-acting regulatory function on the maternally inherited chromosome and that excessive RTL1 expression and decreased DLK1 and RTL 1 expression are relevant to upd( 14)pat-like and upd(14)mat-like phenotypes, respectively.
Abstract: Deletions and epimutations affecting the human 14q32.2 imprinted region in individuals with paternal and maternal upd(14)-like phenotypes
TL;DR: A novel chaos genetic algorithm based on the chaos optimization algorithm (COA) and genetic algorithm (GA), which makes use of the ergodicity and internal randomness of chaos iterations, is presented to overcome premature local optimum and increase the convergence speed of genetic algorithm.
Abstract: Genetic algorithms (GA) have been widely applied to solve water resources system optimization. With the increase of the complexity and the larger problem scale of water resources system, GAs are most frequently faced with the problems of premature convergence, slow iterations to reach the global optimal solution and getting stuck at a local optimum. A novel chaos genetic algorithm (CGA) based on the chaos optimization algorithm (COA) and genetic algorithm (GA), which makes use of the ergodicity and internal randomness of chaos iterations, is presented to overcome premature local optimum and increase the convergence speed of genetic algorithm. CGA integrates powerful global searching capability of the GA with that of powerful local searching capability of the COA. Two measures are adopted in order to improve the performance of the GA. The first one is the adoption of chaos optimization of the initialization to improve species quality and to maintain the population diversity. The second is the utilization of annealing chaotic mutation operation to replace standard mutation operator in order to avoid the search being trapped in local optimum. The Rosenbrock function and Schaffer function, which are complex and global optimum functions and often used as benchmarks for contemporary optimization algorithms for GAs and Evolutionary computation, are first employed to examine the performance of the GA and CGA. The test results indicate that CGA can improve convergence speed and solution accuracy. Furthermore, the developed model is applied for the monthly operation of a hydropower reservoir with a series of monthly inflow of 38 years. The results show that the long term average annual energy based CGA is the best and its convergent speed not only is faster than dynamic programming largely, but also overpasses the standard GA. Thus, the proposed approach is feasible and effective in optimal operations of complex reservoir systems.
TL;DR: The identification and subsequent characterization of oncogenes in human tumours is making it possible to unveil the molecular bases of human neoplasia, and it was reasoned that cellular genes may become activated by somatic mutations that mimic the changes imposed upon these loci during retroviral transduction.
Abstract: The identification and subsequent characterization of oncogenes in human tumours is making it possible to unveil the molecular bases of human neoplasia [I]. The concept of oncogene emanated from work started over 20 years ago with tumour viruses. Genetic and biochemical evidence defined the existence of small regions within the viral genome whose expression was sufficient to trigger carcinogenesis. More than two dozen of these viral oncogenes have been identified and characterized so far, particularly since the advent of recombinant DNA technology [2]. The realization that some of these viral oncogenes had a cellular origin [3] alerted scientists to the possibility that related oncogenes may also exist in non-virally induced neoplasms including those of humans. I t was reasoned that cellular genes (protooncogenes) may become activated by somatic mutations that mimic the changes imposed upon these loci during retroviral transduction. Testing this hypothesis became possible thanks to the development of gene transfer technologies during the 1970s [4]. Gene transfer assays revealed that about 20% of human tumours contained dominant oncogenes capable of inducing the malignant transformation of suitable rodent cells [5-71. Most of these transforming genes were subsequently found to be members of the ras gene family [8]. ras oncogenes had been previously identified as the transforming principle of several strains of murine sarcoma retroviruses [9,10]. To date, three ras genes, designated H-ras, K-ras, and N-ras, have been isolated from humans as well as other mammals. In addition, ras genes have been identified in birds, insects, mol-
TL;DR: PIK3CA mutation is significantly associated with other key molecular events in colorectal cancer, and MGMT loss likely contributes to the development of Pik3CA G>A mutation, and Pyrosequencing is useful in detecting PIK3 CA mutation in archival paraffin tumor tissue.
TL;DR: Infevers (Internet Fevers), a website dedicated to mutations responsible for hereditary autoinflammatory diseases, was created in 2002 and has continued to evolve, and its new design will lead to a more comprehensive comparative analysis and interpretation of auto‐inflammatory sequence variants.
Abstract: Infevers (Internet Fevers; http://fmf.igh.cnrs.fr/ISSAID/infevers), a website dedicated to mutations responsible for hereditary autoinflammatory diseases, was created in 2002 and has continued to evolve. This new version includes eight genes; six were already present: MEFV, MVK, TNFRSF1A, NLRP3, NOD2, PSTPIP1, and two are new, LPIN2 and NLRP7. Currently, Infevers contains over 540 sequence variants. Several new database functions were recently instituted. The website now accepts confidential data and complex alleles. For each gene, a newly created menu offers: 1) a tabular list of the variants that can be sorted by several parameters; 2) a gene graph providing a schematic representation of the variants along the gene; 3) statistical analysis of the data according to the phenotype, alteration type, and location of the mutation in the gene; 4) the cDNA and gDNA sequences of each gene, showing the nucleotide changes along the sequence, with a color-based code highlighting the gene domains, the first ATG, and the termination codon; and 5) a "download" menu making all tables and figures available for the users, which, except for the gene graphs, are all automatically generated and updated upon submission of the variants. Finally, the entire database was curated to comply with the HUGO Gene Nomenclature Committee (HGNC) and HGVS nomenclature guidelines, and wherever necessary, an informative note was provided. Infevers has already proven useful for the scientific community with a mean number of visits per month of 200 in 2002 and 800 in 2007, and its new design will lead to a more comprehensive comparative analysis and interpretation of auto-inflammatory sequence variants.
TL;DR: A novel autosomal-recessive syndrome that consists of female to male sex reversal and renal, adrenal, and lung dysgenesis and is associated with additional developmental defects is reported and attribute a pivotal role to WNT4 signaling during organogenesis in humans.
Abstract: The WNT-signaling pathway plays a major role during mammalian embryogenesis. We report a novel autosomal-recessive syndrome that consists of female to male sex reversal and renal, adrenal, and lung dysgenesis and is associated with additional developmental defects. Using a candidate-gene approach, we identified a disease-causing homozygous missense mutation in the human WNT4 gene. The mutation was found to result in markedly reduced WNT4 mRNA levels in vivo and in vitro and to downregulate WNT4-dependant inhibition of β-catenin degradation. Taken together with previous observations in animal models, the present data attribute a pivotal role to WNT4 signaling during organogenesis in humans.
TL;DR: Findings support the hypothesis that pain intensity and pain interference score are validated measures of advanced disease in men with prostate cancer.
Abstract: and pain intensity are significant predictors of overall survival in men with castrate-refractory prostate cancer. Furthermore, pain interference score and pain intensity are statistically significant predictors of overall survival even when adjusting for established prognostic factors. It is known that high levels of alkaline phosphatase, PSA, and lactate dehydrogenase; low levels of hemoglobin; and high Gleason scores are indicators of advanced progression and death. Thus, these findings support the hypothesis that pain intensity and pain interference score are validated measures of advanced disease in men with prostate cancer. We agree with Klepstad and Kaasa in that investigating the relationship between pain and clinical outcomes in cancer patients is a fruitful area of research.
TL;DR: The Align‐GVGD grades defined here are applicable to both the genetic epidemiology problem of classifying rare missense substitutions observed in known susceptibility genes and the molecular epidemiological problem of analyzing rare missens substitution observed during case‐control mutation screening studies of candidate susceptibility genes.
Abstract: Many individually rare missense substitutions are encountered during deep resequencing of candidate susceptibility genes and clinical mutation screening of known susceptibility genes BRCA1 and BRCA2 are among the most resequenced of all genes, and clinical mutation screening of these genes provides an extensive data set for analysis of rare missense substitutions Align-GVGD is a mathematically simple missense substitution analysis algorithm, based on the Grantham difference, which has already contributed to classification of missense substitutions in BRCA1, BRCA2, and CHEK2 However, the distribution of genetic risk as a function of Align-GVGD's output variables Grantham variation (GV) and Grantham deviation (GD) has not been well characterized Here, we used data from the Myriad Genetic Laboratories database of nearly 70,000 full-sequence tests plus two risk estimates, one approximating the odds ratio and the other reflecting strength of selection, to display the distribution of risk in the GV-GD plane as a series of surfaces We abstracted contours from the surfaces and used the contours to define a sequence of missense substitution grades ordered from greatest risk to least risk The grades were validated internally using a third, personal and family history-based, measure of risk The Align-GVGD grades defined here are applicable to both the genetic epidemiology problem of classifying rare missense substitutions observed in known susceptibility genes and the molecular epidemiology problem of analyzing rare missense substitutions observed during case-control mutation screening studies of candidate susceptibility genes
TL;DR: In high-risk families, selected in a genetics service setting, women who test positive for the familial BRCA1/BRCA2 mutation are likely to have cumulative breast cancer risks in keeping with the estimates obtained originally from large families.
Abstract: The identification of a BRCA1 or BRCA2 mutation in familial breast cancer kindreds allows genetic testing of at risk relatives. However, considerable controversy exists regarding the cancer risks in women who test positive for the family mutation. We reviewed 385 unrelated families (223 with BRCA1 and 162 with BRCA2 mutations) ascertained through two regional cancer genetics services. We estimated the penetrance for both breast and ovarian cancer in female mutation carriers (904 proven mutation carriers – 1442 females in total assumed to carry the mutation) and also assessed the effect on penetrance of mutation position and birth cohort. Breast cancer penetrance to 70 and to 80 years was 68% (95%CI 64.7–71.3%) and 79.5% (95%CI 75.5–83.5%) respectively for BRCA1 and 75% (95%CI 71.7–78.3%) and 88% (95%CI 85.3–91.7%) for BRCA2. Ovarian cancer risk to 70 and to 80 years was 60% (95%CI 65–71%) and 65% (95%CI 75–84%) for BRCA1 and 30% (95%CI 25.5–34.5%) and 37% (95%CI 31.5–42.5%) for BRCA2. These risks were borne out by a prospective study of cancer in the families and genetic testing of unaffected relatives. We also found evidence of a strong cohort effect with women born after 1940 having a cumulative risk of 22% for breast cancer by 40 years of age compared to 8% in women born before 1930 (p = 0.0005). In high-risk families, selected in a genetics service setting, women who test positive for the familial BRCA1/BRCA2 mutation are likely to have cumulative breast cancer risks in keeping with the estimates obtained originally from large families. This is particularly true for women born after 1940.
TL;DR: In this article, two new self-adaptive member grouping strategies and a new strategy to set the initial population are discussed, and the effect of the proposed strategies on the performance of the GA for capturing the global optimum is tested on the optimization of 2d and 3d truss structures.
10 May 2008
TL;DR: This paper addresses the problem of finding a small set of mutation operators which is still sufficient for measuring test effectiveness by defining a statistical analysis procedure that allows it to identify such a set, together with an associated linear model that predicts mutation adequacy with high accuracy.
Abstract: Mutants are automatically-generated, possibly faulty variants of programs. The mutation adequacy ratio of a test suite is the ratio of non-equivalent mutants it is able to identify to the total number of non-equivalent mutants. This ratio can be used as a measure of test effectiveness. However, it can be expensive to calculate, due to the large number of different mutation operators that have been proposed for generating the mutants. In this paper, we address the problem of finding a small set of mutation operators which is still sufficient for measuring test effectiveness. We do this by defining a statistical analysis procedure that allows us to identify such a set, together with an associated linear model that predicts mutation adequacy with high accuracy. We confirm the validity of our procedure through cross-validation and the application of other, alternative statistical analyses.
TL;DR: Results are in contrast to the view that molecular rates are time dependent, and the rate of evolution of the same HVR I region, determined using DNA sequences from 162 known age sub-fossil bones spanning a 37,000-year period, was 0.7%.
Abstract: Precise estimations of molecular rates are fundamental to our understanding of the processes of evolution. In principle, mutation and evolutionary rates for neutral regions of the same species are expected to be equal. However, a number of recent studies have shown that mutation rates estimated from pedigree material are much faster than evolutionary rates measured over longer time periods. To resolve this apparent contradiction, we have examined the hypervariable region (HVR I) of the mitochondrial genome using families of Adelie penguins (Pygoscelis adeliae) from the Antarctic. We sequenced 344 bps of the HVR I from penguins comprising 508 families with 915 chicks, together with both their parents. All of the 62 germline heteroplasmies that we detected in mothers were also detected in their offspring, consistent with maternal inheritance. These data give an estimated mutation rate (m) of 0.55 mutations/site/Myrs (HPD 95% confidence interval of 0.29-0.88 mutations/site/Myrs) after accounting for the persistence of these heteroplasmies and the sensitivity of current detection methods. In comparison, the rate of evolution (k) of the same HVR I region, determined using DNA sequences from 162 known age sub-fossil bones spanning a 37,000-year period, was 0.86 substitutions/site/Myrs (HPD 95% confidence interval of 0.53 and 1.17). Importantly, the latter rate is not statistically different from our estimate of the mutation rate. These results are in contrast to the view that molecular rates are time dependent.
TL;DR: Estimation of population parameters for the common ancestors of humans and the great apes showed a major reduction in X chromosome effective population size peculiar to the human-chimpanzee common ancestor, possibly due to selective sweeps on the X prior to separation of the 2 species.
Abstract: Estimation of population parameters for the common ancestors of humans and the great apes is important in understanding our evolutionary history. In particular, inference of population size for the human-chimpanzee common ancestor may shed light on the process by which the 2 species separated and on whether the human population experienced a severe size reduction in its early evolutionary history. In this study, the Bayesian method of ancestral inference of Rannala and Yang (2003. Bayes estimation of species divergence times and ancestral population sizes using DNA sequences from multiple loci. Genetics. 164:1645-1656) was extended to accommodate variable mutation rates among loci and random species-specific sequencing errors. The model was applied to analyze a genome-wide data set of similar to 15,000 neutral loci (7.4 Mb) aligned for human, chimpanzee, gorilla, orangutan, and macaque. We obtained robust and precise estimates for effective population sizes along the hominoid lineage extending back similar to 30 Myr to the cercopithecoid divergence. The results showed that ancestral populations were 5-10 times larger than modern humans along the entire hominoid lineage. The estimates were robust to the priors used and to model assumptions about recombination. The unusually low X chromosome divergence between human and chimpanzee could not be explained by variation in the male mutation bias or by current models of hybridization and introgression. Instead, our parameter estimates were consistent with a simple instantaneous process for human-chimpanzee speciation but showed a major reduction in X chromosome effective population size peculiar to the human-chimpanzee common ancestor, possibly due to selective sweeps on the X prior to separation of the 2 species.
TL;DR: In this paper, a representation theoretic interpretation of matrix mutation, using tilting theory in cluster categories of hereditary algebras, was given. But this interpretation is restricted to finite types.
Abstract: Matrix mutation appears in the definition of cluster algebras of Fomin and Zelevinsky. We give a representation theoretic interpretation of matrix mutation, using tilting theory in cluster categories of hereditary alge- bras. Using this, we obtain a representation theoretic interpretation of cluster mutation in case of acyclic cluster algebras of finite type.
TL;DR: It is found that the TS mutation powerfully and selectively slows VDI while sparing or possibly speeding the kinetics of CDI, a promising starting point for exploring the underlying pathophysiology of autism.
Abstract: Calcium entry into excitable cells is an important physiological signal, supported by and highly sensitive to the activity of voltage-gated Ca2+ channels. After membrane depolarization, Ca2+ channels first open but then undergo various forms of negative feedback regulation including voltage- and calcium-dependent inactivation (VDI and CDI, respectively). Inactivation of Ca2+ channel activity is perturbed in a rare yet devastating disorder known as Timothy syndrome (TS), whose features include autism or autism spectrum disorder along with severe cardiac arrhythmia and developmental abnormalities. Most cases of TS arise from a sporadic single nucleotide change that generates a mutation (G406R) in the pore-forming subunit of the L-type Ca2+ channel Ca(V)1.2. We found that the TS mutation powerfully and selectively slows VDI while sparing or possibly speeding the kinetics of CDI. The deceleration of VDI was observed when the L-type channels were expressed with beta1 subunits prominent in brain, as well as beta2 subunits of importance for the heart. Dissociation of VDI and CDI was further substantiated by measurements of Ca2+ channel gating currents and by analysis of another channel mutation (I1624A) that hastens VDI, acting upstream of the step involving Gly406. As highlighted by the TS mutation, CDI does not proceed to completeness but levels off at approximately 50%, consistent with a change in gating modes and not an absorbing inactivation process. Thus, the TS mutation offers a unique perspective on mechanisms of inactivation as well as a promising starting point for exploring the underlying pathophysiology of autism.
TL;DR: This paper used association mapping to characterize the phenotypic effects of the dw3 mutation and fine map a second, epistatic dwarfing quantitative trait loci on sorghum chromosome 9 (Sb-HT9.1).
Abstract: Of the four major dwarfing genes described in sorghum, only Dw3 has been cloned. We used association mapping to characterize the phenotypic effects of the dw3 mutation and to fine map a second, epistatic dwarfing QTL on sorghum chromosome 9 (Sb-HT9.1). Our panel of 378 sorghum inbreds includes 230 sorghum conversion (SC) lines, which are exotic lines that have been introgressed with dwarfing quantitative trait loci (QTL) from a common parent. The causal mutation in dw3 associates with reduced lower internode length and an elongation of the apex, consistent with its role as an auxin efflux carrier. Lines carrying the dw3 mutation display high haplotype homozygosity over several megabases in the Dw3 region, but most markers linked to Dw3 do not associate significantly with plant height due to allele sharing between Dw3 and dw3 individuals. Using markers with a high mutation rate and the dw3 mutation as an interaction term, significant trait associations were detected across a 7-Mb region around Sb-HT9.1, largely due to higher detection power in the SC lines. Conversely, the likely QTL interval for Sb-HT9.1 was reduced to ∼100 kb, demonstrating that the unique structure of this association panel provides both power and resolution for a genomewide scan.
TL;DR: It is suggested that research into further increasing this mutation rate artificially as an antiviral treatment requires a theoretical reevaluation, especially relating to the so-called error threshold.
Abstract: RNA viruses have an extremely high mutation rate, and we argue that the most plausible explanation for this is a trade-off with replication speed. We suggest that research into further increasing this mutation rate artificially as an antiviral treatment requires a theoretical reevaluation, especially relating to the so-called error threshold. The main evolutionary consequence of a high mutation rate appears to have been to restrict RNA viruses to a small genome; they thus rapidly exploit a limited array of possibilities. Investigating this constraint to their evolution, and how it is occasionally overcome, promises to be fruitful. We explain the many terms used in investigating RNA viral evolution and highlight the specific experimental and comparative work that needs to be done.
TL;DR: In the limit of rare mutations, it is shown that a possible approximation is a jump process, justifying rigorously the so-called trait substitution sequence, and unify different points of view concerning mutation-selection evolutionary models.
Abstract: We are interested in modelling Darwinian evolution, resulting from the interplay of phenotypic variation and natural selection through ecological interactions Our models are rooted in the microscopic, stochastic description of a population of discrete individuals characterized by one or several adaptive traits The population is modelled as a stochastic point process whose generator captures the probabilistic dynamics over continuous time of birth, mutation, and death, as influenced by each individual's trait values, and interactions between individuals An offspring usually inherits the trait values of her progenitor, except when a mutation causes the offspring to take an instantaneous mutation step at birth to new trait values We look for tractable large population approximations By combining various scalings on population size, birth and death rates, mutation rate, mutation step, or time, a single microscopic model is shown to lead to contrasting macroscopic limits, of different nature: deterministic, in the form of ordinary, integro-, or partial differential equations, or probabilistic, like stochastic partial differential equations or superprocesses In the limit of rare mutations, we show that a possible approximation is a jump process, justifying rigorously the so-called trait substitution sequence We thus unify different points of view concerning mutation-selection evolutionary models
TL;DR: The Q148H mutation is responsible for resistance to Raltegravir whereas the G140S mutation increases viral fitness in the G 140S/Q148H context.
Abstract: Raltegravir (MK-0518) is the first integrase (IN) inhibitor to be approved by the US FDA and is currently used in clinical treatment of viruses resistant to other antiretroviral compounds. Virological failure of Raltegravir treatment is associated with mutations in the IN gene following two main distinct genetic pathways involving either the N155 or Q148 residue. Importantly, in most cases, an additional mutation at the position G140 is associated with the Q148 pathway. Here, we investigated the viral DNA kinetics for mutants identified in Raltegravir-resistant patients. We found that (i) integration is impaired for Q148H when compared with the wild-type, G140S and G140S/Q148H mutants; and (ii) the N155H and G140S mutations confer lower levels of resistance than the Q148H mutation. We also characterized the corresponding recombinant INs properties. Enzymatic performances closely parallel ex vivo studies. The Q148H mutation ‘freezes’ IN into a catalytically inactive state. By contrast, the conformational transition converting the inactive form into an active form is rescued by the G140S/Q148H double mutation. In conclusion, the Q148H mutation is responsible for resistance to Raltegravir whereas the G140S mutation increases viral fitness in the G140S/Q148H context. Altogether, these results account for the predominance of G140S/Q148H mutants in clinical trials using Raltegravir.