Abstract: The fate of a newly arising beneficial mutation depends on many factors, such as the population size and the availability and fitness effects of other mutations that accumulate in the population. It has proved difficult to understand how these factors influence the trajectories of particular mutations, since experiments have primarily focused on characterizing successful clones emerging from a small number of evolving populations. Here, we present the results of a massively parallel experiment designed to measure the full spectrum of possible fates of new beneficial mutations in hundreds of experimental yeast populations, whether these mutations are ultimately successful or not. Using strains in which a particular class of beneficial mutation is detectable by fluorescence, we followed the trajectories of these beneficial mutations across 592 independent populations for 1000 generations. We find that the fitness advantage provided by individual mutations plays a surprisingly small role. Rather, underlying “background” genetic variation is quickly generated in our initially clonal populations and plays a crucial role in determining the fate of each individual beneficial mutation in the evolving population.

Abstract: In this study, a new mutation operator has been developed to increase Genetic Algorithm (GA) performance to find the shortest distance in the known Traveling Salesman Problem (TSP). We called this method as Greedy Sub Tour Mutation (GSTM). There exist two different greedy search methods and a component that provides a distortion in this new operator. The developed GSTM operator was tested with simple GA mutation operators in 14 different TSP examples selected from TSPLIB. The application of this GSTM operator gives much more effective results regarding to the best and average error values. The GSTM operator used with simple GAs decreases the best error values according to the other mutation operators with the ratio of between 74.24% and 88.32% and average error values between 59.42% and 79.51%.

Abstract: The genetic code is redundant with most amino acids using multiple codons. In many organisms, codon usage is biased toward particular codons. Understanding the adaptive and nonadaptive forces driving the evolution of codon usage bias (CUB) has been an area of intense focus and debate in the fields of molecular and evolutionary biology. However, their relative importance in shaping genomic patterns of CUB remains unsolved. Using a nested model of protein translation and population genetics, we show that observed gene level variation of CUB in Saccharomyces cerevisiae can be explained almost entirely by selection for efficient ribosomal usage, genetic drift, and biased mutation. The correlation between observed codon counts within individual genes and our model predictions is 0.96. Although a variety of factors shape patterns of CUB at the level of individual sites within genes, our results suggest that selection for efficient ribosome usage is a central force in shaping codon usage at the genomic scale. In addition, our model allows direct estimation of codon-specific mutation rates and elongation times and can be readily applied to any organism with high-throughput expression datasets. More generally, we have developed a natural framework for integrating models of molecular processes to population genetics models to quantitatively estimate parameters underlying fundamental biological processes, such a protein translation.

Abstract: To accelerate functional genomic research in tomato, we developed a Micro-Tom TILLING (Targeting Induced Local Lesions In Genomes) platform. DNA pools were constructed from 3,052 ethyl methanesulfonate (EMS) mutant lines treated with 0.5 or 1.0% EMS. The mutation frequency was calculated by screening 10 genes. The 0.5% EMS population had a mild mutation frequency of one mutation per 1,710kb, whereas the 1.0% EMS population had a frequency of one mutation per 737kb, a frequency suitable for producing an allelic series of mutations in the target genes. The overall mutation frequency was one mutation per 1,237kb, which affected an average of three alleles per kilobase screened. To assess whether a Micro-Tom TILLING platform could be used for efficient mutant isolation, six ethylene receptor genes in tomato (SlETR1–SlETR6) were screened. Two allelic mutants of SlETR1 (Sletr1-1 and Sletr1-2) that resulted in reduced ethylene responses were identified, indicating that our Micro-Tom TILLING platform provides a powerful tool for the rapid detection of mutations in an EMS mutant library. This work provides a practical and publicly accessible tool for the study of fruit biology and for obtaining novel genetic material that can be used to improve important agronomic traits in tomato.

Abstract: Background: Genetic analysis is commonly performed in patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Study Objective: The objective of the study was to describe comprehensive CYP21A2 mutation analysis in a large cohort of CAH patients. Methods: Targeted CYP21A2 mutation analysis was performed in 213 patients and 232 parents from 182 unrelated families. Complete exons of CYP21A2 were sequenced in patients in whom positive mutations were not identified by targeted mutation analysis. Copy number variation and deletions were determined using Southern blot analysis and PCR methods. Genotype was correlated with phenotype. Results: In our heterogeneous U.S. cohort, targeted CYP21A2 mutation analysis did not identify mutations on one allele in 19 probands (10.4%). Sequencing identified six novel mutations (p.Gln262fs, IVS8+1G>A, IVS9-1G>A, p.R408H, p.Gly424fs, p.R426P) and nine previously reported rare mutations. The majority of patients (79%) were compound heterozygotes and 69% of nonclassic (NC) patients were compound heterozygous for a classic and a NC mutation. Duplicated CYP21A2 haplotypes, de novo mutations and uniparental disomy were present in 2.7% of probands and 1.9 and 0.9% of patients from informative families, respectively. Genotype accurately predicted phenotype in 90.5, 85.1, and 97.8% of patients with salt-wasting, simple virilizing, and NC mutations, respectively. Conclusions: Extensive genetic analysis beyond targeted CYP21A2 mutational detection is often required to accurately determine genotype in patients with CAH due to the high frequency of complex genetic variation.

Abstract: In this paper, self-adaptive differential evolution (DE) is enhanced by incorporating the JADE mutation strategy and hybridized with modified multi-trajectory search (MMTS) algorithm (SaDE-MMTS) to solve large-scale continuous optimization problems. The JADE mutation strategy, the “DE/current-to-pbest” which is a variation of the classic “DE/current-to-best”, is used for generating mutant vectors. After the mutation phase, the binomial (uniform) crossover, the exponential crossover as well as no crossover option are used to generate each pair of target and trial vectors. By utilizing the self-adaptation in SaDE, both trial vector generation strategies and their associated control parameter values are gradually self-adapted by learning from their previous experiences in generating promising solutions. Consequently, suitable offspring generation strategy along with associated parameter settings will be determined adaptively to match different phases of the search process. MMTS is applied frequently to refine several diversely distributed solutions at different search stages satisfying both the global and the local search requirement. The initialization of step sizes is also defined by a self-adaption during every MMTS step. The success rates of both SaDE and the MMTS are determined and compared; consequently, future function evaluations for both search algorithms are assigned proportionally to their recent past performance. The proposed SaDE-MMTS is employed to solve the 19 numerical optimization problems in special issue of soft computing on scalability of evolutionary algorithms for large-scale continuous optimization problems and competitive results are presented.

Abstract: Approximately 1 of every 250 newborns has some abnormality of genital and/or gonadal development. However, a specific molecular cause is identified in only 20% of these cases of disorder of sex development (DSD). We identified a family of French origin presenting with 46,XY DSD and congenital heart disease. Sequencing of the ORF of GATA4 identified a heterozygous missense mutation (p.Gly221Arg) in the conserved N-terminal zinc finger of GATA4. This mutation was not observed in 450 ancestry-matched control individuals. The mutation compromised the ability of the protein to bind to and transactivate the anti-Mullerian hormone (AMH) promoter. The mutation does not interfere with the direct protein–protein interaction, but it disrupts synergistic activation of the AMH promoter by GATA4 and NR5A1. The p.Gly221Arg mutant protein also failed to bind to a known protein partner FOG2 that is essential for gonad formation. Our data demonstrate the key role of GATA4 in human testicular development.

Abstract: The BRCA1 mutation c.5266dupC was originally described as a founder mutation in the Ashkenazi Jewish (AJ) population. However, this mutation is also present at appreciable frequency in several European countries, which raises intriguing questions about the origins of the mutation. We genotyped 245 carrier families from 14 different population groups (Russian, Latvian, Ukrainian, Czech, Slovak, Polish, Danish, Dutch, French, German, Italian, Greek, Brazilian and AJ) for seven microsatellite markers and confirmed that all mutation carriers share a common haplotype from a single founder individual. Using a maximum likelihood method that allows for both recombination and mutational events of marker loci, we estimated that the mutation arose some 1800 years ago in either Scandinavia or what is now northern Russia and subsequently spread to the various populations we genotyped during the following centuries, including the AJ population. Age estimates and the molecular evolution profile of the most common linked haplotype in the carrier populations studied further suggest that c.5266dupC likely entered the AJ gene pool in Poland approximately 400-500 years ago. Our results illustrate that (1) BRCA1 c.5266dupC originated from a single common ancestor and was a common European mutation long before becoming an AJ founder mutation and (2) the mutation is likely present in many additional European countries where genetic screening of BRCA1 may not yet be common practice.

Abstract: We are interested in the study of models describing the evolution of a polymorphic population with mutation and selection in the specific scales of the biological framework of adaptive dynamics. The population size is assumed to be large and the mutation rate small. We prove that under a good combination of these two scales, the population process is approximated in the long time scale of mutations by a Markov pure jump process describing the successive trait equilibria of the population. This process, which generalizes the so-called trait substitution sequence, is called polymorphic evolution sequence. Then we introduce a scaling of the size of mutations and we study the polymorphic evolution sequence in the limit of small mutations. From this study in the neighborhood of evolutionary singularities, we obtain a full mathematical justification of a heuristic criterion for the phenomenon of evolutionary branching. To this end we finely analyze the asymptotic behavior of 3-dimensional competitive Lotka-Volterra systems.

Abstract: Understanding the impact of crossover on performance is a major problem in the theory of genetic algorithms (GAs). We present new insight on working principles of crossover by analyzing the performance of crossover-based GAs on the simple functions OneMax and Jump.First, we assess the potential speedup by crossover when combined with a fitness-invariant bit shuffling operator that simulates a lineage of independent evolution on a function of unitation. Theoretical and empirical results show drastic speedups for both functions.Second, we consider a simple GA without shuffling and investigate the interplay of mutation and crossover on Jump. If the crossover probability is small, subsequent mutations create sufficient diversity, even for very small populations. Contrarily, with high crossover probabilities crossover tends to lose diversity more quickly than mutation can create it. This has a drastic impact on the performance on Jump. We complement our theoretical findings by Monte Carlo simulations on the population diversity.

Abstract: We present a new method for proving lower bounds on the expected running time of evolutionary algorithms. It is based on fitness-level partitions and an additional condition on transition probabilities between fitness levels. The method is versatile, intuitive, elegant, and very powerful. It yields exact or near-exact lower bounds for LO, OneMax, long k-paths, and all functions with a unique optimum. Most lower bounds are very general: they hold for all evolutionary algorithms that only use bit-flip mutation as variation operator---i.e. for all selection operators and population models. The lower bounds are stated with their dependence on the mutation rate. These results have very strong implications. They allow to determine the optimal mutation-based algorithm for LO and OneMax, i.e., which algorithm minimizes the expected number of fitness evaluations. This includes the choice of the optimal mutation rate.

Abstract: Fermentation processes by nature are complex, time-varying, and highly nonlinear. As dynamic systems their modeling and further high-quality control are a serious challenge. The conventional optimization methods cannot overcome the fermentation processes peculiarities and do not lead to a satisfying solution. As an alternative, genetic algorithms as a stochastic global optimization method can be applied. For the purpose of parameter identification of a fed-batch cultivation of S. cerevisiae altogether four kinds of simple and four kinds of multipopulation genetic algorithms have been considered. Each of them is characterized with a different sequence of implementation of main genetic operators, namely, selection, crossover, and mutation. The influence of the most important genetic algorithm parameters—generation gap, crossover, and mutation rates has—been investigated too. Among the considered genetic algorithm parameters, generation gap influences most significantly the algorithm convergence time, saving up to 40% of time without affecting the model accuracy.

Abstract: Population bottlenecks can restrict variation at functional genes, reducing the ability of populations to adapt to new and changing environments. Understanding how populations generate adaptive genetic variation following bottlenecks is therefore central to evolutionary biology. Genes of the major histocompatibility complex (MHC) are ideal models for studying adaptive genetic variation due to their central role in pathogen recognition. While de novo MHC sequence variation is generated by point mutation, gene conversion can generate new haplotypes by transferring sections of DNA within and across duplicated MHC loci. However, the extent to which gene conversion generates new MHC haplotypes in wild populations is poorly understood. We developed a 454 sequencing protocol to screen MHC class I exon 3 variation across all 13 island populations of Berthelot’s pipit (Anthus berthelotii). We reveal that just 11–15 MHC haplotypes were retained when the Berthelot’s pipit dispersed across its island range in the North Atlantic ca. 75 000 years ago. Since then, at least 26 new haplotypes have been generated in situ across populations. We show that most of these haplotypes were generated by gene conversion across divergent lineages, and that the rate of gene conversion exceeded that of point mutation by an order of magnitude. Gene conversion resulted in significantly more changes at nucleotide sites directly involved with pathogen recognition, indicating selection for functional variants. We suggest that the creation of new variants by gene conversion is the predominant mechanism generating MHC variation in genetically depauperate populations, thus allowing them to respond to pathogenic challenges.

Abstract: Context The field of mutation analysis has been growing, both in the number of published papers and the number of active researchers. This special issue provides a sampling of recent advances and ideas. But do all the new researchers know where we started? Objective To imagine where we are going, we must first know where we are. To understand where we are, we must know where we have been. This paper reviews past mutation analysis research, considers the present, then imagines possible future directions. Method A retrospective study of past trends lets us the ability to see the current state of mutation research in a clear context, allowing us to imagine and then create future vectors. Results The value of mutation has greatly expanded since the early view of mutation as an expensive way to unit test subroutines. Our understanding of what mutation is and how it can help has become much deeper and broader. Conclusion Mutation analysis has been around for 35 years, but we are just now beginning to see its full potential. The papers in this issue and future mutation workshops will eventually allow us to realize this potential.

Abstract: Large-scale next generation resequencing of X chromosome genes identified a missense mutation in the CLIC2 gene on Xq28 in a male with X-linked intellectual disability (XLID) and not found in healthy individuals. At the same time, numerous nsSNPs (nonsynonomous SNP) have been reported in the CLIC2 gene in healthy individuals indicating that the CLIC2 protein can tolerate amino acid substitutions and be fully functional. To test the possibility that p.H101Q is a disease-causing mutation, we performed in silico simulations to calculate the effects of the p.H101Q mutation on CLIC2 stability, dynamics, and ionization states while comparing the effects obtained for presumably harmless nsSNPs. It was found that p.H101Q, in contrast with other nsSNPs, (a) lessens the flexibility of the joint loop which is important for the normal function of CLIC2, (b) makes the overall 3D structure of CLIC2 more stable and thus reduces the possibility of the large conformational change expected to occur when CLIC2 moves from a soluble to membrane form, and (c) removes the positively charged residue, H101, which may be important for the membrane association of CLIC2. The results of in silico modeling, in conjunction with the polymorphism analysis, suggest that p.H101Q may be a disease-causing mutation, the first one suggested in the CLIC family.

Abstract: We reviewed FLT3 and NPM1 mutation data in a large cohort of patients with myelodysplastic syndrome (MDS). The frequencies of FLT3 and NPM1 mutation were 2.0% and 4.4%, respectively, and mutations were restricted to cases of intermediate- and high-risk MDS. Cytogenetic abnormalities were identified in 46.9% of cases. FLT3 mutations were associated with a complex karyotype (P = .009), whereas NPM1 mutations were associated with a diploid karyotype (P < .001). FLT3 mutation (P < .001) was associated with progression to acute myeloid leukemia (AML), as were a higher bone marrow (BM) blast count (P < .001) and complex cytogenetics (P = .039). No patient with an NPM1 mutation alone had disease that progressed to AML. Cox proportional regression multivariate analysis indicated that FLT3 mutation, NPM1 mutation, complex cytogenetics, BM blast count, pancytopenia, and age were independent factors that correlated with progression-free survival. We conclude that FLT3 and NPM1 mutations are rare in MDS, but assessment of mutation status is potentially useful for predicting progression to AML.

Abstract: Panel A shows the binding patterns of heme with respect to mutations R159 and R396 in 25-hydroxyvitamin D 24-hydroxylase encoded by CYP24A1, indicating that hydrogen bonds exist between carboxyl groups of the heme propionate groups and R159 or R396 (Protein Data Bank entry, 3K9Y). Panel B shows the binding patterns of heme with respect to R159Q and R396W in the 24-hydroxylase mutant, indicating that no hydrogen bonds exist between the heme propionate groups and R159Q or R396W, in comparison with those in native 24-hydroxylase, which will weaken the binding of heme in the 24-hydroxylase mutant and hinder the catabolism of 1,25-dihydroxyvitamin D3. To the Editor: Schlingmann et al. (Aug. 4 issue)1 report that mutations in CYP24A1 are associated with increased sensitivity to vitamin D in patients with idiopathic infantile hypercalcemia. Since CYP24A1 encodes 25-hydroxyvitamin D 24-hydroxylase, the key enzyme of 1,25-dihydroxyvitamin D3 degradation, 2,3 mutations in CYP24A1 may alter the interacting patterns of 24-hydroxylase with 1,25-dihydroxyvitamin D3. In molecular-modeling simulations, we found that among the four missense mutations (R159Q, E322K, R396W, and L409S), only L409S weakens the binding of 1,25-dihydroxyvitamin D3 to 24-hydroxylase, whereas the other three mutations exert negligible influence. Since 1,25-dihydroxyvitamin D3 catabolism is heme-dependent in 24-hydroxylase,4 it is intriguing to explore whether the heme binding is influenced by the mutations. As expected, the other three mutations all change the interactions between heme and 24-hydroxylase. For instance, R159Q and R396W dramatically weaken the binding of heme to 24-hydroxylase because of the destruction of hydrogen bonds between the heme propionate group and arginine,5 which hinders the catabolism of 1,25-dihydroxyvitamin D3 (Fig. 1). These findings indicate that a mutation-induced loss of function in CYP24A1 acts through two pathways that influence the binding of 1,25-dihydroxyvitamin D3 or heme in 24-hydroxylase.

Abstract: Automating software testing activities can increase the quality and drastically decrease the cost of software development. Toward this direction, various automated test data generation tools have been developed. The majority of existing tools aim at structural testing, while a quite limited number aim at a higher level of testing thoroughness such as mutation. In this paper, an attempt toward automating the generation of mutation-based test cases by utilizing existing automated tools is proposed. This is achieved by reducing the killing mutants' problem into a covering branches one. To this extent, this paper is motivated by the use of state of the art techniques and tools suitable for covering program branches when performing mutation. Tools and techniques such as symbolic execution, concolic execution, and evolutionary testing can be easily adopted toward automating the test input generation activity for the weak mutation testing criterion by simply utilizing a special form of the mutant schemata technique. The propositions made in this paper integrate three automated tools in order to illustrate and examine the method's feasibility and effectiveness. The obtained results, based on a set of Java program units, indicate the applicability and effectiveness of the suggested technique. The results advocate that the proposed approach is able to guide existing automating tools in producing test cases according to the weak mutation testing criterion. Additionally, experimental results with the proposed mutation testing regime show that weak mutation is able to speedup the mutant execution time by at least 4.79 times when compared with strong mutation.

Abstract: PURPOSE To present an Arg213Trp missense mutation in the XLRS1 gene in a family with juvenile X-linked retinoschisis in which one affected male had a normal electroretinogram scotopic b-wave amplitude. METHODS Two affected males and one unaffected male from this family with X-linked retinoschisis underwent standard clinical examination including an electroretinogram. Mutations in the XLRS1 gene were detected by sequence analysis and by restriction enzyme assay for loss of an MSP-I restriction site. RESULTS A missense mutation of C to T at nucleotide position 637 was identified in exon 6 of the XLRS1 gene. This changed the positively charged arginine to a nonpolar tryptophan (Arg213Trp) within the biologically important discoidin domain. Clinical examination revealed intraretinal cysts in a spoke-wheel distribution and early macular atrophy of the retinal pigment epithelium. Whereas the older affected patient had an "electronegative" electroretinogram typical of retinoschisis, the 13-year-old grandson with the same XLRS1 mutation had a normal electroretinogram scotopic b-wave. CONCLUSION Although the electroretinogram is a key diagnostic test for X-linked retinoschisis, this report of a normal electroretinogram scotopic b-wave in a male with molecularly confirmed X-linked retinoschisis indicates that caution is advised in relying on the electroretinogram in differential diagnosis of this condition.

Abstract: Handling multimodal functions is a very important and challenging task in evolutionary computation community, since most of the real-world applications exhibit highly multi-modal landscapes. Motivated by the dynamics and the proximity characteristics of Differential Evolution's mutation strategies tending to distribute the individuals of the population to the vicinity of the problem's minima, we introduce two new Differential Evolution mutation strategies. The new mutation strategies incorporate spatial information about the neighborhood of each potential solution and exhibit a niching formation, without incorporating any additional parameter. Experimental results on eight well known multimodal functions and comparisons with some state-of-the-art algorithms indicate that the proposed mutation strategies are competitive and very promising, since they are able to reliably locate and maintain many global optima throughout the evolution process.

Abstract: With the advent of high-throughput DNA sequencing, it is now straightforward and inexpensive to generate high-density small nucleotide polymorphism (SNP) maps. Here we combined high-throughput sequencing with bulk segregant analysis to expedite mutation mapping. The general map location of a mutation can be identified by a single backcross to a strain enriched in SNPs compared to a standard wild-type strain. Bulk segregant analysis simultaneously increases the likelihood of determining the precise nature of the mutation. We present here a high-density SNP map between Neurospora crassa Mauriceville-1-c (FGSC2225) and OR74A (FGSC2489), the strains most typically used by Neurospora researchers to carry out mapping crosses. We further have demonstrated the utility of the Mauriceville sequence and our approach by mapping the mutation responsible for the only existing temperature-sensitive (ts) cell cycle mutation in Neurospora, nuclear division cycle-1 (ndc-1). The single T-to-C point mutation maps to the gene encoding ornithine decarboxylase (ODC), spe-1 (NCU01271), and changes a Phe to a Ser residue within a highly conserved motif next to the catalytic site of the enzyme. By growth on spermidine and complementation with a wild-type spe-1 gene, we showed that the defect in spe-1 is responsible for the ts ndc-1 mutation. Based on our results, we propose changing ndc-1 to spe-1(ndc), which reflects that this mutation results in an ODC with a specific nuclear division defect.

Abstract: Background: Most cases of multiple endocrine neoplasia type 2B (MEN-2B) are attributable to a germline methionine to threonine mutation at codon 918 (M918T) of the RET proto-oncogene; very few cases of a germline alanine to phenylalanine mutation at codon 883 (A883F) are reported without a clear description of the clinical course. Nevertheless, RET-A883F is currently considered to be among the highest risk mutations, and prophylactic thyroidectomy is recommended as early as 6 months of life. Further characterization of the clinical behavior of RET-A883F mutation is warranted. We present the clinical data for a family with MEN-2B associated with RET-A883F mutation. Summary: The proband, a 39-year-old woman, had multifocal medullary thyroid carcinoma (MTC) with cervical lymphadenopathy, but no evidence of distant metastases. She was disease free after surgical resection. She also had bilateral pheochromocytomas and mucosal neuromas leading to the clinical diagnosis of MEN-2B. Genetic testing showed that the...

Abstract: The invention provides compositions, methods, and kits related to half-Ig binding proteins that include a functional antibody binding site and a CH3 domain wherein the CH3 domain includes at least one mutation to inhibit CH3-CH3 dimerization.