Abstract: Cancer genome sequencing provides the first direct information on how mutation rates vary across the human genome in somatic cells. Testing diverse genetic and epigenetic features, here we show that mutation rates in cancer genomes are strikingly related to chromatin organization. Indeed, at the megabase scale, a single feature—levels of the heterochromatin-associated histone modification H3K9me3—can account for more than 40% of mutation-rate variation, and a combination of features can account for more than 55%. The strong association between mutation rates and chromatin organization is upheld in samples from different tissues and for different mutation types. This suggests that the arrangement of the genome into heterochromatin- and euchromatin-like domains is a dominant influence on regional mutation-rate variation in human somatic cells.

Abstract: Differential evolution (DE) is one of the most powerful stochastic real parameter optimizers of current interest In this paper, we propose a new mutation strategy, a fitness- induced parent selection scheme for the binomial crossover of DE, and a simple but effective scheme of adapting two of its most important control parameters with an objective of achieving improved performance The new mutation operator, which we call DE/current-to-gr_best/1, js a variant of the classical DE/current-to-best/1 scheme It uses the best of a group (whose size is q% of the population size) of randomly selected solutions from current generation to perturb the parent (target) vector, unlike DE/current-to-best/1 that always picks the best vector of the entire population to perturb the target vector In our modified framework of recombination, a biased parent selection scheme has been incorporated by letting each mutant undergo the usual binomial crossover with one of the p top-ranked individuals from the current population and not with the target vector with the same index as used in all variants of DE A DE variant obtained by integrating the proposed mutation, crossover, and parameter adaptation strategies with the classical DE framework (developed in 1995) is compared with two classical and four state-of-the-art adaptive DE variants over 25 standard numerical benchmarks taken from the IEEE Congress on Evolutionary Computation 2005 competition and special session on real parameter optimization Our comparative study indicates that the proposed schemes improve the performance of DE by a large magnitude such that it becomes capable of enjoying statistical superiority over the state-of-the-art DE variants for a wide variety of test problems Finally, we experimentally demonstrate that, if one or more of our proposed strategies are integrated with existing powerful DE variants such as jDE and JADE, their performances can also be enhanced

Abstract: Mutation dictates the tempo and mode of evolution, and like all traits, the mutation rate is subject to evolutionary modification. Here, we report refined estimates of the mutation rate for a prokaryote with an exceptionally small genome and for a unicellular eukaryote with a large genome. Combined with prior results, these estimates provide the basis for a potentially unifying explanation for the wide range in mutation rates that exists among organisms. Natural selection appears to reduce the mutation rate of a species to a level that scales negatively with both the effective population size (Ne), which imposes a drift barrier to the evolution of molecular refinements, and the genomic content of coding DNA, which is proportional to the target size for deleterious mutations. As a consequence of an expansion in genome size, some microbial eukaryotes with large Ne appear to have evolved mutation rates that are lower than those known to occur in prokaryotes, but multicellular eukaryotes have experienced elevations in the genome-wide deleterious mutation rate because of substantial reductions in Ne.

Abstract: In this paper, a neighborhood mutation strategy is proposed and integrated with various niching differential evolution (DE) algorithms to solve multimodal optimization problems. Although variants of DE are highly effective in locating a single global optimum, no DE variant performs competitively when solving multi-optima problems. In the proposed neighborhood based differential evolution, the mutation is performed within each Euclidean neighborhood. The neighborhood mutation is able to maintain the multiple optima found during the evolution and evolve toward the respective global/local optimum. To test the performance of the proposed neighborhood mutation DE, a total of 29 problem instances are used. The proposed algorithms are compared with a number of state-of-the-art multimodal optimization approaches and the experimental results suggest that although the idea of neighborhood mutation is simple, it is able to provide better and more consistent performance over the state-of-the-art multimodal algorithms. In addition, a comparative survey on niching algorithms and their applications are also presented.

Abstract: The paper reflects on the methodological challenges involved in research on the movement and mutation of fast-moving policies, through globalizing networks and across translocal settings. Inspired ...

Abstract: Mutations are the raw material of evolution but have been difficult to study directly. We report the largest study of new mutations to date, comprising 2,058 germline changes discovered by analyzing 85,289 Icelanders at 2,477 microsatellites. The paternal-to-maternal mutation rate ratio is 3.3, and the rate in fathers doubles from age 20 to 58, whereas there is no association with age in mothers. Longer microsatellite alleles are more mutagenic and tend to decrease in length, whereas the opposite is seen for shorter alleles. We use these empirical observations to build a model that we apply to individuals for whom we have both genome sequence and microsatellite data, allowing us to estimate key parameters of evolution without calibration to the fossil record. We infer that the sequence mutation rate is 1.4-2.3×10(-8) mutations per base pair per generation (90% credible interval) and that human-chimpanzee speciation occurred 3.7-6.6 million years ago.

Abstract: In representation theory of algebras the notion of 'mutation' often plays important roles, and two cases are well known, i.e. 'cluster tilting mutation' and 'exceptional mutation'. In this paper we focus on 'tilting mutation', which has a disadvantage that it is often impossible, i.e. some of summands of a tilting object can not be replaced to get a new tilting object. The aim of this paper is to take away this disadvantage by introducing 'silting mutation' for silting objects as a generalization of 'tilting mutation'. We shall develop a basic theory of silting mutation. In particular, we introduce a partial order on the set of silting objects and establish the relationship with 'silting mutation' by generalizing the theory of Riedtmann-Schofield and Happel-Unger. We show that iterated silting mutation act transitively on the set of silting objects for local, hereditary or canonical algebras. Finally we give a bijection between silting subcategories and certain t-structures.

Abstract: To assess the quality of test suites, mutation analysis seeds artificial defects (mutations) into programs; a nondetected mutation indicates a weakness in the test suite We present an automated approach to generate unit tests that detect these mutations for object-oriented classes This has two advantages: First, the resulting test suite is optimized toward finding defects modeled by mutation operators rather than covering code Second, the state change caused by mutations induces oracles that precisely detect the mutants Evaluated on 10 open source libraries, our μtest prototype generates test suites that find significantly more seeded defects than the original manually written test suites

Abstract: Pathological data from autopsies genotyped for Parkinson's disease (PD)-related mutations in alpha-synuclein, Parkin, PINK1, DJ1, LRRK2, and glucocerebrosidase have accumulated in recent years. The aim of this review is to systematically review all pathological reports of mutation carriers and to identify pathological patterns and gaps in the currently available data. A systematic review of the English literature was done using the terms "Parkinson's disease," "brain pathology," "autopsy," the specific gene nomenclature, and any combination of the above. Most studies included reports of convenience samples: either cases that were preidentified as mutation carriers before autopsy or screens of Lewy body brain banks. Nineteen autopsies of alpha-synuclein mutation carriers, 49 of LRRK2 mutation carriers, nine of Parkin mutation carriers, one of a PINK1 mutation carrier, and 86 of glucocerebrosidase mutation carriers were identified. Most autopsies of alpha-synuclein, LRRK2 G2019S, and glucocerebrosidase mutation carriers demonstrated Lewy body pathology, as opposed to Parkin and LRRK2 non-G2019S mutation carriers. However, there was a marked variability in pathological findings, even among carriers of identical mutations. Pathological data from DJ1 mutation carriers, nonmanifesting mutation carriers (e.g., of LRRK2 mutations), and carriers of a single Parkin mutation were lacking. In gathering together all studies of PD autopsies with an identified genetic risk, this review highlights the wealth of information generated as well as shortcomings in the available data. In particular, there is a need for larger, unbiased pathological studies. Differential association of Lewy pathology with specific mutations may reflect heterogeneity in pathogenic mechanisms among the different PD-related genes.

Abstract: Knowledge of the rate and pattern of new mutation is critical to the understanding of human disease and evolution. We used extensive autozygosity in a genealogically well-defined population of Hutterites to estimate the human sequence mutation rate over multiple generations. We sequenced whole genomes from 5 parent-offspring trios and identified 44 segments of autozygosity. Using the number of meioses separating each pair of autozygous alleles and the 72 validated heterozygous single-nucleotide variants (SNVs) from 512 Mb of autozygous DNA, we obtained an SNV mutation rate of 1.20 × 10(-8) (95% confidence interval 0.89-1.43 × 10(-8)) mutations per base pair per generation. The mutation rate for bases within CpG dinucleotides (9.72 × 10(-8)) was 9.5-fold that of non-CpG bases, and there was strong evidence (P = 2.67 × 10(-4)) for a paternal bias in the origin of new mutations (85% paternal). We observed a non-uniform distribution of heterozygous SNVs (both newly identified and known) in the autozygous segments (P = 0.001), which is suggestive of mutational hotspots or sites of long-range gene conversion.

Abstract: Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous disorder associated with bone fragility and susceptibility to fractures after minimal trauma. OI type V has an autosomal-dominant pattern of inheritance and is not caused by mutations in the type I collagen genes COL1A1 and COL1A2. The most remarkable and pathognomonic feature, observed in ∼65% of affected individuals, is a predisposition to develop hyperplastic callus after fractures or surgical interventions. To identify the molecular cause of OI type V, we performed whole-exome sequencing in a female with OI type V and her unaffected parents and searched for de novo mutations. We found a heterozygous de novo mutation in the 5′-untranslated region of IFITM5 (the gene encoding Interferon induced transmembrane protein 5), 14 bp upstream of the annotated translation initiation codon (c.−14C>T). Subsequently, we identified an identical heterozygous de novo mutation in a second individual with OI type V by Sanger sequencing, thereby confirming that this is the causal mutation for the phenotype. IFITM5 is a protein that is highly enriched in osteoblasts and has a putative function in bone formation and osteoblast maturation. The mutation c.−14C>T introduces an upstream start codon that is in frame with the reference open-reading frame of IFITM5 and is embedded into a stronger Kozak consensus sequence for translation initiation than the annotated start codon. In vitro, eukaryotic cells were able to recognize this start codon, and they used it instead of the reference translation initiation signal. This suggests that five amino acids (Met-Ala-Leu-Glu-Pro) are added to the N terminus and alter IFITM5 function in individuals with the mutation.

Abstract: Two studies recently identified a GGGGCC hexanucleotide repeat expansion in a non-coding region of the chromosome 9 open-reading frame 72 gene (C9ORF72) as the cause of chromosome 9p-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). In a cohort of 231 probands with ALS, we identified the C9ORF72 mutation in 17 familial (27.4%) and six sporadic (3.6%) cases. Patients with the mutation presented with typical motor features of ALS, although subjects with the C9ORF72 mutation had more frequent bulbar onset, compared to those without this mutation. Dementia was significantly more common in ALS patients and families with the C9ORF72 mutation and was usually early-onset FTD. There was striking clinical heterogeneity among the members of individual families with the mutation. The associated neuropathology was a combination of ALS with TDP-ir inclusions and FTLD-TDP. In addition to TDP-43-immunoreactive pathology, a consistent and specific feature of cases with the C9ORF72 mutation was the presence of ubiquitin-positive, TDP-43-negative inclusions in a variety of neuroanatomical regions, such as the cerebellar cortex. These findings support the C9ORF72 mutation as an important newly recognized cause of ALS, provide a more detailed characterization of the associated clinical and pathological features and further demonstrate the clinical and molecular overlap between ALS and FTD.

Abstract: Genetic mapping of mutations in model systems has facilitated the identification of genes contributing to fundamental biological processes including human diseases. However, this approach has historically required the prior characterization of informative markers. Here we report a fast and cost-effective method for genetic mapping using next-generation sequencing that combines single nucleotide polymorphism discovery, mutation localization, and potential identification of causal sequence variants. In contrast to prior approaches, we have developed a hidden Markov model to narrowly define the mutation area by inferring recombination breakpoints of chromosomes in the mutant pool. In addition, we created an interactive online software resource to facilitate automated analysis of sequencing data and demonstrate its utility in the zebrafish and mouse models. Our novel methodology and online tools will make next-generation sequencing an easily applicable resource for mutation mapping in all model systems.

Abstract: Mutation plays a central role in all evolutionary processes and is also the basis of genetic disorders. Established base-substitution mutation rates in eukaryotes range between ∼5 × 10−10 and 5 × 10−8 per site per generation, but here we report a genome-wide estimate for Paramecium tetraurelia that is more than an order of magnitude lower than any previous eukaryotic estimate. Nevertheless, when the mutation rate per cell division is extrapolated to the length of the sexual cycle for this protist, the measure obtained is comparable to that for multicellular species with similar genome sizes. Because Paramecium has a transcriptionally silent germ-line nucleus, these results are consistent with the hypothesis that natural selection operates on the cumulative germ-line replication fidelity per episode of somatic gene expression, with the germ-line mutation rate per cell division evolving downward to the lower barrier imposed by random genetic drift. We observe ciliate-specific modifications of widely conserved amino acid sites in DNA polymerases as one potential explanation for unusually high levels of replication fidelity.

Abstract: USH2A sequencing in three affected members of a large family, referred for the recessive USH2 syndrome, identified a single pathogenic alteration in one of them and a different mutation in the two affected nieces. As the patients carried a common USH2A haplotype, they likely shared a mutation not found by standard sequencing techniques. Analysis of RNA from nasal cells in one affected individual identified an additional pseudoexon (PE) resulting from a deep intronic mutation. This was confirmed by minigene assay. This is the first example in Usher syndrome (USH) with a mutation causing activation of a PE. The finding of this alteration in eight other individuals of mixed European origin emphasizes the importance of including RNA analysis in a comprehensive diagnostic service. Finally, this mutation, which would not have been found by whole-exome sequencing, could offer, for the first time in USH, the possibility of therapeutic correction by antisense oligonucleotides (AONs).

Abstract: S.K. Narayan, MD, DM G. Gorman, MRCPI R.N. Kalaria, FRCP G.A. Ford, FRCP P.F. Chinnery, PhD, FRCP, FMedSci THE MINIMUM PREVALENCE OF CADASIL IN NORTHEAST ENGLAND Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary small vessel brain disease, and is caused by mutations in NOTCH3. The disorder is often overlooked and misdiagnosed, and the population prevalences are generally not known. Over 100 families exist in France, with similar numbers in the United Kingdom,1 and 200 in Germany.2 In Finland, the reported prevalence is 2–4 per 100,000,3 and in west Scotland, 1.98 per 100,000 have a definite diagnosis, and 4.14 per 100,000 are predicted mutation carriers.4 However, both of these study populations include relative genetic isolates. We carried out a study to determine the prevalence of CADASIL in an outbred Western European population in the northeast of England.

Abstract: DNA mutations are the source of genetic variation within populations. The majority of mutations with observable effects are deleterious. In humans mutations in the germ line can cause genetic disease. In somatic cells multiple rounds of mutations and selection lead to cancer. The study of genetic variation has progressed rapidly since the completion of the draft sequence of the human genome. Recent advances in sequencing technology, most importantly the introduction of massively parallel sequencing (MPS), have resulted in more than a hundred-fold reduction in the time and cost required for sequencing nucleic acids. These improvements have greatly expanded the use of sequencing as a practical tool for mutation analysis. While in the past the high cost of sequencing limited mutation analysis to selectable markers or small forward mutation targets assumed to be representative for the genome overall, current platforms allow whole genome sequencing for less than $5000. This has already given rise to direct estimates of germline mutation rates in multiple organisms including humans by comparing whole genome sequences between parents and offspring. Here we present a brief history of the field of mutation research, with a focus on classical tools for the measurement of mutation rates. We then review MPS, how it is currently applied and the new insight into human and animal mutation frequencies and spectra that has been obtained from whole genome sequencing. While great progress has been made, we note that the single most important limitation of current MPS approaches for mutation analysis is the inability to address low-abundance mutations that turn somatic tissues into mosaics of cells. Such mutations are at the basis of intra-tumor heterogeneity, with important implications for clinical diagnosis, and could also contribute to somatic diseases other than cancer, including aging. Some possible approaches to gain access to low-abundance mutations are discussed, with a brief overview of new sequencing platforms that are currently waiting in the wings to advance this exploding field even further.

Abstract: Many fault localization techniques operate by crosscutting coverage information of passed and failed test executions. Generally, their accuracy depends on the utilized coverage elements and on the selected test cases. This paper proposes a novel fault localization method using mutation and investigates its accuracy when using classical test selection criteria such as mutation, branch and block. A controlled experiment shows that (1) the mutation based approach is quite effective at identifying "unknown" faulty program statements. Additionally, the experimental results reveal (2) that the mutation-based test suites are significantly more effective at supporting fault localization than block or branch-based test suites. Further, (3) evidence in support of facilitating mutation alternatives, such as mutant sampling, in order to diminish mutation overheads is also given.

Abstract: In mammals, the Y chromosome plays the pivotal role in male sex determination and is essential for normal sperm production. Yet only three Y chromosomes have been completely sequenced to date—those of human, chimpanzee, and rhesus macaque. While Y chromosomes are notoriously difficult to sequence owing to their highly repetitive genomic landscapes, these dedicated sequencing efforts have generated tremendous yields in medical, biological, and evolutionary insight. Knowledge of the complex structural organization of the human Y chromosome and a complete catalog of its gene content have provided a deeper understanding of the mechanisms that generate disease-causing mutations and large-scale rearrangements. Variation among human Y-chromosome sequences has been an invaluable tool for understanding relationships among human populations. Comprehensive comparisons of the human Y-chromosome sequence with those of other primates have illuminated aspects of Y-chromosome evolutionary dynamics over much longer timescales (>25 million years compared with 100,000 years). The future sequencing of additional Y chromosomes will provide a basis for a more comprehensive understanding of the evolution of Y chromosomes and their roles in reproductive biology.

Abstract: In a family with a germline mutation in JAK2, thrombocytosis was noted in five family members carrying the mutation and not in family members without the mutation. Baseline colony formation was una...

Abstract: n engl j med 367;23 nejm.org december 6, 2012 2255 bust than the PA:A ratio. Rajagopalan et al. also suggest that sex differences in aortic diameter could confound our results. However, in multivariate models, we observed no difference in the strength of the associations between a PA:A ratio of more than 1 and severe exacerbations in men (odds ratio, 3.35; 95% CI, 2.43 to 4.61; P<0.001) or women (odds ratio, 3.36; 95% CI, 2.51 to 4.48; P<0.001). Though we agree that electrocardiographically gated CT could improve the performance of the PA:A ratio, these studies are not frequently performed, and our robust findings support the practical value of nongated scans. J. Michael Wells, M.D.

Abstract: The baker's yeast mutation collections are extensively used genetic resources that are the basis for many genome-wide screens and new technologies. Anecdotal evidence has previously pointed to the putative existence of a neighboring gene effect (NGE) in these collections. NGE occurs when the phenotype of a strain carrying a particular perturbed gene is due to the lack of proper function of its adjacent gene. Here we performed a large-scale study of NGEs, presenting a network-based algorithm for detecting NGEs and validating software predictions using complementation experiments. We applied our approach to four datasets uncovering a similar magnitude of NGE in each (7-15%). These results have important consequences for systems biology, as the mutation collections are extensively used in almost every aspect of the field, from genetic network analysis to functional gene annotation.