Showing papers on "Mutation (genetic algorithm) published in 2003"

Human Gene Mutation Database (HGMD): 2003 update.

Abstract: The Human Gene Mutation Database (HGMD) constitutes a comprehensive core collection of data on germ-line mutations in nuclear genes underlying or associated with human inherited disease (www.hgmd.org). Data catalogued includes: single base-pair substitutions in coding, regulatory and splicing-relevant regions; micro-deletions and micro-insertions; indels; triplet repeat expansions as well as gross deletions; insertions; duplications; and complex rearrangements. Each mutation is entered into HGMD only once in order to avoid confusion between recurrent and identical-by-descent lesions. By March 2003, the database contained in excess of 39,415 different lesions detected in 1,516 different nuclear genes, with new entries currently accumulating at a rate exceeding 5,000 per annum. Since its inception, HGMD has been expanded to include cDNA reference sequences for more than 87% of listed genes, splice junction sequences, disease-associated and functional polymorphisms, as well as links to data present in publicly available online locus-specific mutation databases. Although HGMD has recently entered into a licensing agreement with Celera Genomics (Rockville, MD), mutation data will continue to be made freely available via the Internet.

Understanding the function–structure and function–mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis

Abstract: Inactivation of the tumor suppressor p53 by missense mutations is the most frequent genetic alteration in human cancers. The common missense mutations in the TP53 gene disrupt the ability of p53 to bind to DNA and consequently to transactivate downstream genes. However, it is still not fully understood how a large number of the remaining mutations affect p53 structure and function. Here, we used a comprehensive site-directed mutagenesis technique and a yeast-based functional assay to construct, express, and evaluate 2,314 p53 mutants representing all possible amino acid substitutions caused by a point mutation throughout the protein (5.9 substitutions per residue), and correlated p53 function with structure- and tumor-derived mutations. This high-resolution mutation analysis allows evaluation of previous predictions and hypotheses through interrelation of function, structure and mutation.

A Trigonometric Mutation Operation to Differential Evolution

Abstract: Previous studies have shown that differential evolution is an efficient, effective and robust evolutionary optimization method. However, the convergence rate of differential evolution in optimizing a computationally expensive objective function still does not meet all our requirements, and attempting to speed up DE is considered necessary. In this paper, a new local search operation, trigonometric mutation, is proposed and embedded into the differential evolution algorithm. This modification enables the algorithm to get a better trade-off between the convergence rate and the robustness. Thus it can be possible to increase the convergence velocity of the differential evolution algorithm and thereby obtain an acceptable solution with a lower number of objective function evaluations. Such an improvement can be advantageous in many real-world problems where the evaluation of a candidate solution is a computationally expensive operation and consequently finding the global optimum or a good sub-optimal solution with the original differential evolution algorithm is too time-consuming, or even impossible within the time available. In this article, the mechanism of the trigonometric mutation operation is presented and analyzed. The modified differential evolution algorithm is demonstrated in cases of two well-known test functions, and is further examined with two practical training problems of neural networks. The obtained numerical simulation results are providing empirical evidences on the efficiency and effectiveness of the proposed modified differential evolution algorithm.

Microsatellite Allele Sizes: A Simple Test to Assess Their Significance on Genetic Differentiation

Abstract: The mutation process at microsatellite loci typically occurs at high rates and with stepwise changes in allele sizes, features that may introduce bias when using classical measures of population differentiation based on allele identity (e.g., F(ST), Nei's Ds genetic distance). Allele size-based measures of differentiation, assuming a stepwise mutation process [e.g., Slatkin's R(ST), Goldstein et al.'s (deltamu)(2)], may better reflect differentiation at microsatellite loci, but they suffer high sampling variance. The relative efficiency of allele size- vs. allele identity-based statistics depends on the relative contributions of mutations vs. drift to population differentiation. We present a simple test based on a randomization procedure of allele sizes to determine whether stepwise-like mutations contributed to genetic differentiation. This test can be applied to any microsatellite data set designed to assess population differentiation and can be interpreted as testing whether F(ST) = R(ST). Computer simulations show that the test efficiently identifies which of F(ST) or R(ST) estimates has the lowest mean square error. A significant test, implying that R(ST) performs better than F(ST), is obtained when the mutation rate, mu, for a stepwise mutation process is (a) >/= m in an island model (m being the migration rate among populations) or (b) >/= 1/t in the case of isolated populations (t being the number of generations since population divergence). The test also informs on the efficiency of other statistics used in phylogenetical reconstruction [e.g., Ds and (deltamu)(2)], a nonsignificant test meaning that allele identity-based statistics perform better than allele size-based ones. This test can also provide insights into the evolutionary history of populations, revealing, for example, phylogeographic patterns, as illustrated by applying it on three published data sets.

Parallel changes in gene expression after 20,000 generations of evolution in Escherichia coli

Abstract: Twelve populations of Escherichia coli, derived from a common ancestor, evolved in a glucose-limited medium for 20,000 generations. Here we use DNA expression arrays to examine whether gene-expression profiles in two populations evolved in parallel, which would indicate adaptation, and to gain insight into the mechanisms underlying their adaptation. We compared the expression profile of the ancestor to that of clones sampled from both populations after 20,000 generations. The expression of 59 genes had changed significantly in both populations. Remarkably, all 59 were changed in the same direction relative to the ancestor. Many of these genes were members of the cAMP-cAMP receptor protein (CRP) and guanosine tetraphosphate (ppGpp) regulons. Sequencing of several genes controlling the effectors of these regulons found a nonsynonymous mutation in spoT in one population. Moving this mutation into the ancestral background showed that it increased fitness and produced many of the expression changes manifest after 20,000 generations. The same mutation had no effect on fitness when introduced into the other evolved population, indicating that a mutation of similar effect was present already. Our study demonstrates the utility of expression arrays for addressing evolutionary issues including the quantitative measurement of parallel evolution in independent lineages and the identification of beneficial mutations.

Idiopathic congenital central hypoventilation syndrome: Analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b

Abstract: Idiopathic congenital central hypoventilation syndrome (CCHS) has been linked to autonomic nervous system dysregulation and/or dysfunction (ANSD) since it was first described in 1970 A genetic basis of CCHS has been proposed because of the reports of four families with two affected children, because of mother-child transmission, and because of a recent report of a polyalanine expansion mutation in PHOX2b in a subset of CCHS subjects We, therefore, studied genes pertinent to early embryologic development of the ANS including mammalian achaete-scute homolog-1 (MASH1), bone morphogenic protein-2 (BMP2), engrailed-1 (EN1), TLX3, endothelin converting enzyme-1 (ECE1), endothelin-1 (EDN1), PHOX2a, and PHOX2b in 67 probands with CCHS, and gender- and ethnicity-matched controls No disease-defining mutations were identified in MASH1, BMP2, EN1, TLX3, ECE1, EDN1, or PHOX2a The 65/67 CCHS probands (97%) were found to be heterozygous for the exon 3 polyalanine expansion mutation identified previously in PHOX2b Further, there was an association between repeat mutation length and severity of the CCHS/ANSD phenotype Of the two probands who did not carry the expansion mutation, one had a nonsense mutation in exon 3 which truncated the protein and the other had no mutation in PHOX2b but had a previously reported EDN3 frameshift point mutation The polyalanine expansion mutation was not found in any of 67 matched controls Of 54 available families (including 97 unaffected parents), whose child carried the PHOX2b mutation, 4 parents demonstrated mosaicism for an expansion mutation identical to that seen in the CCHS cases, suggesting that not all mutations in affected probands with unaffected parents are de novo We also studied four women with CCHS who were heterozygous for the PHOX2b mutation, each with one child Three of the four children were also affected and had the same mutation, demonstrating autosomal dominant inheritance of the mutation Assay of the PHOX2b polyalanine repeat mutation represents a highly sensitive and specific technique for confirming the diagnosis of CCHS Identification of the CCHS mutation will lead to clarification of the phenotype, allow for prenatal diagnosis for parents of CCHS probands and adults with CCHS in future pregnancies, and potentially direct intervention strategies for the treatment of CCHS

The eto1, eto2, and eto3 Mutations and Cytokinin Treatment Increase Ethylene Biosynthesis in Arabidopsis by Increasing the Stability of ACS Protein

Abstract: The Arabidopsis ethylene-overproducing mutants eto1, eto2, and eto3 have been suggested to affect the post-transcriptional regulation of 1-aminocyclopropane-1-carboxylic acid synthase (ACS). Here, we present the positional cloning of the gene corresponding to the dominant eto3 mutation and show that the eto3 phenotype is the result of a missense mutation within the C-terminal domain of ACS9, which encodes one isoform of the Arabidopsis ACS gene family. This mutation is analogous to the dominant eto2 mutation that affects the C-terminal domain of the highly similar ACS5. Analysis of purified recombinant ACS5 and epitope-tagged ACS5 in transgenic Arabidopsis revealed that eto2 does not increase the specific activity of the enzyme either in vitro or in vivo; rather, it increases the half-life of the protein. In a similar manner, cytokinin treatment increased the stability of ACS5 by a mechanism that is at least partially independent of the eto2 mutation. The eto1 mutation was found to act by increasing the function of ACS5 by stabilizing this protein. These results suggest that an important mechanism by which ethylene biosynthesis is controlled is the regulation of the stability of ACS, mediated at least in part through the C-terminal domain.

Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis

Abstract: Huntington disease is caused by the expansion of a CAG repeat encoding an extended glutamine tract in a protein called huntingtin. Although the mutant protein is widely expressed, the earliest and most striking neuropathological changes are observed in the striatum. Here we show dramatic mutation length increases (gains of up to 1000 CAG repeats) in human striatal cells early in the disease course, most likely before the onset of pathological cell loss. Studies of knock-in HD mouse models indicate that the size of the initial CAG repeat mutation may influence both onset and tissue-specific patterns of age-dependent, expansion-biased mutation length variability. Given that CAG repeat length strongly correlates with clinical severity, we suggest that somatic increases of mutation length may play a major role in the progressive nature and cell-selective aspects of both adult-onset and juvenile-onset HD pathogenesis and we discuss the implications of this interpretation of the data presented.

Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database.

Abstract: Fibrillin is the major component of extracellular microfibrils. Mutations in the fibrillin gene on chromosome 15 (FBN1) were first described in the heritable connective disorder, Marfan syndrome (MFS). FBN1 has also been shown to harbor mutations related to a spectrum of conditions phenotypically related to MFS, called "type-1 fibrillinopathies." In 1995, in an effort to standardize the information regarding these mutations and to facilitate their mutational analysis and identification of structure/function and phenotype/genotype relationships, we created a human FBN1 mutation database, UMD-FBN1. This database gives access to a software package that provides specific routines and optimized multicriteria research and sorting tools. For each mutation, information is provided at the gene, protein, and clinical levels. This tool is now a worldwide reference and is frequently used by teams working in the field; more than 220,000 interrogations have been made to it since January 1998. The database has recently been modified to follow the guidelines on mutation databases of the HUGO Mutation Database Initiative (MDI) and the Human Genome Variation Society (HGVS), including their approved mutation nomenclature. The current update shows 559 entries, of which 421 are novel. UMD-FBN1 is accessible at www.umd.be/. We have also recently developed a FBN1 polymorphism database in order to facilitate diagnostics.

The solitary wave of asexual evolution

Abstract: Using a previously undescribed approach, we develop an analytic model that predicts whether an asexual population accumulates advantageous or deleterious mutations over time and the rate at which either process occurs. The model considers a large number of linked identical loci, or nucleotide sites; assumes that the selection coefficient per site is much less than the mutation rate per genome; and includes back and compensating mutations. Using analysis and Monte Carlo simulations, we demonstrate the accuracy of our results over almost the entire range of population sizes. Two limiting cases of our results, when either deleterious or advantageous mutations can be neglected, correspond to the Fisher-Muller effect and Muller's ratchet, respectively. By comparing predictions of our model (no recombination) to those of simple single-locus models (strong recombination), we show that the accumulation of advantageous mutations is slowed by linkage over a broad, finite range of population size. This supports the view of Fisher and Muller, who argued in the 1930s that progressive evolution of organisms is slowed because loci at which beneficial mutations can occur are often linked together on the same chromosome. These results follow from our main finding, that distribution of sequences over the mutation number evolves as a traveling wave whose speed and width depend on population size and other parameters. The model explains a logarithmic dependence of steady-state fitness on the population size reported recently for an RNA virus.

Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis

Abstract: Haemochromatosis (HH) is a clinically and genetically heterogeneous disease caused by inappropriate iron absorption. Most HH patients are homozygous for the C282Y mutation in the HFE gene. However, penetrance of the C282Y mutation is incomplete, and other genetic factors may well affect the HH phenotype. Ferroportin and TFR2 mutations also cause HH, and two HAMP mutations have recently been reported that causes juvenile haemochromatosis (JH) in the homozygous state. Here, we report evidence for digenic inheritance of HH. We have detected two new HAMP mutations in two different families, in which there is concordance between severity of iron overload and heterozygosity for HAMP mutations when present with the HFE C282Y mutation. In family A, the proband has a JH phenotype and is heterozygous for C282Y and a novel HAMP mutation Met50del IVS2+1(-G). This is a four nucleotide ATGG deletion which causes a frameshift. The proband's unaffected mother is also heterozygous for Met50del IVS2+1(-G), but lacks the C282Y mutation and is heterozygous for the HFE H63D mutation. Met50del IVS2+1(-G) was absent from 642 control chromosomes. In family B, a second novel, less severe HAMP mutation, G71D, was identified. This was detected in the general population at an allele frequency of 0.3%. We propose that the phenotype of C282Y heterozygotes and homozygotes may be modified by heterozygosity for mutations which disrupt the function of hepcidin in iron homeostasis, with the severity of iron overload corresponding to the severity of the HAMP mutation.

Stability of the G-matrix in a population experiencing pleiotropic mutation, stabilizing selection, and genetic drift.

Abstract: Quantitative genetics theory provides a framework that predicts the effects of selection on a phenotype consisting of a suite of complex traits. However, the ability of existing theory to reconstruct the history of selection or to predict the future trajectory of evolution depends upon the evolutionary dynamics of the genetic variance-covariance matrix (G-matrix). Thus, the central focus of the emerging field of comparative quantitative genetics is the evolution of the G-matrix. Existing analytical theory reveals little about the dynamics of G, because the problem is too complex to be mathematically tractable. As a first step toward a predictive theory of G-matrix evolution, our goal was to use stochastic computer models to investigate factors that might contribute to the stability of G over evolutionary time. We were concerned with the relatively simple case of two quantitative traits in a population experiencing stabilizing selection, pleiotropic mutation, and random genetic drift. Our results show that G-matrix stability is enhanced by strong correlational selection and large effective population size. In addition, the nature of mutations at pleiotropic loci can dramatically influence stability of G. In particular, when a mutation at a single locus simultaneously changes the value of the two traits (due to pleiotropy) and these effects are correlated, mutation can generate extreme stability of G. Thus, the central message of our study is that the empirical question regarding G-matrix stability is not necessarily a general question of whether G is stable across various taxonomic levels. Rather, we should expect the G-matrix to be extremely stable for some suites of characters and unstable for others over similar spans of evolutionary time.

Particle swarm optimization with mutation

Abstract: The particle swarm optimization algorithms converges rapidly during the initial stages of a search, but often slows considerably and can get trapped in local optima. This paper examines the use of mutation to both speed up convergence and escape local minima. It compares the effectiveness of the basic particle swarm optimization scheme (BPSO) with each of BPSO with mutation, constriction particle swarm optimization (CPSO) with mutation, and CPSO without mutation. The four test functions used were the Sphere, Ackley, Rastrigin and Rosenbrock functions of dimensions 10, 20 and 30. The results show that mutation hinders the motion of the swarm on the sphere but the combination of CPSO with mutation provides a significant improvement in performance for the Rastrigin and Rosenbrock functions for all dimensions and the Ackley function for dimensions 20 and 30, with no improvement for the 10 dimensional case.

Estimating allele age.

Abstract: The age of an allele can be estimated both from genetic variation among different copies (intra-allelic variation) and from its frequency. Estimates based on intra-allelic variation follow from the exponential decay of linkage disequilibrium because of recombination and mutation. The confidence interval depends both on the uncertainty in recombination and mutation rates and on randomness of the genealogy of chromosomes that carry the allele (the intra-allelic genealogy). Several approximate methods to account for variation in the intra-allelic genealogy have been derived. Allele frequency alone also provides an estimate of age. Estimates based on frequency and on intra-allelic variability can be combined to provide a more accurate estimate or can be contrasted to show that an allele has been subject to natural selection. These methods have been applied to numerous cases, including alleles associated with cystic fibrosis, idiopathic torsion dystonia, and resistance to infection by HIV. We emphasize that estimates of allele age depend on assumptions about demographic history and natural selection.

Molecular Analysis of Hereditary Nonpolyposis Colorectal Cancer in the United States: High Mutation Detection Rate among Clinically Selected Families and Characterization of an American Founder Genomic Deletion of the MSH2 Gene

Abstract: The identification of germline mutations in families with HNPCC is hampered by genetic heterogeneity and clinical variability. In previous studies, MSH2 and MLH1 mutations were found in approximately two-thirds of the Amsterdam-criteria–positive families and in much lower percentages of the Amsterdam-criteria–negative families. Therefore, a considerable proportion of HNPCC seems not to be accounted for by the major mismatch repair (MMR) genes. Does the latter result from a lack of sensitivity of mutation detection techniques, or do additional genes underlie the remaining cases? In this study we address these questions by thoroughly investigating a cohort of clinically selected North American families with HNPCC. We analyzed 59 clinically well-defined U.S. families with HNPCC for MSH2, MLH1, and MSH6 mutations. To maximize mutation detection, different techniques were employed, including denaturing gradient gel electrophoresis, Southern analysis, microsatellite instability, immunohistochemistry, and monoallelic expression analysis. In 45 (92%) of the 49 Amsterdam-criteria–positive families and in 7 (70%) of the 10 Amsterdam-criteria–negative families, a mutation was detected in one of the three analyzed MMR genes. Forty-nine mutations were in MSH2 or MLH1, and only three were in MSH6. A considerable proportion (27%) of the mutations were genomic rearrangements (12 in MSH2 and 2 in MLH1). Notably, a deletion encompassing exons 1–6 of MSH2 was detected in seven apparently unrelated families (12% of the total cohort) and was subsequently proven to be a founder. Screening of a second U.S. cohort with HNPCC from Ohio allowed the identification of two additional kindreds with the identical founder deletion. In the present study, we show that optimal mutation detection in HNPCC is achieved by combining accurate and expert clinical selection with an extensive mutation detection strategy. Notably, we identified a common North American deletion in MSH2, accounting for ∼10% of our cohort. Genealogical, molecular, and haplotype studies showed that this deletion represents a North American founder mutation that could be traced back to the 19th century.

The amino-acid mutational spectrum of human genetic disease

Abstract: Background Nonsynonymous mutations in the coding regions of human genes are responsible for phenotypic differences between humans and for susceptibility to genetic disease. Computational methods were recently used to predict deleterious effects of nonsynonymous human mutations and polymorphisms. Here we focus on understanding the amino-acid mutation spectrum of human genetic disease. We compare the disease spectrum to the spectra of mutual amino-acid mutation frequencies, non-disease polymorphisms in human genes, and substitutions fixed between species.

Standardizing mutation nomenclature: Why bother?

Abstract: Lydon, April 12, 2008—a XBG patient and his parents sued the department of clinical diagnosis in Lydon, the XBG mutation database, and the journal Human Mutation. The complaint was that serious and culpable mistakes were made during the clinical diagnosis of the pregnancy in the XBGfamily, that ultimately led to the birth of an affected child. A paper published in Human Mutation listed the sequence variant detected in the family as "nonpathogenic." Careful examination would have revealed that the change was clearly pathogenic (a nonsense mutation). However, the accused parties failed to verify the data of the original report and just copied it. Is this imaginary news item pure fiction? Or, might it come true? When a clinical diagnosis is based on the detection of a variant in the DNA sequence (mutation), one wants to be absolutely sure. One of the most reliable decision tools available is to search the literature for confirmative reports. Nowadays, general or gene/diseasespecific databases are often available that make this task rather simple. Consequently, when a sequence variant is detected, it is becoming general practice to check these repositories for previous reports of the change and accept the conclusion submitted by the author, ‘‘pathogenic’’ or ‘‘not pathogenic.’’ For this process to be reliable, it is critical that mutation reports do not contain errors and that descriptions are unique and unequivocal. For this latter purpose, the HUGO Mutation Database Initiative (MDI) instigated an ad-hoc committee to formulate rules for the description of sequence variants [Beutler, 1993; Beaudet and Tsui, 1993; Beutler et al., 1996]. Based on initial suggestions, the nomenclature committee published several discussion papers describing rules for the description of sequence changes that are currently widely accepted [Antonarakis et al., 1998; den Dunnen and Antonarakis, 2000]. Because of the importance of the issue and the overall consensus on the rules, Human Mutation is adopting an editorial policy that requests absolute compliance of these mutation nomenclature rules before manuscripts will be accepted and published. A quick review across a range of journals that report sequence changes highlights the most offended rules (den Dunnen, in preparation). First, most papers fail to explicitly define which sequence file was used as a reference for numbering residues (nucleotides and amino acids). Consequently, a best guess is made, trying to deduce the numbering used—and errors are introduced. When a cDNA sequence is used as a reference, it is not clearly stated where nucleotide residue 1 is located, i.e., at the start of the sequence file or at the A of the ATG translation initiation codon (the rule). In addition, many papers contain descriptions of intronic sequence changes based on an exon/intron numbering without specifying intron position, intron numbering, and the reference sequence file used. These simple, but basic, omissions make it difficult to correctly deduce the change reported. Intronic changes reported as c.IVS2–1A>G are inconclusive, while a notation like c.123–1A4G is clear. Second, changes are frequently reported at the protein level without listing the change at the DNA level. DNA description of mutations is absolutely essential, since the amino acid code is degenerate. Errors can occur if one tries to deduce the underlying DNA change simply from the amino acid change. In addition, it is not uncommon that the one-letter amino acid code is used incorrectly: ‘‘A’’ is not only used for Alanine (correct), but also for Arginine, Asparagine, and Aspartic acid (incorrect). Third, descriptions are often used that are not unequivocal. Examples include: 1. Insertions and deletions are reported in the formats c.123insAAG and c.123delGTG, where some mean starting at position 123 and others mean starting after position 123. The correct descriptions have the format c.123_124insAAG and c.123_125delGTG, respectively. 2. The use of a ‘‘–’’ (minus) sign to indicate both range and intronic nucleotides 50 of a splice acceptor site are incorrect. Correct for range is: ‘‘_’’ (underscore), as in c.123_126del. 3. Changes at the DNA level are reported as A786G. That is the format for changes at the amino acid level. Correct notation is: c.786A4G. 4. Describing a variant as ‘‘L41L’’ is wrong. It is uninformative and equivocal (there are five possibilities at the DNA level). So, the description should be given at the DNA level.

Likelihood-Based Estimation of Microsatellite Mutation Rates

Abstract: Microsatellites are widely used in genetic analyses, many of which require reliable estimates of microsatellite mutation rates, yet the factors determining mutation rates are uncertain. The most straightforward and conclusive method by which to study mutation is direct observation of allele transmissions in parent-child pairs, and studies of this type suggest a positive, possibly exponential, relationship between mutation rate and allele size, together with a bias toward length increase. Except for microsatellites on the Y chromosome, however, previous analyses have not made full use of available data and may have introduced bias: mutations have been identified only where child genotypes could not be generated by transmission from parents' genotypes, so that the probability that a mutation is detected depends on the distribution of allele lengths and varies with allele length. We introduce a likelihood-based approach that has two key advantages over existing methods. First, we can make formal comparisons between competing models of microsatellite evolution; second, we obtain asymptotically unbiased and efficient parameter estimates. Application to data composed of 118,866 parent-offspring transmissions of AC microsatellites supports the hypothesis that mutation rate increases exponentially with microsatellite length, with a suggestion that contractions become more likely than expansions as length increases. This would lead to a stationary distribution for allele length maintained by mutational balance. There is no evidence that contractions and expansions differ in their step size distributions.

Balancing autonomy and responsibility: the ethics of generating and disclosing genetic information - Commentary - Reply

Abstract: Using data obtained during a retrospective interview study of 30 women who had undergone genetic testing-BRCA½ mutation searching-this paper describes how women, previously diagnosed with breast/ovarian cancer, perceivetheir role in generating genetic information about themselves and their families. It observes that when describing their motivations for undergoing DNA testing and their experiences of disclosing genetic information within the family these women provide care based ethical justifications for their actions. Finally, it argues that generating genetic information and disclosing this information to kin raise different types of ethical issues. The implications of these findings for ethical debates about informed choice in the context of genetic testing are discussed.

Immune inspired somatic contiguous hypermutation for function optimisation

Abstract: When considering function optimisation, there is a trade off between quality of solutions and the number of evaluations it takes to find that solution. Hybrid genetic algorithms have been widely used for function optimisation and have been shown to perform extremely well on these tasks. This paper presents a novel algorithm inspired by the mammalian immune system, combined with a unique mutation mechanism. Results are presented for the optimisation of twelve functions, ranging in dimensionality from one to twenty. Results show that the immune inspired algorithm performs significantly fewer evaluations when compared to a hybrid genetic algorithm, whilst not sacrificing quality of the solution obtained.

Apolipoprotein Eε4 Modifies Alzheimer's Disease Onset in an E280A PS1 Kindred

Abstract: We previously have identified a large kindred from Colombia in which Alzheimer's disease (AD) is caused by the E280A presenilin 1 (PS1) mutation. The objective of this study was to examine whether environmental and genetic factors are responsible for variation in the phenotypic expression of the E280A PS1 mutation. We genotyped coding and promoter polymorphisms of the APOE gene in carriers of the E280A PS1 mutation. Kaplan–Meier product-limit and Cox proportional hazard models were used in the statistical analyses. DNA was available from 114 carriers of the E280A PS1 mutation, including 52 subjects with AD. APOE e4 allele carriers were more likely to develop AD at an earlier age than subjects without the e4 allele (hazard ratio, 2.07; 95% confidence interval, 1.07–3.99; p = 0.030). Subjects with low education were more likely to develop AD later than those with higher education (hazard ratio, 0.476; 95% confidence interval, 0.26–0.87). Low educational level was associated with rural residence (p < 0.001). Promoter APOE variants did not influence either the onset or the duration of the disease. This study is the first to our knowledge to demonstrate that genetic and environmental factors influence age of onset in a kindred with a familial AD mutation. Ann Neurol 2003

Strikingly higher frequency in centenarians and twins of mtDNA mutation causing remodeling of replication origin in leukocytes

Abstract: The presence of a genetic component in longevity is well known. Here, the association of a mtDNA mutation with a prolonged life span in humans was investigated. Large-scale screening of the mtDNA main control region in leukocytes from subjects of an Italian population revealed a homoplasmic C150T transition near an origin of heavy mtDNA-strand synthesis in ≈17% of 52 subjects 99–106 years old, but, in contrast, in only 3.4% of 117 younger individuals (P = 0.0035). Evidence was obtained for the contribution of somatic events, under probable nuclear genetic control, to the striking selective accumulation of the mutation in centenarians. In another study, among leukocyte mtDNA samples from 20 monozygotic and 18 dizygotic twins, 60–75 years old, 30% (P = 0.0007) and 22% (P = 0.011), respectively, of the individuals involved exhibited the homoplasmic C150T mutation. In a different system, i.e., in five human fibroblast longitudinal studies, convincing evidence for the aging-related somatic expansion of the C150T mutation, up to homoplasmy, was obtained. Most significantly, 5′ end analysis of nascent heavy mtDNA strands consistently revealed a new replication origin at position 149, substituting for that at 151, only in C150T mutation-carrying samples of fibroblasts or immortalized lymphocytes. Considering the aging-related health risks that the centenarians have survived and the developmental risks of twin gestations, it is proposed that selection for a remodeled replication origin, inherited or somatically acquired, provides a survival advantage and underlies the observed high incidence of the C150T mutation in centenarians and twins.

Introduction to Population Genetics

Abstract: 1. Introduction. 2. Genetic Variation. 3. The Hardy-Weinberg Principle. 4. Recombination, Linkage, and Disequilibrium. 5. Natural Selection I: Basic Models. 6. Mutation. 7. Genetic Drift. 8. Inbreeding and Nonrandom Mating. 9. Population Subdivision and Gene Flow. 10. Molecular Population Genetics. 11. Molecular Evolution and Phylogenetics. 12. Natural Selection II: Balancing Selection and Advanced Models. 13. Quantitative Genetics. Appendix A. Probability and Random Variables. Appendix B. Computer Software for Population Genetics. Answers to Problems, Literature Cited. Index.

Genetic variability of hepatitis A virus.

Abstract: Knowledge of the molecular biology of hepatitis A virus (HAV) has increased exponentially since its identification. HAV exploits all known mechanisms of genetic variation to ensure survival, including mutation and genetic recombination. HAV has been characterized by the emergence of different genotypes, three human antigenic variants and only one major serotype. This paper reviews the genetic variability and molecular epidemiology of HAV. Its evolutionary mechanisms are described with particular emphasis on genetic recombination and HAV mutation rate. Genotypic classification methods are also discussed.

GJB2 deafness gene shows a specific spectrum of mutations in Japan, including a frequent founder mutation

Abstract: Mutations in the GJB2 gene (connexin 26) are the major cause of autosomal recessive non-syndromic hearing impairment in many populations. In contrast to the volume of information regarding the involvement of GJB2 mutations in hearing impairment in populations of European ancestry, less is known regarding other ethnic groups. In this study, we analyzed the GJB2 gene for mutations in 1227 hearing-impaired Japanese individuals. This revealed a unique spectrum of GJB2 mutations, different from that found in the Caucasian population. The most frequent mutation in Japanese, 235delC, has never been reported in Caucasians. To investigate a possible founder effect for the 235delC mutation, we analyzed single nucleotide polymorphisms in the vicinity of the GJB2 gene. Results were consistent with inheritance of the 235delC mutation from a common ancestor. The results of this study have important implications for genetic diagnostic testing for deafness in the Japanese population.

Compositions and methods for identifying plants having increased tolerance to imidazolinone herbicides

Abstract: The present invention provides compositions and methods for assaying commercially relevant imidazolinone herbicide tolerance conferred by a Brassica napus AHAS1 PM1 mutation and a Brassica napus AHAS3 PM2 mutation in a plant.

Adapting Crossover and Mutation Rates in Genetic Algorithms

Abstract: It is well known that a judicious choice of crossover and/or mutation rates is critical to the success of genetic algorithms. Most earlier researches focused on finding optimal crossover or mutation rates, which vary for different problems, and even for different stages of the genetic process in a problem. In this paper, a generic scheme for adapting the crossover and mutation probabilities is proposed. The crossover and mutation rates are adapted in response to the evaluation results of the respective offspring in the next generation. Experimental results show that the proposed scheme significantly improves the performance of genetic algorithms and outperforms previous work.