Abstract: Gene expression programming, a genotype/phenotype genetic algorithm (linear and ramified), is presented here for the first time as a new technique for the creation of computer programs. Gene expression programming uses character linear chromosomes composed of genes structurally organized in a head and a tail. The chromosomes function as a genome and are subjected to modification by means of mutation, transposition, root transposition, gene transposition, gene recombination, and oneand two-point recombination. The chromosomes encode expression trees which are the object of selection. The creation of these separate entities (genome and expression tree) with distinct functions allows the algorithm to perform with high efficiency that greatly surpasses existing adaptive techniques. The suite of problems chosen to illustrate the power and versatility of gene expression programming includes symbolic regression, sequence induction with and without constant creation, block stacking, cellular automata rules for the density-classification problem, and two problems of boolean concept learning: the 11-multiplexer and the GP rule problem.

Abstract: Little is known about the nature of genetic variation underlying complex diseases in humans. One popular view proposes that mapping efforts should focus on identification of susceptibility mutations that are relatively old and at high frequency. It is generally assumed—at least for modeling purposes—that selection against complex disease mutations is so weak that it can be ignored. In this article, I propose an explicit model for the evolution of complex disease loci, incorporating mutation, random genetic drift, and the possibility of purifying selection against susceptibility mutations. I show that, for the most plausible range of mutation rates, neutral susceptibility alleles are unlikely to be at intermediate frequencies and contribute little to the overall genetic variance for the disease. Instead, it seems likely that the bulk of genetic variance underlying diseases is due to loci where susceptibility mutations are mildly deleterious and where there is a high overall mutation rate to the susceptible class. At such loci, the total frequency of susceptibility mutations may be quite high, but there is likely to be extensive allelic heterogeneity at many of these loci. I discuss some practical implications of these results for gene mapping efforts.

Abstract: Genetic variations in ovulation rate which occur in different breeds of sheep provide useful models to explore the mechanisms regulating the development of antral follicles. The Booroola gene, an autosomal mutation that affects ovulation rate, has been known for over two decades and despite intensive research it has not yet been identified. Using resources from human genome mapping and known data about gene linkage and chromosome location in the sheep, we selected the gene encoding the Bone Morphogenetic Protein receptor (BMPR) type 1 B (ALK-6) as a candidate site for the mutation. The BMPR1B gene in the human is located at the region linked with the Booroola mutation, syntenic to chromosome 6 in the sheep. A fragment of the sheep BMPR1B gene was cloned from an ovarian cDNA and the deduced aminoacid (AA) sequence is over 98% homologous to the known mammalian sequences. cDNA and genomic DNA from 20 Booroola genotypes were screened and two point mutation were found in the kinase domain of the receptor, one at base 746 of the coding region (A in the ++ to a G in FF animals) which results in a change from a glutamine in the wild type to a arginine in the Booroola animals. Another point mutation was identified at position 1113, (C to A) but this mutation does not change the coding aminoacid. The first mutation was confirmed in genomic DNA from 10 ewes from an independent Brazilian flock which segregates the Booroola phenotype. In all instances homozygous FecB gene carrier (n=11) had only the 746 A to G mutation, non gene carriers (n=14) had only the wild type sequence and heterozygote gene carriers (n=5) had both sequences. This mutation in the subdomain 3 of the kinase domain could result in an alteration in the expression and/or phosphorylation of SMADs, resulting in the phenotype characteristic of the Booroola animals which is the 'precocious' development of a large number of small antral follicles resulting in increased ovulation rate.

Abstract: (CIS), 50 pTa, 19 pT1, and43 pT2–4. All 48 mutations identified were identical tothe germinal activating mutations that cause thanato-phoric dysplasia, a lethal form of dwarfism. TheS249C mutation, found in 33 of the 48 mutated tu-mors, was the most common. The frequency of mu-tations was higher in pTa tumors (37 of 50, 74%) thanin CIS (0 of 20, 0%;

Abstract: A basic principle of genetics is that the likelihood that a particular mutation occurs is independent of its phenotypic consequences. The concept of adaptive mutation seemed to challenge this principle with the discoveries of mutations stimulated by stress, some of which allow adaptation to the stress. The emerging mechanisms of adaptive genetic change cast evolution, development and heredity into a new perspective, indicating new models for the genetic changes that fuel these processes.

Abstract: This paper presents experimental results on the major benchmarking functions used for performance evaluation of Genetic Algorithms (GAs). Parameters considered include the effect of population size, crossover probability, mutation rate and pseudorandom generator. The general computational behavior of two basic GAs models, the Generational Replacement Model (GRM) and the Steady State Replacement Model (SSRM) is evaluated.

Abstract: Among the several factors that affect the appearance and spread of acquired antibiotic resistance, the mutation frequency and the biological cost of resistance are of special importance. Measurements of the mutation frequency to rifampicin resistance in Helicobacter pylori strains isolated from dyspeptic patients showed that approximately 1/4 of the isolates had higher mutation frequencies than Enterobacteriaceae mismatch-repair defective mutants. This high mutation frequency could explain why resistance is so frequently acquired during antibiotic treatment of H. pylori infections. Inactivation of the mutS gene had no substantial effect on the mutation frequency, suggesting that MutS-dependent mismatch repair is absent in this bacterium. Furthermore, clarithromycin resistance conferred a biological cost, as measured by a decreased competitive ability of the resistant mutants in mice. In clinical isolates this cost could be reduced, indicating that compensation is a clinically relevant phenomenon that could act to stabilize resistant bacteria in a population.

Abstract: This review describes in vitro mutation induction methods in fruits and the in vitro selection procedures available for early screening. Results obtained through in vitro mutation techniques, including somaclonal variation, are reviewed and compared with the current achievements and future prospects of transgenic breeding. Plant improvement based on mutations, which change one or a few specific traits of a cultivar, can contribute to fruit improvement without altering the requirements of fruit industry. Induced mutations have well defined limitations in fruit breeding applications, but their possibilities may be expanded by the use of in vitro techniques. Tissue culture increases the efficiency of mutagenic treatments for variation induction, handling of large populations, use of ready selection methods, and rapid cloning of selected variants. Molecular techniques can provide a better understanding of the potential and limitations of mutation breeding e.g. molecular marker-assisted selection, which can lead to the early identification of useful variants. The relatively high number of research reports compared with the low number of cultivars released suggests that mutagenesis in combination with tissue culture is either ineffective or has yet to be exploited in fruits. Positive achievement recorded in other species seem to support the hypothesis that in vitro mutation induction has high potential also for fruit improvement. The possible contribution of a well-pondered and coordinated use of the numerous mutation induction, mutant selection, and field validation procedures available to advances in fruit breeding is discussed.

Abstract: This paper presents an exhaustive study of the Simple Genetic Algorithm (SGA), Steady State Genetic Algorithm (SSGA) and Replacement Genetic Algorithm (RGA). The performance of each method is analyzed in relation to several operators types of crossover, selection and mutation, as well as in relation to the probabilities of crossover and mutation with and without dynamic change of its values during the optimization process. In addition, the space reduction of the design variables and global elitism are analyzed. All GAs are effective when used with its best operations and values of parameters. For each GA, both sets of best operation types and parameters are found. The dynamic change of crossover and mutation probabilities, the space reduction and the global elitism during the evolution process show that great improvement can be achieved for all GA types. These GAs are applied to TEAM benchmark problem 22.

Abstract: The need for test adequacy criteria is widely recognized. Several criteria have been proposed for the assessment of adequacy of tests at the unit level. However, there remains a lack of criteria for the assessment of the adequacy of tests generated during integration testing. We present a mutation based interprocedural criterion, named Interface Mutation (IM), suitable for use during integration testing. A case study to evaluate the proposed criterion is reported. In the study, the UNIX sort utility was seeded with errors and Interface Mutation evaluated by measuring the cost of its application and its error revealing effectiveness. Alternative IM criteria using different sets of Interface Mutation operators were also evaluated. While comparing the error revealing effectiveness of these Interface Mutation-based test sets with same size randomly generated test sets, we observed that in most cases Interface Mutation based test sets are superior. The results suggest that Interface Mutation offers a viable test adequacy criteria for use at the integration level.

Abstract: Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the catabolism of 5-fluorouracil (5FU), and it is suggested that patients with a partial deficiency of this enzyme are at risk from developing a severe 5FU-associated toxicity. In this study, we demonstrated that a lethal toxicity after a treatment with 5FU was attributable to a complete deficiency of DPD. Analysis of the DPD gene for the presence of mutations showed that the patient was homozygous for a G→A mutation in the invariant GT splice donor site flanking exon 14 (IVS14+1G>A). As a consequence, no significant residual activity of DPD was detected in peripheral blood mononuclear cells. To determine the frequency of the IVS14+1G>A mutation in the Dutch population, we developed a novel PCR-based method allowing the rapid analysis of the IVS14+1G>A mutation by RFLP. Screening for the presence of this mutation in 1357 Caucasians showed an allele frequency of 0.91%. In our view, the apparently high prevalence of the IVS14+1G>A mutation in the normal population, with 1.8% heterozygotes, warrants genetic screening for the presence of this mutation in cancer patients before the administration of 5FU.

Abstract: Background— We recently reported a mutation in the PRKAG2 gene to be responsible for a familial syndrome of ventricular preexcitation, atrial fibrillation, conduction defects, and cardiac hypertrophy. We now report a novel mutation in PRKAG2 causing Wolff-Parkinson-White syndrome and conduction system disease with onset in childhood and the absence of cardiac hypertrophy. Methods and Results— DNA was extracted from white blood cells obtained from family members. PRKAG2 exons were amplified by polymerase chain reaction and were screened for mutations by direct sequencing. The genomic organization of the PRKAG2 gene was determined using inter-exon long-range polymerase chain reaction for cDNA sequence not available in the genome database. A missense mutation, Arg531Gly, was identified in all affected individuals but was absent in 150 unrelated individuals. The PRKAG2 gene was determined to consist of 16 exons and is at least 280 kb in size. Conclusions— We identified a novel mutation (Arg531Gly) in the γ-2 ...

Abstract: Results: Diagnostic criteria for MFS were fulfilled in 94 patients, 62 (66%) of whom had an FBN1 mutation. A significantly higher incidence of ectopia lentis was found in the patients with MFS with an FBN1 mutation vs those without (P=.04). Among the 77 patients who did not meet the criteria, an FBN1 mutation was found in 9 patients (12%). No correlation was found between the severity of the phenotype and the position and nature of the FBN1 mutation. Conclusions: This study showed a significant difference in the number of FBN1 mutations between patients fulfilling and those not fulfilling the diagnostic criteria for MFS, which seems to be a good predictor of the presence of an FBN1 mutation. A comprehensive clinical evaluation is mandatory before establishing a definitive diagnosis. An FBN1 mutation analysis is helpful to identify individuals at high risk for MFS who need careful follow-up, particularly in families displaying phenotypic variability and in children. Arch Intern Med. 2001;161:2447-2454

Abstract: A missense mutation in the neurofilament light chain gene (NEFL, NF-L) at chromosome 8p21 was recently reported in a single Charcot-Marie-Tooth type 2 family (CMT2). This new CMT2 variant is designated CMT2E. The NEFL gene mutation showed co-segregation with the disease phenotype and is thus most likely the disease-causing mutation. However, the possibility that it is a closely linked rare polymorphism can not be ruled out with certainty. We observed a novel NEFL missense mutation in a second CMT family, providing supporting evidence that CMT2E is caused by NEFL gene mutations.

Abstract: Mutation analysis of metabolic disorders, such as the fatty acid oxidation defects, offers an additional, and often superior, tool for specific diagnosis compared to traditional enzymatic assays. With the advancement of the structural part of the Human Genome Project and the creation of mutation databases, procedures for convenient and reliable genetic analyses are being developed. The most straightforward application of mutation analysis is to specific diagnoses in suspected patients, particularly in the context of family studies and for prenatal/preimplantation analysis. In addition, from these practical uses emerges the possibility to study genotype–phenotype relationships and investigate the molecular pathogenesis resulting from specific mutations or groups of mutations. In the present review we summarize current knowledge regarding genotype–phenotype relationships in three disorders of mitochondrial fatty acid oxidation: very-long chain acyl-CoA dehydrogenase (VLCAD, also ACADVL), medium-chain acyl-CoA dehydrogenase (MCAD, also ACADM), and short-chain acyl-CoA dehydrogenase (SCAD, also ACADS) deficiencies. On the basis of this knowledge we discuss current understanding of the structural implications of mutation type, as well as the modulating effect of the mitochondrial protein quality control systems, composed of molecular chaperones and intracellular proteases. We propose that the unraveling of the genetic and cellular determinants of the modulating effects of protein quality control systems may help to assess the balance between genetic and environmental factors in the clinical expression of a given mutation. The realization that the effect of the monogene, such as disease-causing mutations in the VLCAD, MCAD, and SCAD genes, may be modified by variations in other genes presages the need for profile analyses of additional genetic variations. The rapid development of mutation detection systems, such as the chip technologies, makes such profile analyses feasible. However, it remains to be seen to what extent mutation analysis will be used for diagnosis of fatty acid oxidation defects and other metabolic disorders. Hum Mutat 18:169–189, 2001. © 2001 Wiley-Liss, Inc.

Abstract: We measured the proportion of mutant mtDNA (mutation load) in 82 primary oocytes from a woman who harbored the A3243G mtDNA mutation. The frequency distribution of mutation load indicates that random drift is the principal mechanism that determines the level of mutant mtDNA within individual oocytes.

Abstract: The per-genome, per-generation rate of spontaneous mutation affecting fitness (U) and the mean fitness cost per mutation (s) are important parameters in evolutionary genetics, but have been estimated for few species. We estimated U and sh (the heterozygous effect of mutations) for two diploid yeast strains differing only in the DNA mismatch-repair deficiency used to elevate the mutation rate in one (mutator) strain. Mutations were allowed to accumulate in 50 replicate lines of each strain, during 36 transfers of randomly chosen single colonies (approximately 600 generations). Among wild-type lines, fitnesses were bimodal, with one mode showing no change in mean fitness. The other mode showed a mean 29.6% fitness decline and the petite phenotype, usually caused by partial deletion of the mitochondrial genome. Excluding petites, maximum-likelihood estimates adjusted for the effect of selection were U = 9.5 x 10(-5) and sh = 0.217 for the wild type. Among the mutator lines, the best fit was obtained with 0.005 or = sh > or = 0.0003. Like other recently tested model organisms, wild-type yeast have low mutation rates, with high mean fitness costs per mutation. Inactivation of mismatch repair increases the frequency of slightly deleterious mutations by approximately two orders of magnitude.

Abstract: β-Thalassemia is the most common hereditary disease in Iran. More than two million carriers of β-thalassemia live in Iran. Since the Iranian population is a mixture of different ethnic groups, it is necessary to determine the frequency and distribution of mutations in the different parts of the country. For this purpose, we divided Iran in to eight different regions according to the geographic and ethnic distribution of the population. Over a 10-year period 1,217 β-thalassemia chromosomes of 164 affected patients and 889 unrelated carriers were studied using the amplification refractory mutation system-polymerase chain reaction technique. We detected 81% β-thalassemia mutations in the studied chromosomes. IVS-II-I (G → A) was the predominant mutation found in our study (34%). Its relative frequency in the north was much higher than other regions, and it lessened toward the south, where the IVS-I-5(G → C) mutation was more common. IVS-I-5 (G → C) (7.55%), codons 8/9 (+G) (4.76%), and IVS-I-110 (G → A) (4.7...

Abstract: METHODS. The entire open reading frame of the ELOVL4 gene was analyzed by direct sequencing in a proband from the K4175 family. The combination of denaturing high-performance liquid chromatography (DHPLC) analysis and direct sequencing of all available family members was used to further assess segregation of identified ELOVL4 variants in the pedigree. RESULTS. A complex mutation, two 1-bp deletions separated by four nucleotides, was detected in all affected members of the family. The mutation results in a frameshift and the truncation of the ELOVL4 protein, similar to the effect of the previously described 5-bp deletion. CONCLUSIONS. The discovery of a second mutation in the ELOVL4 gene segregating with macular dystrophy phenotypes confirms the role of this gene in a subset of dominant macular dystrophies with a wide range of clinical expressions and suggests a role for modifying genes and/or environmental factors in the disease process. (Invest Ophthalmol Vis Sci. 2001; 42:3331–3336)

Abstract: RAD51 colocalizes with both BRCA1 and BRCA2, and genetic variants in RAD51 would be candidate BRCA1/2 modifiers. We searched for RAD51 polymorphisms by sequencing 20 individuals. We compared the polymorphism allele frequencies between female BRCA1/2 mutation carriers with and without breast or ovarian cancer and between population-based ovarian cancer cases with BRCA1/2 mutations to cases and controls without mutations. We discovered two single nucleotide polymorphisms (SNPs) at positions 135 g-->c and 172 g-->t of the 5' untranslated region. In an initial group of BRCA1/2 mutation carriers, 14 (21%) of 67 breast cancer cases carried a "c" allele at RAD51:135 g-->c, whereas 8 (7%) of 119 women without breast cancer carried this allele. In a second set of 466 mutation carriers from three centers, the association of RAD51:135 g-->c with breast cancer risk was not confirmed. Analyses restricted to the 216 BRCA2 mutation carriers, however, showed a statistically significant association of the 135 "c" allele with the risk of breast cancer (adjusted odds ratio, 3.2; 95% confidence limit, 1.4-40). BRCA1/2 mutation carriers with ovarian cancer were only about one half as likely to carry the RAD51:135 g-->c SNP. Analysis of the RAD51:135 g-->c SNP in 738 subjects from an Israeli ovarian cancer case-control study was consistent with a lower risk of ovarian cancer among BRCA1/2 mutation carriers with the "c" allele. We have identified a RAD51 5' untranslated region SNP that may be associated with an increased risk of breast cancer and a lower risk of ovarian cancer among BRCA2 mutation carriers. The biochemical basis of this risk modifier is currently unknown.

Abstract: Mutation and crossover are the main search operators of different variants of evolutionary algorithms. Despite the many discussions on the importance of crossover nobody has proved rigorously for some explicitly defined fitness functions fn : {0,1}n → ℝ that a genetic algorithm with crossover can optimize fn in expected polynomial time while all evolution strategies based only on mutation (and selection) need expected exponential time. Here such functions and proofs are presented for a genetic algorithm without any idealization. For some functions one-point crossover is appropriate while for others uniform crossover is the right choice.

Abstract: Selection acting on codon usage can cause patterns of synonymous evolution to deviate considerably from those expected under neutrality. To investigate the quantitative relationship between parameters of mutation, selection, and demography, and patterns of synonymous site divergence, we have developed a novel combination of population genetic models and likelihood methods of phylogenetic sequence analysis. Comparing 50 orthologous gene pairs from Drosophila melanogaster and D. virilis and 27 from D. melanogaster and D. simulans, we show considerable variation between amino acids and genes in the strength of selection acting on codon usage and find evidence for both long-term and short-term changes in the strength of selection between species. Remarkably, D. melanogaster shows no evidence of current selection on codon usage, while its sister species D. simulans experiences only half the selection pressure for codon usage of their common ancestor. We also find evidence for considerable base asymmetries in the rate of mutation, such that the average synonymous mutation rate is 20-30% higher than in noncoding regions. A Bayesian approach is adopted to investigate how accounting for selection on codon usage influences estimates of the parameters of mutation.

Abstract: Publisher Summary This chapter presents an overview of the genetics of Parkinson's disease (PD). Parkinsonism is clinically characterized by the triad of tremor, rigidity, and bradykinesia. PD is the most common cause of Parkinsonism and the second most prevalent neurodegenerative disorder after Alzheimer's disease. Earlier, PD was thought to have no genetic basis, and epidemiological data appeared to support this view. Cross-sectional studies also suggested that either there is no genetic basis, or that it is only evident in early-onset PD. Differing disease concordance rates between monozygotic and dizygotic twins in longitudinal studies including those using 18F-dopa positron emission tomography support heritability in PD. Studies show that Parkin mutations usually occur either as homozygous or compound heterozygous mutations (with different mutations in both alleles). However, many have been reported in which, despite extensive screening, only one of the alleles appears to be mutated. This chapter starts with a discussion on genetics of familial Parkinson's disease and then explains the term Parkinsonism-plus genes. The chapter concludes with explaining sporadic PD, genetic associations, and familial genes.

Abstract: Germline mutations in BRCA1 and BRCA2 genes predispose to hereditary breast and ovarian cancer. Our aim was to find associations between the clinical characteristics and positive mutation status in 148 breast cancer families in order to predict the probability of finding a BRCA mutation in a family. Several factors were associated with mutations in univariate analysis, whereas in multivariate analysis (logistic regression with backward selection) only the age of the youngest breast cancer patient and the number of ovarian cancer cases in a family were independent predictors of BRCA mutations. A logistic model was devised to estimate the probability for a family of harbouring a mutation in either BRCA1 or BRCA2. Altogether, 63 out of 148 families (43%) and 28 out of 29 (97%) mutation carrier families obtained probabilities over 10%. The mean probability was 55% for mutation-positive families and 11% for mutation-negative families. The models by Couch et al (1997) and Shattuck-Eidens et al (1997) previously designed for BRCA1 were also tested for their applicability to distinguish carrier families with mutations in either gene. The probability model should be a useful tool in genetic counselling and focusing the mutation analyses, and thus increasing also the cost-effectiveness of the genetic screening.

Abstract: A newly identified Alzheimer's mutation leads to the suggestion that protofibril intermediates in amyloid plaque formation may be a crucial factor in pathogenicity.