Showing papers on "Mutation (genetic algorithm) published in 2009"

A groupwise association test for rare mutations using a weighted sum statistic.

Abstract: Resequencing is an emerging tool for identification of rare disease-associated mutations. Rare mutations are difficult to tag with SNP genotyping, as genotyping studies are designed to detect common variants. However, studies have shown that genetic heterogeneity is a probable scenario for common diseases, in which multiple rare mutations together explain a large proportion of the genetic basis for the disease. Thus, we propose a weighted-sum method to jointly analyse a group of mutations in order to test for groupwise association with disease status. For example, such a group of mutations may result from resequencing a gene. We compare the proposed weighted-sum method to alternative methods and show that it is powerful for identifying disease-associated genes, both on simulated and Encode data. Using the weighted-sum method, a resequencing study can identify a disease-associated gene with an overall population attributable risk (PAR) of 2%, even when each individual mutation has much lower PAR, using 1,000 to 7,000 affected and unaffected individuals, depending on the underlying genetic model. This study thus demonstrates that resequencing studies can identify important genetic associations, provided that specialised analysis methods, such as the weighted-sum method, are used.

SHOREmap: simultaneous mapping and mutation identification by deep sequencing

Abstract: Supplementary Figure 1 Method workflow Supplementary Figure 2 Visual output from SHOREmap DENOVO Supplementary Table 1 Top 10 ranked mutations from the SHOREmap ANNOTATE output Supplementary Table 2 Command line programs, parameters and run time used for the computational analysis of Illumina data Supplementary Table 3 Identification of additional AT4G35090 mutant alleles Supplementary Table 4 Output of SHOREmap ANNOTATE using the interval based on SHOREmap DENOVO data Supplementary Note Mapping large deletions, QTLs and dominant or recessive lethal mutations. Supplementary Methods Lab protocols and computational algorithms Supplementary Data SHORE and SHOREmap example files

Mutation in TET2 in myeloid cancers.

Abstract: To the Editor: The finding of Delhommeau and colleagues that TET2 mutations occur in myeloid cancers (May 28 issue)1 has been confirmed by others.2-5 The presence of single-copy and doublecopy TET2 defects and the frequent occurrence of frameshift, nonsense, or deletion mutations are consistent with the notion that TET2 is a tumor suppressor. Delhommeau et al. suggest a role for TET2 in disease progression. We looked into this possibility by studying stored, serial bone marrow samples from eight patients with myeloproliferative neoplasms. Mutant TET2 was not detected in any of the follow-up samples, even though leukemic or fibrotic transformation occurred in three of these patients. These results are consistent with observations of similar frequencies of TET2 mutations in chronic and advanced-phase myeloproliferative neoplasms.3 We therefore believe that it is difficult to assign a specific role in the pathogenesis or progression of myeloproliferative neoplasms to mutant TET2.

A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis.

Abstract: beta-Amyloid precursor protein (APP) mutations cause familial Alzheimer's disease with nearly complete penetrance. We found an APP mutation [alanine-673-->valine-673 (A673V)] that causes disease only in the homozygous state, whereas heterozygous carriers were unaffected, consistent with a recessive Mendelian trait of inheritance. The A673V mutation affected APP processing, resulting in enhanced beta-amyloid (Abeta) production and formation of amyloid fibrils in vitro. Co-incubation of mutated and wild-type peptides conferred instability on Abeta aggregates and inhibited amyloidogenesis and neurotoxicity. The highly amyloidogenic effect of the A673V mutation in the homozygous state and its anti-amyloidogenic effect in the heterozygous state account for the autosomal recessive pattern of inheritance and have implications for genetic screening and the potential treatment of Alzheimer's disease.

2009 version of the Chompret criteria for Li Fraumeni syndrome.

Abstract: in 474FrenchfamiliessuggestiveofLFS,including232familiesfulfillingtheChompret criteria; obtained a mutation detection rate of 29% (67of232families);andestimatedthesensitivityandspecificityoftheChompret criteria to be 82% and 58%, respectively. We also pro-posedextendingtheChompretcriteriatocovertheclinicalpresen-tation of the 82 families in which we identified germline

A genome-wide view of Caenorhabditis elegans base-substitution mutation processes

Abstract: Knowledge of mutation processes is central to understanding virtually all evolutionary phenomena and the underlying nature of genetic disorders and cancers. However, the limitations of standard molecular mutation detection methods have historically precluded a genome-wide understanding of mutation rates and spectra in the nuclear genomes of multicellular organisms. We applied two high-throughput DNA sequencing technologies to identify and characterize hundreds of spontaneously arising base-substitution mutations in 10 Caenorhabditis elegans mutation-accumulation (MA)-line nuclear genomes. C. elegans mutation rate estimates were similar to previous calculations based on smaller numbers of mutations. Mutations were distributed uniformly within and among chromosomes and were not associated with recombination rate variation in the MA lines, suggesting that intragenomic variation in genetic hitchhiking and/or background selection are primarily responsible for the chromosomal distribution patterns of polymorphic nucleotides in C. elegans natural populations. A strong mutational bias from G/C to A/T nucleotides was detected in the MA lines, implicating oxidative DNA damage as a major endogenous mutagenic force in C. elegans. The observed mutational bias also suggests that the C. elegans nuclear genome cannot be at equilibrium because of mutation alone. Transversions dominate the spectrum of spontaneous mutations observed here, whereas transitions dominate patterns of allegedly neutral polymorphism in natural populations of C. elegans and many other animal species; this observation challenges the assumption that natural patterns of molecular variation in noncoding regions of the nuclear genome accurately reflect underlying mutation processes.

Purging the genome with sexual selection : reducing mutation load through selection on males

Abstract: Healthy males are likely to have higher mating success than unhealthy males because of differential expression of condition-dependent traits such as mate searching intensity, fighting ability, display vigor, and some types of exaggerated morphological characters. We therefore expect that most new mutations that are deleterious for overall fitness may also be deleterious for male mating success. From this perspective, sexual selection is not limited to influencing those genes directly involved in exaggerated morphological traits but rather affects most, if not all, genes in the genome. If true, sexual selection can be an important force acting to reduce the frequency of deleterious mutations and, as a result, mutation load. We review the literature and find various forms of indirect evidence that sexual selection helps to eliminate deleterious mutations. However, direct evidence is scant, and there are almost no data available to address a key issue: is selection in males stronger than selection in females? In addition, the total effect of sexual selection on mutation load is complicated by possible increases in mutation rate that may be attributable to sexual selection. Finally, sexual selection affects population fitness not only through mutation load but also through sexual conflict, making it difficult to empirically measure how sexual selection affects load. Several lines of enquiry are suggested to better fill large gaps in our understanding of sexual selection and its effect on genetic load.

NOS1AP Is a Genetic Modifier of the Long-QT Syndrome

Abstract: Background— In congenital long-QT syndrome (LQTS), a genetically heterogeneous disorder that predisposes to sudden cardiac death, genetic factors other than the primary mutation may modify the probability of life-threatening events. Recent evidence indicates that common variants in NOS1AP are associated with the QT-interval duration in the general population. Methods and Results— We tested the hypothesis that common variants in NOS1AP modify the risk of clinical manifestations and the degree of QT-interval prolongation in a South African LQTS population (500 subjects, 205 mutation carriers) segregating a founder mutation in KCNQ1 (A341V) using a family-based association analysis. NOS1AP variants were significantly associated with the occurrence of symptoms (rs4657139, P=0.019; rs16847548, P=0.003), with clinical severity, as manifested by a greater probability for cardiac arrest and sudden death (rs4657139, P=0.028; rs16847548, P=0.014), and with greater likelihood of having a QT interval in the top 40% o...

The erratic mitochondrial clock: variations of mutation rate, not population size, affect mtDNA diversity across birds and mammals

Abstract: During the last ten years, major advances have been made in characterizing and understanding the evolution of mitochondrial DNA, the most popular marker of molecular biodiversity. Several important results were recently reported using mammals as model organisms, including (i) the absence of relationship between mitochondrial DNA diversity and life-history or ecological variables, (ii) the absence of prominent adaptive selection, contrary to what was found in invertebrates, and (iii) the unexpectedly large variation in neutral substitution rate among lineages, revealing a possible link with species maximal longevity. We propose to challenge these results thanks to the bird/mammal comparison. Direct estimates of population size are available in birds, and this group presents striking life-history trait differences with mammals (higher mass-specific metabolic rate and longevity). These properties make birds the ideal model to directly test for population size effects, and to discriminate between competing hypotheses about the causes of substitution rate variation. A phylogenetic analysis of cytochrome b third-codon position confirms that the mitochondrial DNA mutation rate is quite variable in birds, passerines being the fastest evolving order. On average, mitochondrial DNA evolves slower in birds than in mammals of similar body size. This result is in agreement with the longevity hypothesis, and contradicts the hypothesis of a metabolic rate-dependent mutation rate. Birds show no footprint of adaptive selection on cytochrome b evolutionary patterns, but no link between direct estimates of population size and cytochrome b diversity. The mutation rate is the best predictor we have of within-species mitochondrial diversity in birds. It partly explains the differences in mitochondrial DNA diversity patterns observed between mammals and birds, previously interpreted as reflecting Hill-Robertson interferences with the W chromosome. Mitochondrial DNA diversity patterns in birds are strongly influenced by the wide, unexpected variation of mutation rate across species. From a fundamental point of view, these results are strongly consistent with a relationship between species maximal longevity and mitochondrial mutation rate, in agreement with the mitochondrial theory of ageing. Form an applied point of view, this study reinforces and extends the message of caution previously expressed for mammals: mitochondrial data tell nothing about species population sizes, and strongly depart the molecular clock assumption.

Extremely high mutation rate of a hammerhead viroid

Abstract: The mutation rates of viroids, plant pathogens with minimal non-protein-coding RNA genomes, are unknown. Their replication is mediated by host RNA polymerases and, in some cases, by hammerhead ribozymes, small self-cleaving motifs embedded in the viroid. By using the principle that the population frequency of nonviable genotypes equals the mutation rate, we screened for changes that inactivated the hammerheads of Chrysanthemum chlorotic mottle viroid. We obtained a mutation rate of 1/400 per site, the highest reported for any biological entity. Such error-prone replication can only be tolerated by extremely simple genomes such as those of viroids and, presumably, the primitive replicons of the RNA world. Our results suggest that the emergence of replication fidelity was critical for the evolution of complexity in the early history of life.

Association of High Iodine Intake with the T1799A BRAF Mutation in Papillary Thyroid Cancer

Abstract: Context: Epidemiological studies have indicated that high iodine intake might be a risk factor for papillary thyroid cancer (PTC), which commonly harbors the oncogenic T1799A BRAF mutation. Objective: The objective of the study was to investigate the relationship between BRAF mutation in PTC and iodine intake in patients. Subjects and Methods: We analyzed and compared the prevalences of the T1799A BRAF mutation in classical PTC of 1032 patients from five regions in China that uniquely harbor different iodine contents in natural drinking water, ranging from normal (10–21 μg/liter) to high (104–287 μg/liter). The BRAF mutation was identified by direct DNA sequencing. Results: The prevalence of BRAF mutation was significantly higher in any of the regions with high iodine content than any of the regions with normal iodine content. Overall, BRAF mutation was found in 387 of 559 PTC with high iodine content (69%) vs. 252 of 473 PTC with normal iodine content (53%), with an odds ratio of 1.97 (95% confidence int...

The Human Gene Mutation Database: providing a comprehensive central mutation database for molecular diagnostics and personalised genomics

Abstract: Reading the recent Editorial in the Journal by Richard Cotton, which publicised the proposed new Human Variome Project, one could be forgiven for thinking that no central repository for inherited human gene mutations of pathological significance currently exists. In practice, however, the Human Gene Mutation Database (HGMD; http://www.hgmd.org) already constitutes a comprehensive collection of single base-pair substitutions in coding (missense and nonsense), regulatory and splicing-relevant regions of human nuclear genes, micro-deletions and microinsertions, indels, repeat expansions, as well as gross gene lesions (deletions, insertions and duplications) and complex gene rearrangements. This unique resource currently contains in excess of 96,000 different germline mutations and disease-associated/ functional polymorphisms—in a total of over 3,600 nuclear genes (December 2009 release)—causing or associated with human inherited disease. HGMD currently provides free access to the bulk of its mutation data to over 30,000 registered academic/non-profit users worldwide. In the absence of any public funding, HGMD is maintained courtesy of a subscription-based version (HGMD Professional), distributed through BIOBASE GmbH (http://www.biobase-international.com). HGMD Professional not only provides access to the very latest mutation data, but also contains valuable extra features, including an expanded search engine, genomic coordinates, additional literature references, Human Genome Variation Society (HGVS) nomenclature (http://www.hgvs. org/mutnomen) and a suite of advanced search tools that greatly enhance the utility of the database. Together with BIOBASE, we are working toward being able to make all HGMD data and search tools available to the academic community free of charge and in a timely fashion, with the costs of upkeep being borne primarily by industry and commerce. We believe that this funding model should not only guarantee the financial viability of HGMD, but also allow this unique resource to be sustainable into the long term, to the benefit of the scientific community. Although HGMD has now become the de facto central disease-associated mutation database, there are several other valuable sources of human mutation data available. Online Mendelian Inheritance in Man (OMIM; http://www.ncbi. nlm.nih.gov/sites/entrez?db=omim) is a formidable genotype–phenotype knowledge base, but it is not comprehensive with respect to mutation data on account of its policy of providing only specimen examples of allelic variants (in a total of 2,328 human genes). In addition to inherited pathological mutations, it should be noted that OMIM also contains some somatic lesions, neutral GUEST EDITORIAL

The Impact of Equivalent Mutants

Abstract: If a mutation is not killed by a test suite, this usuallymeans that the test suite is not adequate. However, itmay also be that the mutant keeps the program’s seman-tics unchanged—and thus cannot be detected by any test.We found such equivalent mutants to be surprisingly com-mon: In an experiment on the JAXEN XPATH query engine,8/20 = 40% of all mutations turned out to be equivalent.Worse, checking the equivalency took us 15 minutes for asingle mutation. Equivalent mutants thus make it impossi-ble to automatically assess test suites by means of mutationtesting. To identify equivalent mutants, we are currently investi-gating the impact of a mutation on the execution: the morea mutation alters the execution, the higher the chance of itbeing non-equivalent. First experiments assessing the im-pact on code coverage are promising.

The causes of mutation accumulation in mitochondrial genomes

Abstract: A fundamental observation across eukaryotic taxa is that mitochondrial genomes have a higher load of deleterious mutations than nuclear genomes. Identifying the evolutionary forces that drive this difference is important to understanding the rates and patterns of sequence evolution, the efficacy of natural selection, the maintenance of sex and recombination and the mechanisms underlying human ageing and many diseases. Recent studies have implicated the presumed asexuality of mitochondrial genomes as responsible for their high mutational load. We review the current body of knowledge on mitochondrial mutation accumulation and recombination, and conclude that asexuality, per se, may not be the primary determinant of the high mutation load in mitochondrial DNA (mtDNA). Very little recombination is required to counter mutation accumulation, and recent evidence suggests that mitochondrial genomes do experience occasional recombination. Instead, a high rate of accumulation of mildly deleterious mutations in mtDNA may result from the small effective population size associated with effectively haploid inheritance. This type of transmission is nearly ubiquitous among mitochondrial genomes. We also describe an experimental framework using variation in mating system between closely related species to disentangle the root causes of mutation accumulation in mitochondrial genomes.

Unmarked gene deletion and host-vector system for the hyperthermophilic crenarchaeon Sulfolobus islandicus

Abstract: Sulfolobus islandicus is being used as a model for studying archaeal biology, geo-biology and evolution. However, no genetic system is available for this organism. To produce an S. islandicus mutant suitable for genetic analyses, we screened for colonies with a spontaneous pyrEF mutation. One mutant was obtained containing only 233 bp of the original pyrE sequence in the mutant allele and it was used as a host to delete the β-glycosidase (lacS) gene. Two unmarked gene deletion methods were employed, namely plasmid integration and segregation, and marker replacement and looping out, and unmarked lacS mutants were obtained by each method. A new alternative recombination mechanism, i.e., marker circularization and integration, was shown to operate in the latter method, which did not yield the designed deletion mutation. Subsequently, Sulfolobus–E. coli plasmid shuttle vectors were constructed, which genetically complemented ΔpyrEFΔlacS mutation after transformation. Thus, a complete set of genetic tools was established for S. islandicus with pyrEF and lacS as genetic markers.

A Cav3.2 T-Type Calcium Channel Point Mutation Has Splice-Variant-Specific Effects on Function and Segregates with Seizure Expression in a Polygenic Rat Model of Absence Epilepsy

Abstract: Low-voltage-activated, or T-type, calcium (Ca2+) channels are believed to play an essential role in the generation of absence seizures in the idiopathic generalized epilepsies (IGEs). We describe a homozygous, missense, single nucleotide (G to C) mutation in the Cav3.2 T-type Ca2+ channel gene (Cacna1h) in the genetic absence epilepsy rats from Strasbourg (GAERS) model of IGE. The GAERS Cav3.2 mutation (gcm) produces an arginine to proline (R1584P) substitution in exon 24 of Cacna1h, encoding a portion of the III–IV linker region in Cav3.2. gcm segregates codominantly with the number of seizures and time in seizure activity in progeny of an F1 intercross. We have further identified two major thalamic Cacna1h splice variants, either with or without exon 25. gcm introduced into the splice variants acts “epistatically,” requiring the presence of exon 25 to produce significantly faster recovery from channel inactivation and greater charge transference during high-frequency bursts. This gain-of-function mutation, the first reported in the GAERS polygenic animal model, has a novel mechanism of action, being dependent on exonic splicing for its functional consequences to be expressed.

Immunodeficiency Associated with FCN3 Mutation and Ficolin-3 Deficiency

Abstract: Ficolin-3, encoded by the FCN3 gene and expressed in the lung and liver, is a recognition molecule in the lectin pathway of the complement system. Heterozygosity for an FCN3 frameshift mutation (rs28357092), leading to a distortion of the C-terminal end of the molecule, occurs in people without disease (allele frequency among whites, 0.01). We describe a patient with recurrent infections who was homozygous for this mutation, who had undetectable serum levels of ficolin-3, and who had a deficiency in ficolin-3-dependent complement activation.

Particle Swarm Optimization with Adaptive Mutation

Abstract: Particle swarm optimization (PSO) has shown its good performance in many optimization problems. However, PSO could often easily fall into local minima because the particles could quickly converge to a position by the attraction of the best particles. Under this circumstance, all the particles could hardly be improved. This paper presents a hybrid PSO (AMPSO) to solve this problem by applying a novel adaptive mutation operator. Experimental results on 8 well-known benchmark functions show that the AMPSO achieves better results than the standard PSO, PSO with Gaussian mutation and PSO with Cauchy mutation on most test cases.

The microbial genetic algorithm

Abstract: We analyse how the conventional Genetic Algorithm can be stripped down and reduced to its basics. We present a minimal, modified version that can be interpreted in terms of horizontal gene transfer, as in bacterial conjugation. Whilst its functionality is effectively similar to the conventional version, it is much easier to program, and recommended for both teaching purposes and practical applications. Despite the simplicity of the core code, it effects Selection, (variable rates of) Recombination, Mutation, Elitism ('for free') and Geographical Distribution.

The breast cancer susceptibility mutation PALB2 1592delT is associated with an aggressive tumor phenotype.

Abstract: Purpose: To determine the effect of the breast cancer susceptibility mutation PALB2 1592delT on tumor phenotype and patient survival. Experimental Design: We defined the PALB2 mutation status in 947 familial and 1,274 sporadic breast cancer patients and 1,079 population controls, and compared tumor characteristics and survival in mutation carriers relative to other familial and sporadic cases and to 79 BRCA1 and 104 BRCA2 mutation carrier cases. Results: The PALB2 1592delT mutation was found in 19 familial [2.0%; odds ratio, 11.03; 95% confidence interval (95% CI), 2.65-97.78; P P = 0.1207) compared with two (0.2%) control individuals. Tumors of the PALB2 mutation carriers presented triple negative (estrogen receptor negative/progesterone receptor negative/HER negative) phenotype more often (54.5%; P P = 0.0027 and P = 0.0017, respectively) and had higher expression of Ki67 ( P = 0.0004 and P = 0.0490, respectively). Carrying a PALB2 mutation was also associated with reduced survival, especially in familial cases (hazard ratio, 2.30; 95% CI, 1.01-5.24; P = 0.0466) and among familial patients with HER2-negative tumors (hazard ratio, 4.57; 95% CI, 1.96-10.64; P = 0.0004). Carrying a BRCA2 mutation was also found to be an independent predictor of poor survival at 10-year follow-up ( P = 0.04). Conclusions: The PALB2 1592delT mutation has a strong effect on familial breast cancer risk. The tumors rising in patients carrying this mutation manifest a phenotype associated with aggressive disease. Our results also suggest a significant impact of carrying a BRCA2 mutation on long-term breast cancer survival.

Role of mutation in Pseudomonas aeruginosa biofilm development.

Abstract: The survival of bacteria in nature is greatly enhanced by their ability to grow within surface-associated communities called biofilms. Commonly, biofilms generate proliferations of bacterial cells, called microcolonies, which are highly recalcitrant, 3-dimensional foci of bacterial growth. Microcolony growth is initiated by only a subpopulation of bacteria within biofilms, but processes responsible for this differentiation remain poorly understood. Under conditions of crowding and intense competition between bacteria within biofilms, microevolutionary processes such as mutation selection may be important for growth; however their influence on microcolony-based biofilm growth and architecture have not previously been explored. To study mutation in-situ within biofilms, we transformed Pseudomonas aeruginosa cells with a green fluorescent protein gene containing a +1 frameshift mutation. Transformed P. aeruginosa cells were non-fluorescent until a mutation causing reversion to the wildtype sequence occurs. Fluorescence-inducing mutations were observed in microcolony structures, but not in other biofilm cells, or in planktonic cultures of P. aeruginosa cells. Thus microcolonies may represent important foci for mutation and evolution within biofilms. We calculated that microcolony-specific increases in mutation frequency were at least 100-fold compared with planktonically grown cultures. We also observed that mutator phenotypes can enhance microcolony-based growth of P. aeruginosa cells. For P. aeruginosa strains defective in DNA fidelity and error repair, we found that microcolony initiation and growth was enhanced with increased mutation frequency of the organism. We suggest that microcolony-based growth can involve mutation and subsequent selection of mutants better adapted to grow on surfaces within crowded-cell environments. This model for biofilm growth is analogous to mutation selection that occurs during neoplastic progression and tumor development, and may help to explain why structural and genetic heterogeneity are characteristic features of bacterial biofilm populations.

Mutation scanning using high-resolution melting.

Abstract: Mutation scanning techniques are used to detect sequence variants without the need for prior knowledge of the identity or precise location of the variant, in contrast with genotyping techniques, which determine the status of a specific variant. High-resolution melting is a recently developed method that shows great potential as a mutation scanning technique. Sensitivity and specificity for mutation detection are extremely high and the technique also has advantages of cost and throughput. Practical considerations for successful mutation scanning by high-resolution melting are also discussed in this review.

Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers

Abstract: Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.

Cryptic Variation in the Human Mutation Rate

Abstract: The mutation rate is known to vary between adjacent sites within the human genome as a consequence of context, the most well-studied example being the influence of CpG dinucelotides. We investigated whether there is additional variation by testing whether there is an excess of sites at which both humans and chimpanzees have a single-nucleotide polymorphism (SNP). We found a highly significant excess of such sites, and we demonstrated that this excess is not due to neighbouring nucleotide effects, ancestral polymorphism, or natural selection. We therefore infer that there is cryptic variation in the mutation rate. However, although this variation in the mutation rate is not associated with the adjacent nucleotides, we show that there are highly nonrandom patterns of nucleotides that extend ∼80 base pairs on either side of sites with coincident SNPs, suggesting that there are extensive and complex context effects. Finally, we estimate the level of variation needed to produce the excess of coincident SNPs and show that there is a similar, or higher, level of variation in the mutation rate associated with this cryptic process than there is associated with adjacent nucleotides, including the CpG effect. We conclude that there is substantial variation in the mutation that has, until now, been hidden from view.