Recurrent Deleterious Mutations Research Articles

Distinct mutational processes shape selection of MHC class I and class II mutations across primary and metastatic tumors

Disruption of antigen presentation via loss of major histocompatibility complex (MHC) expression is a strategy whereby cancer cells escape immune surveillance and develop resistance to immunotherapy. Here, we develop the personalized genomics algorithm Hapster and accurately call somatic mutations within the MHC genes of 10,001 primary and 2,199 metastatic tumors, creating a catalog of 1,663 non-synonymous mutations that provide key insights into MHC mutagenesis. We find that MHC class I genes are among the most frequently mutated genes in both primary and metastatic tumors, while MHC class II mutations are more restricted. Recurrent deleterious mutations are found within haplotype- and cancer-type-specific hotspots associated with distinct mutational processes. Functional classification of MHC residues reveals significant positive selection for mutations disruptive to the B2M, peptide, and Tcell binding interfaces, as well as to MHC chaperones.

The effects of weak selection on neutral diversity at linked sites.

The effects of selection on variability at linked sites have an important influence on levels and patterns of within-population variation across the genome. Most theoretical models of these effects have assumed that selection is sufficiently strong that allele frequency changes at the loci concerned are largely deterministic. These models have led to the conclusion that directional selection for selectively favorable mutations, or against recurrent deleterious mutations, reduces nucleotide site diversity at linked neutral sites. Recent work has shown, however, that fixations of weakly selected mutations, accompanied by significant stochastic changes in allele frequencies, can sometimes cause higher diversity at linked sites when compared with the effects of fixations of neutral mutations. This study extends this work by deriving approximate expressions for the mean conditional times to fixation and loss of mutations subject to selection, and analyzing the conditions under which selection increases rather than reduces these times. Simulations are used to examine the relations between diversity at a neutral site and the fixation and loss times of mutations at a linked site that is subject to selection. It is shown that the long-term level of neutral diversity can be increased over the purely neutral value by recurrent fixations and losses of linked, weakly selected dominant or partially dominant favorable mutations, or linked recessive or partially recessive deleterious mutations. The results are used to examine the conditions under which associative overdominance, as opposed to background selection, is likely to operate.

Evolution of linkage and genome expansion in protocells: The origin of chromosomes.

Chromosomes are likely to have assembled from unlinked genes in early evolution. Genetic linkage reduces the assortment load and intragenomic conflict in reproducing protocell models to the extent that chromosomes can go to fixation even if chromosomes suffer from a replicative disadvantage, relative to unlinked genes, proportional to their length. Here we numerically show that chromosomes spread within protocells even if recurrent deleterious mutations affecting replicating genes (as ribozymes) are considered. Dosage effect selects for optimal genomic composition within protocells that carries over to the genic composition of emerging chromosomes. Lacking an accurate segregation mechanism, protocells continue to benefit from the stochastic corrector principle (group selection of early replicators), but now at the chromosome level. A remarkable feature of this process is the appearance of multigene families (in optimal genic proportions) on chromosomes. An added benefit of chromosome formation is an increase in the selectively maintainable genome size (number of different genes), primarily due to the marked reduction of the assortment load. The establishment of chromosomes is under strong positive selection in protocells harboring unlinked genes. The error threshold of replication is raised to higher genome size by linkage due to the fact that deleterious mutations affecting protocells metabolism (hence fitness) show antagonistic (diminishing return) epistasis. This result strengthens the established benefit conferred by chromosomes on protocells allowing for the fixation of highly specific and efficient enzymes.

Novel Genetic Variations in Acute Myeloid Leukemia in Pakistani Population.

Acute myeloid leukemia (AML) is a hematological malignancy characterized by clonal expansion of blast cells that exhibit great genetic heterogeneity. In this study, we describe the mutational landscape and its clinico-pathological significance in 26 myeloid neoplasm patients from a South Asian population (Pakistan) by using ultra-deep targeted next-generation DNA sequencing of 54 genes (∼5000×) and its subsequent bioinformatics analysis. The data analysis indicated novel non-silent somatic mutational events previously not reported in AML, including nine non-synonymous and one stop-gain mutations. Notably, two recurrent somatic non-synonymous mutations, i.e., STAG2 (causing p.L526F) and BCORL1 (p.A400V), were observed in three unrelated cases each. The BCOR was found to have three independent non-synonymous somatic mutations in three cases. Further, the SRSF2 with a protein truncating somatic mutation (p.Q88X) was observed for the first time in AML in this study. The prioritization of germline mutations with ClinVar, SIFT, Polyphen2, and Combined Annotation Dependent Depletion (CADD) highlighted 18 predicted deleterious/pathogenic mutations, including two recurrent deleterious mutations, i.e., a novel heterozygous non-synonymous SNV in GATA2 (p.T358P) and a frameshift insertion in NPM1 (p.L258fs), found in two unrelated cases each. The WT1 was observed with three independent potential detrimental germline mutations in three different cases. Collectively, non-silent somatic and/or germline mutations were observed in 23 (88.46%) of the cases (0.92 mutation per case). Furthermore, the pharmGKB database exploration showed a missense SNV rs1042522 in TP53, exhibiting decreased response to anti-cancer drugs, in 19 (73%) of the cases. This genomic profiling of AML provides deep insight into the disease pathophysiology. Identification of pharmacogenomics markers will help to adopt personalized approach for the management of AML patients in Pakistan.

Background selection and FST : Consequences for detecting local adaptation.

Background selection is a process whereby recurrent deleterious mutations cause a decrease in the effective population size and genetic diversity at linked loci. Several authors have suggested that variation in the intensity of background selection could cause variation in FST across the genome, which could confound signals of local adaptation in genome scans. We performed realistic simulations of DNA sequences, using recombination maps from humans and sticklebacks, to investigate how variation in the intensity of background selection affects FST and other statistics of population differentiation in sexual, outcrossing species. We show that, in populations connected by gene flow, Weir and Cockerham's (1984; Evolution, 38, 1358) estimator of FST is largely insensitive to locus-to-locus variation in the intensity of background selection. Unlike FST , however, dXY is negatively correlated with background selection. Moreover, background selection does not greatly affect the false-positive rate in FST outlier studies in populations connected by gene flow. Overall, our study indicates that background selection will not greatly interfere with finding the variants responsible for local adaptation.

Prevalence of BRCA1 and BRCA2 Mutations Among High-Risk Saudi Patients With Breast Cancer.

PurposeOver the past three decades, the incidence rate of breast cancer (BC) among Arab women has continually increased. However, data on the prevalence of BRCA1/2 mutations are scarce. Although the population in Saudi Arabia is at large homogeneous and consanguinity is common, especially in the central, eastern, and southern regions of the country, the prevalence of BRCA1 and BRCA2 mutations and the characteristics of BC are not well studied in the country.MethodsThis prospective observational study intended to determine the prevalence of BRCA1 and BRCA2 mutations and sought to examine the clinicopathologic features of BC associated with these mutations. ResultsOf 310 patients, 270 (87%) had no mutation. BRCA mutations were identified in 40 patients; BRCA1 mutations were found in 11% of patients, and BRCA2 mutations were found in 2% of patients. Variants of unknown significance were found in 15% of patients (45 patients). Triple-negative BC (TNBC) accounted for 86% of all patients with BC and mutations. The following three recurrent deleterious founder BRCA1 mutations were observed: c.4136_4137delCT was observed in five unrelated patients, c.5530delC was observed in three unrelated patients, and c.4524G>A mutations were observed in five unrelated patients. One novel mutation was identified in the BRCA1 gene (c.5512 dup [p.Glu1838Glyfs*42]). ConclusionAmong high-risk Saudi patients with BC, BRCA1 mutations are prevalent (11%). TNBC is the most common BC subtype. Furthermore, age alone does not have a significant association with mutation, but a combination of risk factors such as age, familial history, and TNBC has a significant association with BRCA mutation.

A Model of Compound Heterozygous, Loss-of-Function Alleles Is Broadly Consistent with Observations from Complex-Disease GWAS Datasets.

The genetic component of complex disease risk in humans remains largely unexplained. A corollary is that the allelic spectrum of genetic variants contributing to complex disease risk is unknown. Theoretical models that relate population genetic processes to the maintenance of genetic variation for quantitative traits may suggest profitable avenues for future experimental design. Here we use forward simulation to model a genomic region evolving under a balance between recurrent deleterious mutation and Gaussian stabilizing selection. We consider multiple genetic and demographic models, and several different methods for identifying genomic regions harboring variants associated with complex disease risk. We demonstrate that the model of gene action, relating genotype to phenotype, has a qualitative effect on several relevant aspects of the population genetic architecture of a complex trait. In particular, the genetic model impacts genetic variance component partitioning across the allele frequency spectrum and the power of statistical tests. Models with partial recessivity closely match the minor allele frequency distribution of significant hits from empirical genome-wide association studies without requiring homozygous effect sizes to be small. We highlight a particular gene-based model of incomplete recessivity that is appealing from first principles. Under that model, deleterious mutations in a genomic region partially fail to complement one another. This model of gene-based recessivity predicts the empirically observed inconsistency between twin and SNP based estimated of dominance heritability. Furthermore, this model predicts considerable levels of unexplained variance associated with intralocus epistasis. Our results suggest a need for improved statistical tools for region based genetic association and heritability estimation.

Recurrent Pathogenic Cyclin D2 Mutations in Myeloid Malignancies

Introduction: Atypical chronic myeloid leukemia (aCML) and chronic neutrophilic leukemia (CNL) are rare hematologic neoplasms characterized by leukocytosis, a hypercellular bone marrow with granulocytic predominance, absence of the Philadelphia chromosome (t(9;22); BCR-ABL1), and absence of PDGFRA/B or FGFR1 gene rearrangements. While oncogenic mutations in colony stimulating factor 3 receptor (CSF3R) are commonly reported in CNL and, to a lesser extent, in aCML, a significant percentage of aCML and CNL cases lack well-defined pathogenetic lesions. In this study, we utilized whole exome sequencing and a functional genomics approach to identify recurrent cyclin D2 (CCND2)mutations in aCML/CNL.Methods: To achieve a more complete understanding of the pathogenic variants underlying these leukemias, genomic DNA was isolated from peripheral blood or bone marrow aspirates from 116 patients with aCML/CNL. Whole exome sequencing was then performed, allowing for the identification of novel and potentially deleterious recurrent mutations. Variants in CCND2 were prioritized for validation based on proximity to functional targets in protein interaction network databases and subsequently confirmed via Sanger sequencing. CCND2 expression was assessed by immunoblotting and immunofluorescence in NIH-3T3 cells. Transforming potential of the CCND2 mutations was assessed by examining IL-3-independent growth of Ba/F3 cells and murine bone marrow colony formation assays. Sensitivity of these mutations to CDK4/6 inhibition was examined via a colorimetric viability assay (MTS) at 72 hours following drug treatment.Results: Out of 116 suspected cases of aCML/CNL, we identified 4 cases (3.4%) that harbored recurrent mutations in CCND2, the gene encoding the cell cycle regulator cyclin D2. The mutations occurred in two nucleotides in a conserved region of the C-terminal PEST degradation domain and encoded either a P281S or a P281L (3 P281S, 1 P281L) variant. These variant proteins exhibited resistance to both degradation and to export from the nucleus, effectively resulting in accumulation of cyclin D2 protein. In turn, this accumulation was associated with increased murine bone marrow colony formation and sensitivity to CDK4/6 inhibition. Subsequent whole exome sequencing of 239 AML samples revealed the presence of the same variants (CCND2 P281S and P281L) in 3 samples (1.3%), suggesting that these variants may occur across multiple subsets of myeloid malignancy.Conclusions: Our study provides evidence of recurrent deleterious CCND2 mutations in aCML/CNL and AML. These mutations may contribute to oncogenesis in myeloid malignancy and are therapeutically targetable through CDK4/6 inhibition. DisclosuresDruker:Agios: Honoraria; Ambit BioSciences: Consultancy; ARIAD: Patents & Royalties, Research Funding; Array: Patents & Royalties; AstraZeneca: Consultancy; Blueprint Medicines: Consultancy, Equity Ownership, Other: travel, accommodations, expenses ; BMS: Research Funding; CTI: Equity Ownership; Curis: Patents & Royalties; Cylene: Consultancy, Equity Ownership; D3 Oncology Solutions: Consultancy; Gilead Sciences: Consultancy, Other: travel, accommodations, expenses ; Lorus: Consultancy, Equity Ownership; MolecularMD: Consultancy, Equity Ownership, Patents & Royalties; Novartis: Research Funding; Oncotide Pharmaceuticals: Research Funding; Pfizer: Patents & Royalties; Roche: Consultancy.

Population screening for BRCA1/BRCA2 mutations: lessons from qualitative analysis of the screening experience.

Population screening for BRCA1/BRCA2. mutations is being considered for Ashkenazi Jews (AJ) because 2.5% carry recurrent deleterious mutations and effective cancer prevention exists. This study aimed to provide a qualitative focus on perspectives of individuals, particularly carriers, who were tested through a screening trial. In this trial, the pretest process included only written information. Interviews were performed with 26 carriers and 10 noncarriers who participated in a BRCA population screening trial for AJ. Attitudes toward screening were generally positive. The main motivator for testing was knowledge of BRCA status to enable cancer risk reduction. Knowledge of carrier status, although challenging, was thus viewed as health-empowering. The screening paradigm was sensed as increasing awareness and as overcoming access, referral, and familial barriers. Streamlining the pretest process was positively perceived as offering gradual, stepwise knowledge commensurate with test results. Participants were concerned that health systems provide the necessary conceptual and infrastructural framework and that individual autonomy be maintained. BRCA screening in AJ is viewed favorably, even by carriers. Stepwise acquisition of knowledge based on test results was viewed as most relevant to the screening context. Screening program development should account for safeguarding autonomy and providing requisite post-test services.Genet Med advance online publication 01 December 2016.

Identification of Multiple Gene Mutations Accounts for a new Genetic Architecture of Primary Ovarian Insufficiency.

Idiopathic primary ovarian insufficiency (POI) is a major cause of amenorrhea and infertility. POI affects 1% of women before age 40 years, and several genetic causes have been reported. To date, POI has been considered a monogenic disorder. The aim of this study was to identify novel gene variations and to investigate if individuals with POI harbor mutation in multiple loci. One hundred well-phenotyped POI patients were systematically screened for variants in 19 known POI loci (and potential candidate genes) using next-generation sequencing. At least one rare protein-altering gene variant was identified in 19 patients, including missense mutations in new candidate genes, namely SMC1β and REC8 (involved in the cohesin complex) and LHX8, a gene encoding a transcription factor. Novel or recurrent deleterious mutations were also detected in the known POI candidate genes NOBOX, FOXL2, SOHLH1, FIGLA, GDF9, BMP15, and GALT. Seven patients harbor mutations in two loci, and this digenicity seems to influence the age of symptom onset. Genetic anomalies in women with POI are more frequent than previously believed. Digenic findings in several cases suggest that POI is not a purely monogenic disorder and points to a role of digenicity. The genotype-phenotype correlations in some kindreds suggest that a synergistic effect of several mutations may underlie the POI phenotype.

Next generation sequencing of Cytokeratin 20-negative Merkel cell carcinoma reveals ultraviolet-signature mutations and recurrent TP53 and RB1 inactivation

Merkel cell carcinoma is a rare but highly aggressive cutaneous neuroendocrine carcinoma. Cytokeratin 20 (CK20) is expressed in ~95% of Merkel cell carcinomas and is useful for distinction from morphologically similar entities including metastatic small-cell lung carcinoma. Lack of CK20 expression may make diagnosis of Merkel cell carcinoma more challenging, and has unknown biological significance. Approximately 80% of CK20-positive Merkel cell carcinomas are associated with the oncogenic Merkel cell polyomavirus. Merkel cell carcinomas lacking Merkel cell polyomavirus display distinct genetic changes from Merkel cell polyomavirus-positive Merkel cell carcinoma, including RB1 inactivating mutations. Unlike CK20-positive Merkel cell carcinoma, the majority of CK20-negative Merkel cell carcinomas are Merkel cell polyomavirus-negative, suggesting CK20-negative Merkel cell carcinomas predominantly arise through virus-independent pathway(s) and may harbor additional genetic differences from conventional Merkel cell carcinoma. Hence, we analyzed 15 CK20-negative Merkel cell carcinoma tumors (10 Merkel cell polyomavirus-negative, four Merkel cell polyomavirus-positive, and one undetermined) using the Ion Ampliseq Comprehensive Cancer Panel, which assesses copy number alterations and mutations in 409 cancer-relevant genes. Twelve tumors displayed prioritized high-level chromosomal gains or losses (average 1.9 per tumor). Non-synonymous high-confidence somatic mutations were detected in 14 tumors (average 11.9 per tumor). Assessing all somatic coding mutations, an ultraviolet-signature mutational profile was present, and more prevalent in Merkel cell polyomavirus-negative tumors. Recurrent deleterious tumor suppressor mutations affected TP53 (9/15, 60%), RB1 (3/15, 20%), and BAP1 (2/15, 13%). Oncogenic activating mutations included PIK3CA (3/15, 20%), AKT1 (1/15, 7%) and EZH2 (1/15, 7%). In conclusion, CK20-negative Merkel cell carcinoma display overlapping genetic changes with CK20-positive Merkel cell carcinoma, including RB1 mutations restricted to Merkel cell polyomavirus-negative tumors. However, some CK20-negative Merkel cell carcinomas harbor mutations not previously described in Merkel cell carcinoma. Hence, CK20-negative Merkel cell carcinomas harbor diverse oncogenic drivers which may represent therapeutic targets in individual tumors.

The Mutational Landscape of Acute Promyelocytic Leukemia Reveals an Interacting Network of Co-Occurrences and Recurrent Mutations.

Preliminary Acute Promyelocytic Leukemia (APL) whole exome sequencing (WES) studies have identified a huge number of somatic mutations affecting more than a hundred different genes mainly in a non-recurrent manner, suggesting that APL is a heterogeneous disease with secondary relevant changes not yet defined. To extend our knowledge of subtle genetic alterations involved in APL that might cooperate with PML/RARA in the leukemogenic process, we performed a comprehensive analysis of somatic mutations in APL combining WES with sequencing of a custom panel of targeted genes by next-generation sequencing. To select a reduced subset of high confidence candidate driver genes, further in silico analysis were carried out. After prioritization and network analysis we found recurrent deleterious mutations in 8 individual genes (STAG2, U2AF1, SMC1A, USP9X, IKZF1, LYN, MYCBP2 and PTPN11) with a strong potential of being involved in APL pathogenesis. Our network analysis of multiple mutations provides a reliable approach to prioritize genes for additional analysis, improving our knowledge of the leukemogenesis interactome. Additionally, we have defined a functional module in the interactome of APL. The hypothesis is that the number, or the specific combinations, of mutations harbored in each patient might not be as important as the disturbance caused in biological key functions, triggered by several not necessarily recurrent mutations.

Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms

Single nucleotide variants (SNVs), particularly loss-of-function mutations, are significant contributors to autism spectrum disorder (ASD) risk. Here we report the first systematic deep sequencing study of 55 postmortem ASD brains for SNVs in 78 known ASD candidate genes. Remarkably, even without parental samples, we find more ASD brains with mutations that are protein-altering (26/55 cases versus 12/50 controls, p = 0.015), deleterious (16/55 versus 5/50, p = 0.016), or loss-of-function (6/55 versus 0/50, p = 0.028) compared to controls, with recurrent deleterious mutations in ARID1B, SCN1A, SCN2A, and SETD2, suggesting these mutations contribute to ASD risk. In several cases, the identified mutations and medical records suggest syndromic ASD diagnoses. Two ASD and one Fragile X premutation case showed deleterious somatic mutations, providing evidence that somatic mutations occur in ASD cases, and supporting a model in which a combination of germline and/or somatic mutations may contribute to ASD risk on a case-by-case basis.

Cumulative BRCA mutation analysis in the Greek population confirms that homogenous ethnic background facilitates genetic testing.

Screening for BRCA 1 and BRCA 2 mutations has long moved from the research lab to the clinic as a routine clinical genetic testing. BRCA molecular alteration pattern varies among ethnic groups which makes it already a less straightforward process to select the appropriate mutations for routine genetic testing on the basis of known clinical significance.The present report comprises an in depth literature review of the so far reported BRCA 1 and BRCA 2 molecular alterations in Greek families. Our analysis of Greek cumulative BRCA 1 and 2 molecular data, produced by several independent groups, confirmed that six recurrent deleterious mutations account for almost 60 % and 70 % of all BRCA 1 and 2 and BRCA 1 mutations, respectively.As a result, it makes more sense to perform BRCA mutation analysis in the clinic in two sequential steps, first conventional analysis for the six most prevalent pathogenic mutations and if none identified, a second step of New Generation Sequencing-based whole genome or whole exome sequencing would follow. Our suggested approach would enable more clinically meaningful, considerably easier and less expensive BRCA analysis in the Greek population which is considered homogenous.

Local neutral networks help maintain inaccurately replicating ribozymes.

The error threshold of replication limits the selectively maintainable genome size against recurrent deleterious mutations for most fitness landscapes. In the context of RNA replication a distinction between the genotypic and the phenotypic error threshold has been made; where the latter concerns the maintenance of secondary structure rather than sequence. RNA secondary structure is treated as a proxy for function. The phenotypic error threshold allows higher per digit mutation rates than its genotypic counterpart, and is known to increase with the frequency of neutral mutations in sequence space. Here we show that the degree of neutrality, i.e. the frequency of nearest-neighbour (one-step) neutral mutants is a remarkably accurate proxy for the overall frequency of such mutants in an experimentally verifiable formula for the phenotypic error threshold; this we achieve by the full numerical solution for the concentration of all sequences in mutation-selection balance up to length 16. We reinforce our previous result that currently known ribozymes could be selectively maintained by the accuracy known from the best available polymerase ribozymes. Furthermore, we show that in silico stabilizing selection can increase the mutational robustness of ribozymes due to the fact that they were produced by artificial directional selection in the first place. Our finding offers a better understanding of the error threshold and provides further insight into the plausibility of an ancient RNA world.

Finnish Fanconi anemia mutations and hereditary predisposition to breast and prostate cancer.

Mutations in downstream Fanconi anemia (FA) pathway genes, BRCA2, PALB2, BRIP1 and RAD51C, explain part of the hereditary breast cancer susceptibility, but the contribution of other FA genes has remained questionable. Due to FA's rarity, the finding of recurrent deleterious FA mutations among breast cancer families is challenging. The use of founder populations, such as the Finns, could provide some advantage in this. Here, we have resolved complementation groups and causative mutations of five FA patients, representing the first mutation confirmed FA cases in Finland. These patients belonged to complementation groups FA-A (n = 3), FA-G (n = 1) and FA-I (n = 1). The prevalence of the six FA causing mutations was then studied in breast (n = 1840) and prostate (n = 565) cancer cohorts, and in matched controls (n = 1176 females, n = 469 males). All mutations were recurrent, but no significant association with cancer susceptibility was observed for any: the prevalence of FANCI c.2957_2969del and c.3041G>A mutations was even highest in healthy males (1.7%). This strengthens the exclusive role of downstream genes in cancer predisposition. From a clinical point of view, current results provide fundamental information of the mutations to be tested first in all suspected FA cases in Finland.

430 Analysis of 2,700 Cancer Exomes to Identify Novel Cancer Drivers and Therapeutic Opportunities

Background: Next generation sequence analysis of cancer exomes provides a comprehensive assessment of somatic mutations; however discerning often rare driver mutations from abundant passenger mutations remains a challenge. Unlike other approaches that rely on computational prediction of a single mutation’s function, we developed an approach that surveys a large collection of cancer exomes to identify genes with characteristic mutation patterns modeled on known oncogenes and tumor suppressor genes. We applied our approach to >2,700 cancer exomes to define the driver mutational landscape of common cancers. Materials and Methods: Somatic mutation data was obtained from The Cancer Genome Atlas. A total of 1,098,928 somatic mutations were integrated and re-annotated from 2,711 patients across 13 cancer types. After filtering for mutations within and in proximity to coding regions, 728,632 mutations remained. The proportion of recurrent hotspot and recurrent deleterious mutations were tabulated for each gene in each cancer type and then an oncogene vs. tumor suppressor vs. passenger classifier was trained on known cancer genes. Results: A median of 51 non-synonymous mutations per sample (range 1 to >20,000) was observed. Our classifier nominated 265 known or predicted oncogenes and 1019 known or predicted tumor suppressors, respectively, from a total of 20,451 genes. The vast majority of identified genes were mutated in small sub-populations of particular cancer types ( 10%), of which most are well-recognized oncogenes. Notably though, 52 additional nominated oncogenes were mutated in 5−10% of at least one cancer type, including functionally diverse genes whose role in cancer has not yet been well established (ANAPC1, NFE2L2, PPP2R1A, U2AF1) or were not previously known to be candidates for mutational activation (ERBB3, MAPK1). Among nominated tumor suppressor genes, 81 were frequently mutated in at least one cancer type (10%). In addition to many known tumor suppressors, other emerging cancer genes and gene families were found to be widely inactivated across many cancer types, including many genes involved in chromatin remodeling (ARID1A, PRBM1) and modification (MLL2, MLL3, MLL4, SETD2). Conclusions: Our analysis is the first of its kind to define the driver mutational landscape of common cancers based on classification of mutation patterns observed across thousands of exomes. We validated nearly all known driver cancer genes across 13 cancer types and nominated a wide spectrum of novel potential drivers, most of which were infrequently altered. Our work suggests several new potential therapeutic targets and identifies additional opportunities for existing targeted therapies.

A Resolution of the Mutation Load Paradox in Humans

Current information on the rate of mutation and the fraction of sites in the genome that are subject to selection suggests that each human has received, on average, at least two new harmful mutations from its parents. These mutations were subsequently removed by natural selection through reduced survival or fertility. It has been argued that the mutation load, the proportional reduction in population mean fitness relative to the fitness of an idealized mutation-free individual, allows a theoretical prediction of the proportion of individuals in the population that fail to reproduce as a consequence of these harmful mutations. Application of this theory to humans implies that at least 88% of individuals should fail to reproduce and that each female would need to have more than 16 offspring to maintain population size. This prediction is clearly at odds with the low reproductive excess of human populations. Here, we derive expressions for the fraction of individuals that fail to reproduce as a consequence of recurrent deleterious mutation () for a model in which selection occurs via differences in relative fitness, such as would occur through competition between individuals. We show that is much smaller than the value predicted by comparing fitness to that of a mutation-free genotype. Under the relative fitness model, we show that depends jointly on U and the selective effects of new deleterious mutations and that a species could tolerate 10's or even 100's of new deleterious mutations per genome each generation.

RAD51C is a susceptibility gene for ovarian cancer

A homozygous mutation in the RAD51C gene was recently found to cause Fanconi anemia-like disorder. Furthermore, six heterozygous deleterious RAD51C mutations were detected in German breast and ovarian cancer families. We screened 277 Finnish familial breast or ovarian cancer patients for RAD51C and identified two recurrent deleterious mutations (c.93delG and c.837+1G>A). These mutations were further genotyped in 491 familial breast cancer patients, 409 unselected ovarian cancer patients and two series of unselected breast cancer cases (884 from Helsinki and 686 from Tampere) and population controls (1279 and 807, respectively). The mutation frequency among all breast cancer cases was not different from the controls (4 out of 2239, 0.2% versus population controls 2 out of 2086, 0.1%, P= 0.7). In the Helsinki series, each mutation was found in four cases with personal or family history of ovarian cancer. No mutations were found among cases with familial breast cancer only, four out of the eight carriers did not have family history of breast cancer. The mutations associated with an increased risk of familial breast and ovarian cancer (OR: 13.59, 95% CI 1.89-97.6, P= 0.026 compared with controls), but especially with familial ovarian cancer in the absence of breast cancer (OR: 213, 95% CI 25.6-1769, P= 0.0002) and also with unselected ovarian cancer (OR: 6.31, 95% CI 1.15-34.6, P= 0.033), with a significantly higher mutation rate among the familial cases (two out of eight, 25%) than the unselected ovarian cancer cases (4 out of 409, 1%) (OR: 33.8, 95% CI 5.15-221, P= 0.005). These results suggest RAD51C as the first moderate-to-high risk susceptibility gene for ovarian cancer.

Deleterious Mutations and Selection for Sex in Finite Diploid Populations

In diploid populations, indirect benefits of sex may stem from segregation and recombination. Although it has been recognized that finite population size is an important component of selection for recombination, its effects on selection for segregation have been somewhat less studied. In this article, we develop analytical two- and three-locus models to study the effect of recurrent deleterious mutations on a modifier gene increasing sex, in a finite diploid population. The model also incorporates effects of mitotic recombination, causing loss of heterozygosity (LOH). Predictions are tested using multilocus simulations representing deleterious mutations occurring at a large number of loci. The model and simulations show that excess of heterozygosity generated by finite population size is an important component of selection for sex, favoring segregation when deleterious alleles are nearly additive to dominant. Furthermore, sex tends to break correlations in homozygosity among selected loci, which disfavors sex when deleterious alleles are either recessive or dominant. As a result, we find that it is difficult to maintain costly sex when deleterious alleles are recessive. LOH tends to favor sex when deleterious mutations are recessive, but the effect is relatively weak for rates of LOH corresponding to current estimates (of the order 10(-4)-10(-5)).