Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers
Adam ShlienBrittany CampbellRichard de BorjaLudmil B. AlexandrovDaniele MericoDavid C. WedgePeter Van LooPatrick TarpeyPaul CouplandSam BehjatiAaron PollettTatiana LipmanAbolfazl HeidariShriya DeshmukhN. AvitzurBettina MeierMoritz GerstungYe HongDiana M. MerinoManasa RamakrishnaMarc RemkeRoland ArnoldGagan B. PanigrahiNeha ThakkarKarl P. HodelErin E. HenningerA. Yasemin GökseninDoua BakryGeorge S. CharamesHarriet DrukerJordan Lerner‐EllisMatthew MistryRina DvirRonald GrantRonit ElhasidRoula FarahGlenn TaylorPaul C. NathanSarah AlexanderShay Ben‐ShacharSimon C. LingSteven GallingerShlomi ConstantiniPeter B. DirksAnnie HuangStephen W. SchererRichard G. GrundyCarol DurnoMelyssa AronsonAnton GartnerM. Stephen MeynMichael D. TaylorZachary F. PursellChristopher E. PearsonDavid MalkinP. Andrew FutrealMichael R. StrattonÉric BouffetCynthia HawkinsPeter J. CampbellUri Tabori
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Summary: The ability of somatic mutation to modify the course of an immune response is well documented. However, emphasis has been placed almost exclusively on the ability of somatic mutation to improve the functional characteristics of representative antibodies. The harmful effects of somatic mutation, its dark side, have been far less well characterized. Yet evidence suggests that the number of B cells directed to wastage pathways as a result of harmful somatic mutation probably far exceeds the number of cells whose antibodies have been improved. Here we review our recent findings in understanding the structural and functional consequences of V‐region mutation.
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Germ plasm
Germinal epithelium
Germ line development
Sexual Differentiation
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Abstract Here we test the feasibility of using decision markets to select studies for replication and provide evidence about the replicability of online experiments. Social scientists ( n = 162) traded on the outcome of close replications of 41 systematically selected MTurk social science experiments published in PNAS 2015–2018, knowing that the 12 studies with the lowest and the 12 with the highest final market prices would be selected for replication, along with 2 randomly selected studies. The replication rate, based on the statistical significance indicator, was 83% for the top-12 and 33% for the bottom-12 group. Overall, 54% of the studies were successfully replicated, with replication effect size estimates averaging 45% of the original effect size estimates. The replication rate varied between 54% and 62% for alternative replication indicators. The observed replicability of MTurk experiments is comparable to that of previous systematic replication projects involving laboratory experiments.
Replication
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Білім берy қоғaмның экономикaлық дaмyының негізі, әлеyметтік тұрaқтылықтың фaкторлaрының бірі, хaлықтың рyхaни-aдaмгершілік әлеyетінің және интеллектyaлдық өсyінің қaйнaр көзі ретінде бaрлық yaқыттaрдa тaптырмaс құндылық болып есептеліп келеді. Aл қaзіргідей aдaм кaпитaлын қaлыптaстырy мен дaмытy мәселесін шешy негізгі міндет ретінде қaрaстырылaтын зaмaндa хaлықтың білімдік қaжеттіліктері өсіп, жоғaры, ортa aрнayлы, кәсіби қосымшa білім aлyғa үміткерлер сaны aртa түсyде. Бұғaн жayaп ретінде білім берy ұйымдaрының сaлaлaнyы aртып, әртүрлі типтегі оқy орындaрының сaны aртyдa, білім берyдің инфрaқұрылымы, бaсқaрy формaлaры, әдістемелік, ғылыми қызмет түрлері дaмyдa. Олaрды білім aлyшылaрдың жеке сұрaныстaры мен мүмкіндіктеріне бaғыттay күшейтілyде. Осығaн орaй білімнің сaпaсынa қойылaтын тaлaптaр aртып, бұл сaлaның әлеyметпен өзaрa әрекеттестігіне негізделген құрылымдық – қызметтік дaмyының көкейтестілігі aртyдa. Мaқaлaдa «серіктестік», «әлеyметтік серіктестік», «білімдегі әлеyметтік серіктестік» ұғым- дaрының мәні aшылып, олaрдың қaлыптaсy және дaмy үрдісіне шолy жaсaлaды, жоғaры оқy орындaрындa педaгогтaрды дaярлayдa әлеyметтік серіктестердің әлеyетін пaйдaлaнyдa бaсшылыққa aлынaтын ұстaнымдaр мен тиімді жолдaры сипaттaлaды. Түйін сөздер: серіктестік, әлеyметтік серіктестік, білімдегі әлеyметтік серіктестік, бірлескен әрекет ұстaнымдaры, әлеуметтік серіктестік әлеуеті. Обрaзовaние является основой экономического рaзвития обществa, одним из фaкторов социaль- ной стaбильности, источником дyховно-нрaвственного потенциaлa и интеллектyaльного ростa людей и во все временa считaлось незaменимой ценностью. И в нaстоящее время, когдa решение проблемы формировaния и рaзвития человеческого кaпитaлa рaссмaтривaется кaк основнaя зaдaчa, рaстyт обрaзовaтельные потребности людей, yвеличивaется количество желaющих полyчить высшее, среднее, специaльное, профессионaльное дополнительное обрaзовaние. В ответ нa это yсиливaется рaзветвленность обрaзовaтельных оргaнизaций, yвеличивaется количество обрaзовaтельных оргaни- зaций рaзличного типa, рaзвивaются инфрaстрyктyрa обрaзовaния, формы yпрaвления, методическaя и нayчнaя деятельность. Yсиливaется их ориентaция нa индивидyaльные потребности и возможности обyчaющихся. В связи с этим повышaются требовaния к кaчествy обрaзовaния, возрaстaет знaчение стрyктyрно-фyнкционaльного рaзвития этой сферы нa основе взaимодействия с обществом. В стaтье рaскрывaется знaчение понятий «пaртнерство», «социaльное пaртнерство», «социaльное пaртнерство в обрaзовaнии», рaссмaтривaется процесс их стaновления и рaзвития, описывaются рyко- водящие принципы и эффективные способы использовaния потенциaлa социaльных пaртнеров в подготовке педaгогических кaдров в высших yчебных зaведениях. Ключевые словa: партнерство, социaльное пaртнерство, социaльное пaртнерство в обрaзовaнии, принципы совместного действия, поненциал социального партнерство. Education is the basis of the economic development of society, one of the factors of social stability, a source of spiritual and moral potential and intellectual growth of people and has always been considered an irreplaceable value. And at the present time, when the solution of the problem of the formation and development of human capital is considered as the main task, the educational needs of people are growing, the number of people wishing to receive higher, secondary, special, professional additional education is increasing. In response to this, the branching of educational organizations is increasing, the number of educational organizations of various types is increasing, the infrastructure of education, forms of management, methodological and scientific activities are developing. Their focus on the individual needs and capabilities of students is increasing. In this regard, the requirements for the quality of education are increasing, the importance of the structural and functional development of this sphere on the basis of interaction with society is increasing. The article reveals the meaning of the concepts of "partnership", "social partnership", "social partnership in education", examines the process of their formation and development, describes the guidelines and effective ways to use the potential of social partners in the training of teachers in higher educational institutions. Keywords: partnership, social partnership, social partnership in education, principles of joint action, the potential of social partnership.
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A compensatory mutation occurs when the fitness loss caused by one mutation is remedied by its epistatic interaction with a second mutation at a different site in the genome. This poorly understood biological phenomenon has important implications, not only for the evolutionary consequences of mutation, but also for the genetic complexity of adaptation. We have carried out the first direct experimental measurement of the average rate of compensatory mutation. An arbitrary selection of 21 missense substitutions with deleterious effects on fitness was introduced by site-directed mutagenesis into the bacteriophage phiX174. For each deleterious mutation, we evolved 8-16 replicate populations to determine the frequency at which a compensatory mutation, instead of the back mutation, was acquired to recover fitness. The overall frequency of compensatory mutation was approximately 70%. Deleterious mutations that were more severe were significantly more likely to be compensated for. Furthermore, experimental reversion of deleterious mutations revealed that compensatory mutations have deleterious effects in a wild-type background. A large diversity of intragenic compensatory mutations was identified from sequencing fitness-recovering genotypes. Subsequent analyses of intragenic mutation diversity revealed a significant degree of clustering around the deleterious mutation in the linear sequence and also within folded protein structures. Moreover, a likelihood analysis of mutation diversity predicts that, on average, a deleterious mutation can be compensated by about nine different intragenic compensatory mutations. We estimate that about half of all compensatory mutations are located extragenically in this organism.
Mutation Accumulation
Reversion
Epistasis
Mutation frequency
Suppressor mutation
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Homology
R gene
Conserved sequence
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Lineage (genetic)
Cell type
Somatic fusion
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Throughout the last decade, the so-called replication crisis has stimulated many researchers to conduct large-scale replication projects. With data from four of these projects, we computed probabilistic forecasts of the replication outcomes, which we then evaluated regarding discrimination, calibration and sharpness. A novel model, which can take into account both inflation and heterogeneity of effects, was used and predicted the effect estimate of the replication study with good performance in two of the four data sets. In the other two data sets, predictive performance was still substantially improved compared to the naive model which does not consider inflation and heterogeneity of effects. The results suggest that many of the estimates from the original studies were inflated, possibly caused by publication bias or questionable research practices, and also that some degree of heterogeneity between original and replication effects should be expected. Moreover, the results indicate that the use of statistical significance as the only criterion for replication success may be questionable, since from a predictive viewpoint, non-significant replication results are often compatible with significant results from the original study. The developed statistical methods as well as the data sets are available in the R package ReplicationSuccess.
Replication
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Founder effect
Stuttering
Statistical genetics
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Nonsynonymous substitution
Pseudogene
Synonymous substitution
Silent mutation
Nonsense mutation
Neutral mutation
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