Browsing by Subject "Indel mutation"

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    Early postzygotic mutations contribute to de novo variation in a healthy monozygotic twin pair
    (B M J Group, 2014) Dal, G. M.; Ergüner, B.; Saǧıroǧlu, M. S.; Yüksel, B.; Onat, O. E.; Alkan C.; Özçelik, T.
    Background: Human de novo single-nucleotide variation (SNV) rate is estimated to range between 0.82-1.70×10-8 mutations per base per generation. However, contribution of early postzygotic mutations to the overall human de novo SNV rate is unknown. Methods: We performed deep whole-genome sequencing (more than 30-fold coverage per individual) of the whole-blood-derived DNA samples of a healthy monozygotic twin pair and their parents. We examined the genotypes of each individual simultaneously for each of the SNVs and discovered de novo SNVs regarding the timing of mutagenesis. Putative de novo SNVs were validated using Sanger-based capillary sequencing. Results: We conservatively characterised 23 de novo SNVs shared by the twin pair, 8 de novo SNVs specific to twin I and 1 de novo SNV specific to twin II. Based on the number of de novo SNVs validated by Sanger sequencing and the number of callable bases of each twin, we calculated the overall de novo SNV rate of 1.31×10-8 and 1.01×10-8 for twin I and twin II, respectively. Of these, rates of the early postzygotic de novo SNVs were estimated to be 0.34×10-8 for twin I and 0.04×10-8 for twin II. Conclusions: Early postzygotic mutations constitute a substantial proportion of de novo mutations in humans. Therefore, genome mosaicism resulting from early mitotic events during embryogenesis is common and could substantially contribute to the development of diseases.
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    Fast and accurate mapping of complete genomics reads
    (Academic Press, 2015) Lee, D.; Hormozdiari, F.; Xin, H.; Hach, F.; Mutlu, O.; Alkan C.
    Many recent advances in genomics and the expectations of personalized medicine are made possible thanks to power of high throughput sequencing (HTS) in sequencing large collections of human genomes. There are tens of different sequencing technologies currently available, and each HTS platform have different strengths and biases. This diversity both makes it possible to use different technologies to correct for shortcomings; but also requires to develop different algorithms for each platform due to the differences in data types and error models. The first problem to tackle in analyzing HTS data for resequencing applications is the read mapping stage, where many tools have been developed for the most popular HTS methods, but publicly available and open source aligners are still lacking for the Complete Genomics (CG) platform. Unfortunately, Burrows-Wheeler based methods are not practical for CG data due to the gapped nature of the reads generated by this method. Here we provide a sensitive read mapper (sirFAST) for the CG technology based on the seed-and-extend paradigm that can quickly map CG reads to a reference genome. We evaluate the performance and accuracy of sirFAST using both simulated and publicly available real data sets, showing high precision and recall rates.
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    ItemOpen Access
    A global reference for human genetic variation
    (Nature Publishing Group, 2015) Auton, A.; Abecasis, G. R.; Altshuler, D. M.; Durbin, R. M.; Bentley, D. R.; Chakravarti, A.; Clark, A. G.; Donnelly, P.; Eichler, E. E.; Flicek, P.; Gabriel, S. B.; Gibbs, R. A.; Green, E. D.; Hurles, M. E.; Knoppers, B. M.; Korbel, J. O.; Lander, E. S.; Lee, C.; Lehrach, H.; Mardis, E. R.; Marth, G. T.; McVean, G. A.; Nickerson, D. A.; Schmidt, J. P.; Sherry, S. T.; Wang, J.; Wilson, R. K.; Boerwinkle, E.; Doddapaneni, H.; Han, Y.; Korchina, V.; Kovar, C.; Lee, S.; Muzny, D.; Reid, J. G.; Zhu, Y.; Chang, Y.; Feng, Q.; Fang, X.; Guo, X.; Jian, M.; Jiang, H.; Jin, X.; Lan, T.; Li, G.; Li, J.; Li, Y.; Liu, S.; Liu, X.; Lu, Y.; Ma, X.; Tang, M.; Wang, B.; Wang, G.; Wu, H.; Wu, R.; Xu, X.; Yin, Y.; Zhang, D.; Zhang, W.; Zhao, J.; Zhao, M.; Zheng, X.; Gupta, N.; Gharani, N.; Toji, L. H.; Gerry, N. P.; Resch, A. M.; Barker, J.; Clarke, L.; Gil, L.; Hunt, S. E.; Kelman, G.; Kulesha, E.; Leinonen, R.; McLaren, W. M.; Radhakrishnan, R.; Roa, A.; Smirnov, D.; Smith, R. E.; Streeter, I.; Thormann, A.; Toneva, I.; Vaughan, B.; Zheng-Bradley, X.; Grocock, R.; Humphray, S.; James, T.; Kingsbury, Z.; Sudbrak, R.; Albrecht, M. W.; Amstislavskiy, V. S.; Borodina, T. A.; Lienhard, M.; Mertes, F.; Sultan, M.; Timmermann, B.; Yaspo, Marie-Laure; Fulton, L.; Ananiev, V.; Belaia, Z.; Beloslyudtsev, D.; Bouk, N.; Chen, C.; Church, D.; Cohen, R.; Cook, C.; Garner, J.; Hefferon, T.; Kimelman, M.; Liu, C.; Lopez, J.; Meric, P.; O'Sullivan, C.; Ostapchuk, Y.; Phan, L.; Ponomarov, S.; Schneider, V.; Shekhtman, E.; Sirotkin, K.; Slotta, D.; Zhang, H.; Balasubramaniam, S.; Burton, J.; Danecek, P.; Keane, T. M.; Kolb-Kokocinski, A.; McCarthy, S.; Stalker, J.; Quail, M.; Davies, C. J.; Gollub, J.; Webster, T.; Wong, B.; Zhan, Y.; Campbell, C. L.; Kong, Y.; Marcketta, A.; Yu, F.; Antunes, L.; Bainbridge, M.; Sabo, A.; Huang, Z.; Coin, L. J. M.; Fang, L.; Li, Q.; Li, Z.; Lin, H.; Liu, B.; Luo, R.; Shao, H.; Xie, Y.; Ye, C.; Yu, C.; Zhang, F.; Zheng, H.; Zhu, H.; Alkan, C.; Dal, E.; Kahveci, F.; Garrison, E. P.; Kural, D.; Lee, W. P.; Leong, W. F.; Stromberg, M.; Ward, A. N.; Wu, J.; Zhang, M.; Daly, M. J.; DePristo, M. A.; Handsaker, R. E.; Banks, E.; Bhatia, G.; Del Angel, G.; Genovese, G.; Li, H.; Kashin, S.; McCarroll, S. A.; Nemesh, J. C.; Poplin, R. E.; Yoon, S. C.; Lihm, J.; Makarov, V.; Gottipati, S.; Keinan, A.; Rodriguez-Flores, J. L.; Rausch, T.; Fritz, M. H.; Stütz, A. M.; Beal, K.; Datta, A.; Herrero, J.; Ritchie, G. R. S.; Zerbino, D.; Sabeti, P. C.; Shlyakhter, I.; Schaffner, S. F.; Vitti, J.; Cooper, D. N.; Ball, E. V.; Stenson, P. D.; Barnes, B.; Bauer, M.; Cheetham, R. K.; Cox, A.; Eberle, M.; Kahn, S.; Murray, L.; Peden, J.; Shaw, R.; Kenny, E. E.; Batzer, M. A.; Konkel, M. K.; Walker, J. A.; MacArthur, D. G.; Lek, M.; Herwig, R.; Ding, L.; Koboldt, D. C.; Larson, D.; Ye, K.; Gravel, S.; Swaroop, A.; Chew, E.; Lappalainen, T.; Erlich, Y.; Gymrek, M.; Willems, T. F.; Simpson, J. T.; Shriver, M. D.; Rosenfeld, J. A.; Bustamante, C. D.; Montgomery, S. B.; De La Vega, F. M.; Byrnes, J. K.; Carroll, A. W.; DeGorter, M. K.; Lacroute, P.; Maples, B. K.; Martin, A. R.; Moreno-Estrada, A.; Shringarpure, S. S.; Zakharia, F.; Halperin, E.; Baran, Y.; Cerveira, E.; Hwang, J.; Malhotra, A.; Plewczynski, D.; Radew, K.; Romanovitch, M.; Zhang, C.; Hyland, F. C. L.; Craig, D. W.; Christoforides, A.; Homer, N.; Izatt, T.; Kurdoglu, A. A.; Sinari, S. A.; Squire, K.; Xiao, C.; Sebat, J.; Antaki, D.; Gujral, M.; Noor, A.; Ye, K.; Burchard, E. G.; Hernandez, R. D.; Gignoux, C. R.; Haussler, D.; Katzman, S. J.; Kent, W. J.; Howie, B.; Ruiz-Linares, A.; Dermitzakis, E. T.; Devine, S. E.; Kang, H. M.; Kidd, J. M.; Blackwell, T.; Caron, S.; Chen, W.; Emery, S.; Fritsche, L.; Fuchsberger, C.; Jun, G.; Li, B.; Lyons, R.; Scheller, C.; Sidore, C.; Song, S.; Sliwerska, E.; Taliun, D.; Tan, A.; Welch, R.; Wing, M. K.; Zhan, X.; Awadalla, P.; Hodgkinson, A.; Li, Y.; Shi, X.; Quitadamo, A.; Lunter, G.; Marchini, J. L.; Myers, S.; Churchhouse, C.; Delaneau, O.; Gupta-Hinch, A.; Kretzschmar, W.; Iqbal, Z.; Mathieson, I.; Menelaou, A.; Rimmer, A.; Xifara, D. K.; Oleksyk, T. K.; Fu, Y.; Liu, X.; Xiong, M.; Jorde, L.; Witherspoon, D.; Xing, J.; Browning, B. L.; Browning, S. R.; Hormozdiari, F.; Sudmant, P. H.; Khurana, E.; Tyler-Smith, C.; Albers, C. A.; Ayub, Q.; Chen, Y.; Colonna, V.; Jostins, L.; Walter, K.; Xue, Y.; Gerstein, M. B.; Abyzov, A.; Balasubramanian, S.; Chen, J.; Clarke, D.; Fu, Y.; Harmanci, A. O.; Jin, M.; Lee, D.; Liu, J.; Mu, X. J.; Zhang, J.; Zhang, Y.; Hartl, C.; Shakir, K.; Degenhardt, J.; Meiers, S.; Raeder, B.; Casale, F. P.; Stegle, O.; Lameijer, E. W.; Hall, I.; Bafna, V.; Michaelson, J.; Gardner, E. J.; Mills, R. E.; Dayama, G.; Chen, K.; Fan, X.; Chong, Z.; Chen, T.; Chaisson, M. J.; Huddleston, J.; Malig, M.; Nelson, B. J.; Parrish, N. F.; Blackburne, B.; Lindsay, S. J.; Ning, Z.; Zhang, Y.; Lam, H.; Sisu, C.; Challis, D.; Evani, U. S.; Lu, J.; Nagaswamy, U.; Yu, J.; Li, W.; Habegger, L.; Yu, H.; Cunningham, F.; Dunham, I.; Lage, K.; Jespersen, J. B.; Horn, H.; Kim, D.; Desalle, R.; Narechania, A.; Sayres, M. A. W.; Mendez, F. L.; Poznik, G. D.; Underhill, P. A.; Mittelman, D.; Banerjee, R.; Cerezo, M.; Fitzgerald, T. W.; Louzada, S.; Massaia, A.; Yang, F.; Kalra, D.; Hale, W.; Dan, X.; Barnes, K. C.; Beiswanger, C.; Cai, H.; Cao, H.; Henn, B.; Jones, D.; Kaye, J. S.; Kent, A.; Kerasidou, A.; Mathias, R.; Ossorio, P. N.; Parker, M.; Rotimi, C. N.; Royal, C. D.; Sandoval, K.; Su, Y.; Tian, Z.; Tishkoff, S.; Via, M.; Wang, Y.; Yang, H.; Yang, L.; Zhu, J.; Bodmer, W.; Bedoya, G.; Cai, Z.; Gao, Y.; Chu, J.; Peltonen, L.; Garcia-Montero, A.; Orfao, A.; Dutil, J.; Martinez-Cruzado, J. C.; Mathias, R. A.; Hennis, A.; Watson, H.; McKenzie, C.; Qadri, F.; LaRocque, R.; Deng, X.; Asogun, D.; Folarin, O.; Happi, C.; Omoniwa, O.; Stremlau, M.; Tariyal, R.; Jallow, M.; Joof, F. S.; Corrah, T.; Rockett, K.; Kwiatkowski, D.; Kooner, J.; Hien, T. T.; Dunstan, S. J.; ThuyHang, N.; Fonnie, R.; Garry, R.; Kanneh, L.; Moses, L.; Schieffelin, J.; Grant, D. S.; Gallo, C.; Poletti, G.; Saleheen, D.; Rasheed, A.; Brooks, L. D.; Felsenfeld, A. L.; McEwen, J. E.; Vaydylevich, Y.; Duncanson, A.; Dunn, M.; Schloss, J. A.
    The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies. © 2015 Macmillan Publishers Limited. All rights reserved.