Post-zygotic Point Mutations Are an Underrecognized Source of De Novo Genomic Variation
Rocio Acuna-Hidalgo,Tan Bo,Michael Kwint,Maartje van de Vorst,Michele Pinelli,Joris A. Veltman,Joris A. Veltman,Alexander Hoischen,Lisenka E.L.M. Vissers,Christian Gilissen +9 more
TLDR
Results show that an important fraction of de novo mutations presumed to be germline in fact occurred either post-zygotically in the offspring or were inherited as a consequence of low-level mosaicism in one of the parents.Abstract:
De novo mutations are recognized both as an important source of genetic variation and as a prominent cause of sporadic disease in humans. Mutations identified as de novo are generally assumed to have occurred during gametogenesis and, consequently, to be present as germline events in an individual. Because Sanger sequencing does not provide the sensitivity to reliably distinguish somatic from germline mutations, the proportion of de novo mutations that occur somatically rather than in the germline remains largely unknown. To determine the contribution of post-zygotic events to de novo mutations, we analyzed a set of 107 de novo mutations in 50 parent-offspring trios. Using four different sequencing techniques, we found that 7 (6.5%) of these presumed germline de novo mutations were in fact present as mosaic mutations in the blood of the offspring and were therefore likely to have occurred post-zygotically. Furthermore, genome-wide analysis of "de novo" variants in the proband led to the identification of 4/4,081 variants that were also detectable in the blood of one of the parents, implying parental mosaicism as the origin of these variants. Thus, our results show that an important fraction of de novo mutations presumed to be germline in fact occurred either post-zygotically in the offspring or were inherited as a consequence of low-level mosaicism in one of the parents.read more
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References
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Integrative genomics viewer
James T. Robinson,Helga Thorvaldsdottir,Wendy Winckler,Mitchell Guttman,Eric S. Lander,Eric S. Lander,Gad Getz,Jill P. Mesirov +7 more
TL;DR: In this article, the authors present an approach for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data.
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Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes
Siddhartha Jaiswal,Pierre Fontanillas,Jason Flannick,Jason Flannick,Alisa K. Manning,Peter V. Grauman,Brenton G. Mar,Brenton G. Mar,R. Coleman Lindsley,Craig H. Mermel,Noël P. Burtt,Alejandro Chavez,John M. Higgins,Vladislav Moltchanov,Vladislav Moltchanov,Frank C. Kuo,Michael J. Kluk,Brian E. Henderson,Leena Kinnunen,Heikki A. Koistinen,Heikki A. Koistinen,Claes Ladenvall,Gad Getz,Adolfo Correa,Benjamin F. Banahan,Stacey Gabriel,Stacey Gabriel,Sekar Kathiresan,Heather M. Stringham,Mark I. McCarthy,Michael Boehnke,Jaakko Tuomilehto,Jaakko Tuomilehto,Jaakko Tuomilehto,Christopher A. Haiman,Leif Groop,Gil Atzmon,James G. Wilson,Donna Neuberg,David Altshuler,Benjamin L. Ebert +40 more
TL;DR: Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease.
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Rate of de novo mutations and the importance of father’s age to disease risk
Augustine Kong,Michael L. Frigge,Gisli Masson,Søren Besenbacher,Søren Besenbacher,Patrick Sulem,Gisli Magnusson,Sigurjon A. Gudjonsson,Asgeir Sigurdsson,Aslaug Jonasdottir,Adalbjorg Jonasdottir,Wendy S.W. Wong,Gunnar Th. Sigurdsson,G. Bragi Walters,Stacy Steinberg,Hannes Helgason,Gudmar Thorleifsson,Daniel F. Gudbjartsson,Agnar Helgason,Agnar Helgason,Olafur T. Magnusson,Unnur Thorsteinsdottir,Unnur Thorsteinsdottir,Kari Stefansson,Kari Stefansson +24 more
TL;DR: A study of genome-wide mutation rates by sequencing the entire genomes of 78 Icelandic parent–offspring trios at high coverage shows that the diversity in mutation rate of single nucleotide polymorphisms is dominated by the age of the father at conception of the child.
Journal ArticleDOI
Age-related mutations associated with clonal hematopoietic expansion and malignancies
Mingchao Xie,Charles Lu,Jiayin Wang,Michael D. McLellan,Kimberly J. Johnson,Michael C. Wendl,Joshua F. McMichael,Heather Schmidt,Venkata Yellapantula,Christopher A. Miller,Bradley A. Ozenberger,John S. Welch,Daniel C. Link,Matthew J. Walter,Elaine R. Mardis,John F. DiPersio,Feng Chen,Richard K. Wilson,Timothy J. Ley,Li Ding +19 more
TL;DR: The analyses show that the blood cells of more than 2% of individuals contain mutations that may represent premalignant events that cause clonal hematopoietic expansion, and several recurrently mutated genes that may be disease initiators are identified.
Journal ArticleDOI
Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome
Sarah B. Ng,Abigail W. Bigham,Kati J. Buckingham,Mark C. Hannibal,Mark C. Hannibal,Margaret J. McMillin,Heidi I. S. Gildersleeve,Anita E. Beck,Anita E. Beck,Holly K. Tabor,Holly K. Tabor,Gregory M. Cooper,Heather C Mefford,Choli Lee,Emily H. Turner,Joshua D. Smith,Mark J. Rieder,Koh-ichiro Yoshiura,Naomichi Matsumoto,Tohru Ohta,Norio Niikawa,Deborah A. Nickerson,Michael J. Bamshad,Michael J. Bamshad,Jay Shendure +24 more
TL;DR: The results strongly suggest that mutations in MLL2, which encodes a Trithorax-group histone methyltransferase, are a major cause of Kabuki syndrome.
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