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The effects of de novo mutations can be as simple as the ears of this feline
known as the "American Curl" having slightly turned back ears.
Image Credit: Wikipedia
Mutations can spontaneously occur in early embryos
Until now, de novo genetic mutations — gene alterations — found for the first time in one child, were believed to be mainly the result of mutations in a sperm or egg (germline) of one parent and passed on to that child.
Researchers from The Netherlands have now succeeded in determining that at least 6.5% of de novo mutations occur during the development post-fertilization of the egg rather than from the germline of a parent. The research was published June 11, 2015 in the American Journal of Human Genetics.
Due to technical difficulties in identifying and validating events after fertilization (post-zygotic), until now there have been very few estimates as to how common are de novo mutations.
"Determining exactly how many mutations occur during the development of a child has been challenging because conventional genetic sequencing is not sensitive enough to reliably identify post-zygotic [after fertilization] mutations."
Christian Gilissen PhD, Assistant Professor in Bioinformatics at Radboud University Medical Centre, Nijmegen, The Netherlands.
De novo gene mutations in the germ line, can lead to:
1) No noticeable effect on the observable characteristics or traits (phenotype) of an organism ( University of California Museum of Paleontology). This can happen if the mutation occurs in a stretch of DNA with no function, or in a protein coding region not affecting an amino acid sequence.
2) Small change in phenotype. A single mutation causes a cat's ears to curl backwards slightly in the breed "American Curl."
3) Big changes in phenotype: DDT resistance in insects is sometimes caused by single mutations. A single mutation can also cause the death of an organism.
Unlike germline mutations, the post-zygotic gene changes are only in a proportion of an individual's cells. This is important because that proportion, as well as the type of cells in which a mutation occurs, may not only determine the clinical outcome of a disease, but affect the risk of the parents having another child with the same disease in future pregnancies.
"Currently, patients with a child with a disease caused by a de novo mutation are at risk of recurrence of between 1 and 5 percent of the same mutation in another child. But if the disease is the result of a post-zygotic change, the recurrence risk will be extremely low."
Christian Gilissen PhD
Better information on the origin of de novo mutations will enable parents to make more informed reproductive choices. As the study mainly focused on the technological aspects of these genetic changes, it is difficult at this stage to foresee the full impact of post-zygotic mutations in terms of treatment options.
Dr. Gilissen: "The knowledge that our genomes may be much more dynamic and changeable than previously thought due to our ability to detect such changes by sophisticated sequencing techniques, will certainly have clinical implications in the future. It may be reasonable to assume that post-zygotic mutations restricted to specific types of cells, or organs, may also be involved in causing disease.
"We now know that to find post-zygotic mutations, our sequencing needs to be even more sensitive. We intend to follow up this work by getting more detail on the prevalence of de novo mutations and testing for these events in other tissues. Most genetic investigations are performed only in blood, so we may have missed some disease-causing mutations by not testing elsewhere."
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.
Rocio Acuna-Hidalgo1, Tan Bo2, Michael P. Kwint1, Maartje van de Vorst1, Michele Pinelli3, Joris A. Veltman1, 4, Alexander Hoischen1, 5, , , Lisenka E.L.M. Vissers1, 5, Christian Gilissen1,
1 Department of Human Genetics, Radboud Institute for Molecular Life Sciences and Donders Institute of Neuroscience, Radboud University Medical Center, Geert Grooteplein 10, 6525 GA Nijmegen, the Netherlands
2 State Key Laboratory of Medical Genetics, Central South University, 110 Xiangya Road, Changsha, Hunan 410078, China
3 Telethon Institute of Genetics and Medicine, Pozzuoli, 80078 Naples, Italy
4 Department of Clinical Genetics, Maastricht University Medical Centre, Universiteitssingel 50, 6229 ER Maastricht, the Netherlands
These authors contributed equally to this work
Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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