Mosaic Mutations

Some genetic abnormalities that appear to have sprung up independently in children are in fact present in a portion of their parents’ cells.

Jul 31, 2014
Kate Yandell

WIKIMEDIA, SCIENCEGENETICSWhen a couple has a child with a genetic disorder, they often ask how likely they are to pass the disorder on to another child. To determine the risk of this happening, clinicians must figure out when the disorder-associated mutation arose: Did it spring up de novo during the creation of the sperm or egg that contributed to the child’s genetic makeup, or did already-present genetic abnormalities in the parents form a causative combination?

There is also a third possibility: one parent might harbor some abnormal cells derived from mutations that arose early on during his or her own life. These mutations may not have obvious health effects and can go unnoticed in most genetic screens. Researchers have long recognized this possibility, but a paper published today (July 31) in The American Journal of Human Genetics attempts to better quantify the phenomenon of mosaicism.

The authors used extra-sensitive molecular methods to analyze the blood of 100 couples who have children with disorders caused by DNA deletions, all of which were initially determined to be de novo. But with the more rigorous blood test, members of four of the couples were found to have the same mutations as their children, but only in a subset of their cells.

“I think this is an important paper that will clarify scientific thinking about when and where new mutations arise,” Steve McCarroll, a geneticist at Harvard Medical School who was not involved in the research, wrote in an e-mail to The Scientist.

“I wouldn't call this surprising—we know, anecdotally, that it's happening,” Michael Ronemus, a research assistant professor at Cold Spring Harbor Laboratory in New York who also did not participate in the research, wrote in an e-mail. “But this is a nice step towards trying to put a number on it, and makes a very solid case for its proposition that parents of a child with a de novo mutation should be tested more carefully to assess . . . the likelihood that they might have another affected child.”

Researchers at Baylor College of Medicine in Houston, Texas, became interested in this question after a collaborator from the U.K. asked them for help in understanding the recurrence of a genetic disease in three children born to one mother and two different fathers. The Baylor team tested the mother’s blood using a form of PCR designed to specifically amplify the region of DNA where the children’s deletions had been found. When the researchers sequenced the amplified DNA, they found that the mother did indeed have some blood cells with the same mutation found in her children. A separate test on a family with two boys with a pair of identical deletions revealed that the father had a small percentage of mutated cells in his blood, even though previous tests had indicated he did not carry the mutation.

This made the researchers wonder whether some parents who have one child with apparently de novo mutations might also show mosaicism in their blood. They suggest that the 4 percent rate of mosaicism they found in the 100 parents they analyzed probably underestimates how often mosaicism among parents contributes to children’s genetic disorders. The researchers only analyzed parents with one affected child who had previously been told their child’s mutation was de novo, excluding more obvious cases of mosaicism. And mutations could have occurred in progenitor cells that didn’t give rise to blood cells.

Egbert Bakker, a molecular geneticist at Leiden University Medical Center in the Netherlands who has worked on mosaicism, noted that even a precise blood test would not detect mutations that occurred in the germ cells once they had differentiated.

Further, the PCR assay the researchers used only can detect a specific type of deletion, not the full range of possible genetic alterations that can cause disease.

“There are parents out there where even if we test with the most sensitive tests we aren’t going to have mutations in their blood,” said study coauthor Ian Campbell, a student in Baylor’s Medical Scientist Training Program. A test that shows mosaicism in the blood suggests heightened risk for having a second child with a disorder, he added, but a test that does not reveal mosaicism does not mean that there is zero risk.

Coauthor Chad Shaw, a statistician at Baylor, noted that mutations can occur throughout the body during all stages of development. “[Mosaicism is] erupting all the time in the process of the development of the organism,” he said—potentially contributing to disease in adults, as well as potential risks to their children. “It’s really only having these new kinds of technologies that we start to see the full extent of this.”

I.M. Campbell et al., “Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders,” The American Journal of Human Genetics, doi:10.1016/j.ajhg.2014.07.003, 2014.

January 2019

Cannabis on Board

Research suggests ill effects of cannabinoids in the womb


Sponsored Product Updates

FORMULATRIX® digital PCR technology to be acquired by QIAGEN
FORMULATRIX® digital PCR technology to be acquired by QIAGEN
FORMULATRIX has announced that their digital PCR assets, including the CONSTELLATION® series of instruments, is being acquired by QIAGEN N.V. (NYSE: QGEN, Frankfurt Stock Exchange: QIA) for up to $260 million ($125 million upfront payment and $135 million of milestones).  QIAGEN has announced plans for a global launch in 2020 of a new series of digital PCR platforms that utilize the advanced dPCR technology developed by FORMULATRIX combined with QIAGEN’s expertise in assay development and automation.
Application of CRISPR/Cas to the Generation of Genetically Engineered Mice
Application of CRISPR/Cas to the Generation of Genetically Engineered Mice
With this application note from Taconic, learn about the power that the CRISPR/Cas system has to revolutionize the field of custom mouse model generation!
Translational Models of Obesity, Dysmetabolism, Diabetes, and Complications
Translational Models of Obesity, Dysmetabolism, Diabetes, and Complications
This webinar, from Crown Bioscience, presents a unique continuum of translational dysmetabolic platforms that more closely mimic human disease. Learn about using next-generation rodent and spontaneously diabetic non-human primate models to accurately model human-relevant disease progression and complications related to obesity and diabetes here!
BiochemAR: an augmented reality app for easy visualization of virtual 3D molecular models
BiochemAR: an augmented reality app for easy visualization of virtual 3D molecular models
Have you played Pokemon Go? Then you've used Augmented Reality (AR) technology! AR technology holds substantial promise and potential for providing a low-cost, easy to use digital platform for the manipulation of virtual 3D objects, including 3D models of biological macromolecules.