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Unexpected Findings Reveal Genetic Mosaicism as Possible Early Marker for Disease

by Victoria A. Fisher, M.P.H.

The underlying process of mosaicism is depicted where an individual carrying a complete paternal and maternal chromosome in all cells undergoes a mutational event that clonally expands to become a detectible subset of the total cellular population. This can result in a mosaic loss on the maternal chromosome in only a portion of the cellular population, a mosaic gain on the maternal chromosome, or a mosaic copy neutral loss of heterozygosity.

The underlying process of mosaicism is depicted where an individual carrying a complete paternal (white) and maternal (black) chromosome in all cells undergoes a mutational event that clonally expands to become a detectible subset of the total cellular population. This can result in a mosaic loss on the maternal chromosome in only a portion of the cellular population (orange), a mosaic gain on the maternal chromosome (yellow), or a mosaic copy neutral loss of heterozygosity (black).

In recent years, DCEG scientists have made surprising observations that a substantial number of adults—individuals who did not have cancer at the time their DNA was scanned—have large structural chromosomal abnormalities, known as mosaicism. In addition, they found that the number of abnormalities an individual may carry appear to increase as they age. Some proportion may be related to environmental exposures, including smoking. These unexpected findings are exciting for a number of reasons; they could lead to new insights on how and why the risk of cancer increases with age, and they might eventually help identify people at higher-than-average risk of developing certain cancers.

When investigators began observing chromosomal mosaicism during quality control checks of data from scores of genome-wide association studies (GWAS), they initially thought the anomalies were due to technical artifacts from the genotyping platform, or the result of poor sample quality. Strangely, DNA from cells assumed to be normal appeared to contain structural aberrations, but they only occurred in a subset of cells from given individuals.

At first, little attention was given to these supposed errors. The abnormalities seemed to be rare and were not considered important to the primary analyses. But over time, a pattern emerged; the abnormalities were found consistently at a low frequency. Stephen J. Chanock, M.D., DCEG Director, and colleagues believed they had stumbled upon something unexpected in the samples: detectable genetic mosaicism in apparently normally functioning cells.

Genetic mosaicism is the presence of DNA alterations in only some of the body's cells. A person with mosaicism has a mixture of normal and mosaic DNA in the same type of cells (most of the samples tested in GWAS came from blood or cheek cells). Like a mosaic piece of art, mosaicism in humans is varied and complex.

“Mosaicism is a somatic event, meaning a mutation occurs sometime in life after fertilization. It is not an inherited genetic variant,” said Mitchell Machiela, Sc.D., a research fellow in the Laboratory of Genetic Susceptibility.

The image depicts changes in the chromosomes, including deletions and duplications. (Illustration by Darryl Leja, NHGRI)

Researchers have found large, mosaic chromosome abnormalities, including deletions and duplications, in some members of the general population. (Illustration by Darryl Leja, NHGRI)

“We define mosaicism quite broadly; it can be limited to a one base pair change in your genome different from what you inherited. Or, it can be as large as an entire chromosome that is lost or duplicated.”

Mosaicism has been recognized clinically for decades and has been established as a cause of miscarriage, birth defects, developmental delay, and cancer. “The really interesting thing about mosaicism is that it can manifest in a lot of different phenotypes,” said Dr. Machiela. “It can be harmful or benign; it really depends where in the genome it happens and how many of the cells are affected, and possibly when in life it occurs. There are still many unanswered questions.” Fortunately, the recent development of more sensitive tools has allowed researchers to study this phenomenon like never before.
After their realization, NCI scientists, including Dr. Chanock, Michael Dean, Ph.D., Chief of the Laboratory of Translational Genomics, Meredith Yeager, Ph.D., Weiyin Zhou, M.S., and many others, set out to document the frequency these structural abnormalities occur in the general population. They looked for signs of large (greater than 2 million DNA base pairs) mosaic abnormalities in more than 31,000 case subjects with cancer and 26,000 control subjects without cancer from 13 existing studies. At the same time, researchers with the NIH-funded Gene Environment Association Studies (GENEVA) consortium looked for chromosome abnormalities larger than 50,000 base pairs in about 50,000 individuals from 12 studies.

In 2012, the groups published two papers showing mosaicism can be detected in a small fraction of people without a prior history of cancer (Jacobs, 2012), (Laurie, 2012). These alterations appear to increase with age, especially after age 50, and may be associated with an increased risk for cancer, in particular hematologic (blood) cancers.

The figure shows the frequency of detectable clonal mosaic events by age and cancer status (cancer free and cancer diagnosis). The analysis excluded 1,000 individuals with unknown age at DNA collection.

Frequency of detectable clonal mosaic events by age and cancer status. The analysis excluded 1,000 individuals with unknown age at DNA collection, and 95% confidence intervals are shown. (Jacobs KB, et al. Nat Genet 2012)

“These studies provide evidence from large population-based studies that genetic mosaicism increases with age and could be a risk factor for cancer. This last point raises an important issue with respect to the stability of a person’s genome and suggests that detection of genetic mosaicism could be an early marker for detecting cancer, or perhaps other chronic diseases of aging,” said Dr. Chanock.

Additional research by Dr. Machiela and collaborators has demonstrated that somatic mosaic chromosomal alterations in the autosomes (any chromosome other than X and Y) are associated with aging and occur at frequencies in excess of 2% from study participants over 80 years of age (Machiela, 2015).

Studies have been extended to examine the sex chromosomes (XX in females and XY in males). For the X chromosome, investigators found that rates of mosaicism are four times higher than in the autosomes (occurring in 0.25% of women), are also associated with aging, and occur most often on the inactivated X chromosome (Machiela, 2016).

For more than 50 years, from the earliest cytogenetic analyses, it has been noted that a fraction of healthy men lose all or some portion of the Y chromosome over the course of their lifetime. However, the phenotypic consequences of mosaic Y loss have not been clear; most scientists considered it a neutral event, related to normal aging. More recently, limited evidence suggests that mosaic Y loss in blood may be associated with risk of some solid tumors and Alzheimer Disease.

Analyses by DCEG investigators have demonstrated that mosaic Y loss is relatively frequent, occurring in 7% of men (Zhou, 2016). “Mosaic Y loss is the most common large-scale detectable mosaic chromosomal event in males,” said Dr. Machiela. “That means we can study it a little better, compared to other mosaic events. In future studies, we hope to definitively establish whether Y chromosome mosaicism is an informative early indicator of cancer risk.”

Investigators also seek to clarify our understanding of the relationship between environmental and genetic exposures and mosaicism. They determined that smoking is an important risk factor for mosaic Y loss; men who smoke are more than three times as likely as nonsmokers to show loss of the Y chromosome in their blood cells, but the association is attenuated with years after cessation. In a genome-wide association study, investigators observed the first example of a common susceptibility locus for genetic mosaicism, specifically mosaic Y loss, on chromosome 14.

“Mosaicism has great potential to be used as an informative genetic intermediate between normal and disease states.”

Scientists believe this research may have future clinical significance. “We are still establishing where mosaicism occurs in the genome and how common it is in the population,” said Dr. Machiela. “These are the very early stages of trying to make links between diseases.”

The use of SNP microarrays and next generation sequencing platforms has yielded new opportunities to investigate whether mosaicism in blood could serve as an effective biomarker for chronic diseases associated with aging (such as cancer, diabetes or neurodegenerative disorders). Plans are underway to see if chromosome abnormalities in other tissue types could be an early predictor of cancer. Investigators also hope to examine the relationship between telomere length and mosaicism.

“Mosaicism has great potential to be used as an informative genetic intermediate between normal and disease states,” said Dr. Chanock. “However, much remains to be understood before mosaicism can be effectively used as a biomarker for early detection.”


Jacobs KB, et al. Detectable clonal mosaicism and its relationship to aging and cancer. Nat Genet 2012.

Laurie CC, et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nat Genet 2012.

Machiela MJ, et al. Characterization of large structural genetic mosaicism in human autosomes. Am J Hum Genet 2015.

Machiela MJ, et al. Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome. Nat Commun 2016.

Zhou W, et al. Mosaic loss of chromosome Y is associated with common variation near TCL1A. Nat Genet 2016.

Additional  References

Machiela MJ, Chanock SJ. Detectable clonal mosaicism in the human genome. Semin Hematol 2013.

Machiela, MJ, Chanock SJ. The ageing genome, clonal mosaicism and chronic disease. Curr Opin Genet Dev 2017.

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Read more articles in the spring 2017 issue of Linkage newsletter.