Genetic Mosaicism Study

Genetic mosaicism describes the presence of DNA alterations in only some of the body's cells; a person with mosaicism, therefore, has a mixture of normal and mosaic DNA in the same cell types. While mosaicism is not always harmful, it has been clinically recognized for decades and is associated with a number of adverse health outcomes, including cancer. Relatively little is known about the mechanisms that initiate and select for mosaic alterations. Mosaicism may serve as an informative genetic intermediate between normal and disease states.

DCEG researchers and their collaborators have found that both inherited germline variation (e.g., at TCL1A) and environmental exposures (e.g., smoking) may predispose to mosaicism in circulating leukocytes. Acquired mosaic alterations have abundant potential to inform cancer etiology and drive oncogenic change. The researchers have found evidence suggesting mosaicism increases risk for hematologic malignancies and select solid tumor subtypes, and can also impact telomere length and blood cell counts.

Studies have also examined sex chromosomes (XX in females and XY in males). In particular, mosaic Y loss has been found to be the most common large-scale detectable event in males. Ongoing genome-wide association studies of mosaic loss of chromosome Y and chromosome X seek to understand better genetic susceptibility to genetic mosaicism.

For more information, contact Mitchell Machiela.

Integrative Tumor Epidemiology Branch - Research Areas

Selected Publications

• Liu A et al, Population analyses of mosaic X chromosome loss identify genetic drivers and widespread signatures of cellular selectionExit Disclaimer. Nature. 2024.
• Brown DW, et al. Shared and distinct genetic etiologies for different types of clonal hematopoiesis. Nat Comms. 2023. 
• Zekavat S, Lin S, Bick A, et al. Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection. Nat Med. 2021. 
• Thompson DJ, Genovese G, Halvardson, et al. Genetic predisposition to mosaic Y chromosome loss in blood. Nature 2019.
•  Machiela MJ, Zhou W, Karlins E, et al. Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome. Nat Commun. 2016.
• Zhou W, Machiela MJ, Freedman ND, et al. Mosaic loss of chromosome Y is associated with common variation near TCL1A. Nat Genet. 2016.

News Summaries of Research Findings

• Variations in Blood Cells May Increase Infection Risk
• Unexpected Findings Reveal Genetic Mosaicism as Possible Early Marker for Disease