Genetic Mosaicism Study

A proposed conceptual framework of myelofibrosis genetic etiology.

Myelofibrosis GWAS Identifies Risk Loci, Mosaicism

Collaboration between DCEG and CIBMTR enabled genomic characterization of this rare subtype of myeloproliferative neoplasm.

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.

Scanning electron micrograph image of white blood cells and bacteria.

Variations in Blood Cells May Increase Infection Risk

Mosaic chromosomal alterations are associated with an increased risk of severe infections, including COVID-19.

For more information, contact Mitchell Machiela.

Integrative Tumor Epidemiology Branch - Research Areas

Selected Publications

Zekavat S, Lin S, Bick A, et al. Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection. Nat Med 2021.
Brown DW, Lin S, Loh P, et al. Genetically predicted telomere length is associated with clonal somatic copy number alterations in peripheral leukocytes. PLoS Genet 2020.
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.

Related Resources

Unexpected Findings Reveal Genetic Mosaicism as Possible Early Marker for Disease