[R03] The landscape of clonal mosaicism of the blood in individuals with Down Syndrome
Ente: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Scadenza: 2028-06-30
Importo max: 312.000 EUR
Paese: US
Descrizione
PROJECT SUMMARY
Aging impacts many functions within cells, from genomic instability to oxidative damage to shifted cellular
metabolism. Similarly, collections of cells change in their relative composition with age—a phenomenon mainly
driven by clonal selection; this process has been extensively studied in the hematopoietic system, where a
clear correlation between clonality changes and age has been described. While these changes are sometimes
precursors to blood malignancies, they are much more commonly observed in their absence and have been
correlated with changes in inflammation status, as well as cardiovascular, liver, and Alzheimer’s disease.
Counterintuitively, this so-called ‘clonal hematopoiesis of indeterminate potential’ (CHIP) has been associated
with both adverse and beneficial outcomes, suggesting a currently unresolved dichotomy.
Individuals with Down syndrome (DS) exhibit global changes in immune activation and altered
hematopoiesis that frequently result in transient preleukemia and elevated leukemia risk. Connecting clonal
hematopoiesis to hematological malignancies, increased levels of CHIP have been observed in individuals with
DS; critically, the frequency is both increased and significantly earlier in life than expected.
One limitation of current CHIP analysis is its phenotype based on the presence or absence of known driver
mutations or large-scale structural variants. However, changes in clonality may presage or be independent of
CHIP and are available through the genome-wide detection of ‘neutral’ mosaic variants. Thus, we hypothesize
that clonal mosaicism of the hematopoietic system (CM-HS) represents a quantitative trait with
increased sensitivity to detect blood clonality alterations for individuals with DS. To test this hypothesis
and implement this framework, we plan to leverage local resources through the Linda Crnic Institute, which
harbors a biobank of samples from individuals with DS with matched genome sequencing data through the
Gabriella Miller Kids First (GMKF) program. We will first analyze ~450 readily available 60× coverage whole-
genome data sets employing our novel approaches for mosaicism detection. Our team also has access to
detailed clinical and multi-omics data; this will allow the correlation of CM-HS with clinical and functional
phenotypes and establish a biosignature of blood clonality changes in DS (Aim 1). Subsequently, we will
migrate our bioinformatic toolkit to the CAVATICA platform to perform analyses across the available Down
syndrome data (~1,700 cases) and matched controls through GMKF (Aim 2).
Together, these analyses will provide novel insight into blood clonality changes in DS through CM-HS
detection. Based on our expectations and preliminary data, we expect that CM-HS can reflect and possibly
predict alterations in the hematopoietic system—be it through inflammation or stem cell selection. The work
proposed here will allow us to develop the analytical framework for CM-HS analysis,
Istituzione: UNIVERSITY OF COLORADO DENVER
PI: Martin Werner Breuss, Matthew D Galbraith, Kelly D. Sullivan
Progetto: 1R03HD121962-01
Settori: Eunice Kennedy Shriver National Institute of Child Health and Human Development
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