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Principal Investigator: Paul L. Auer
Organization: VANDERBILT UNIVERSITY MEDICAL CENTER
Fiscal Year: 2024
Award: $703,426
Funding agency: National Institute on Aging
Project Summary
With age, dividing cells acquire DNA mutations. A small number of these somatic mutations confer a selective
advantage leading to a clonal proliferation of cells harboring the somatic mutation. In blood, this process is
termed ‘clonal hematopoiesis’. These mutations include both point mutations in cancer driver genes (eg. clonal
hematopoiesis of indeterminate potential ‘CHIP’) and megabase-scale deletions, duplications and copy-neutral
loss-of-heterozygosity (eg, mosaic chromosomal alterations, ‘mCAs’). CHIP and mCAs have each been
detected in ~5% of individuals over 60. While both predict shorter lifespans, CHIP leads to a myeloid biased
stem cell differentiation while mCAs lead to a lymphoid biased stem cell differentiation. As a result, CHIP and
mCAs have distinct disease associations with infection, cardiovascular disease, cancer and other diseases of
aging. Although CHIP has been an area of significant research activity, multiple gaps persist in our knowledge
of mCAs and their impacts on aging and population health. mCA clones that expand to make up a larger
proportion of the blood predict worse health consequences. However, we do not know why some mCA clones
but not others expand, what factors predict the rate of clonal expansion and how rate of expansion associates
with disease outcomes. Overall, we hypothesize that mCAs with higher rates of clonal expansion confer a
greater impact on health and that the propensity to expand has genetic and environmental underpinnings that
are mediated through gene expression. A barrier to addressing this gap is a paucity of large well-annotated
collections of longitudinally-sampled blood. Fortuitously, our team has two recent accomplishments that enable
us to address this gap: 1) a survey of mCAs in 67,000 whole genomes and 2) development of a novel
computational method to estimate the rate of mCA expansion from single timepoints. In Aim 1, we will
measure the rate of mCA expansion by leveraging unique serial blood samples (collected up to 19 years apart)
from 729 individuals with mCAs from three deeply phenotyped cohorts. In Aim 2, we will refine our method for
clonal expansion rate estimation and apply this method at population scale to estimate mCA clonal expansion
rates in 1.3 million individuals from several diverse cohorts. We will identify genetic and environmental factors
predisposing to clonal expansion and establish the relationship between mCA clonal expansion and disease. In
Aim 3, we will analyze bulk and single-cell RNA-sequencing to ascertain the cell type specific biological impact
of mCAs and identify pathways leading to clonal expansion. Our multidisciplinary team with deep expertise in
computational genomics, statistics, hematology and human epidemiology is uniquely poised for success in this
effort. Successful execution of our aims will inform risk models to stratify individuals with mCAs for
personalized prevention, such as interventions or enhanced screening, and identify new biological pathways to
target for therapeutic development. Finally, our study serves as a model for insights on somatic mosaicism in
other tissues and disease sites beyond the blood to support healthy aging and improve population health.
Terms: <Aberrant Chromosome><Address><Affect><Age><Aging><Allelic Loss><Area><B-Cell CLL><B-Cell Chronic Lymphocytic Leukemia><B-Cell Chronic Lymphogenous Leukemia><B-Cell Chronic Lymphoid Leukemia><B-Cell Lymphocytic Leukemia><B-Lymphocytic Leukemia><Biological><Blood><Blood Cells><Blood Fractioning><Blood Precursor Cell><Blood Reticuloendothelial System><Blood Sample><Blood specimen><Body Tissues><Cancers><Cardiovascular Diseases><Cell Body><Cell Growth in Number><Cell Lineage><Cell Multiplication><Cell Proliferation><Cells><Cellular Proliferation><Chromosomal Aberrations><Chromosomal Abnormalities><Chromosomal Alterations><Chromosome Aberrations><Chromosome Alterations><Chromosome Anomalies><Chromosome abnormality><Chromosomes><Chronic B-Lymphocytic Leukemia><Chronic Disease><Chronic Illness><Chronic Lymphatic Leukemia><Chronic Lymphoblastic Leukemia><Chronic Lymphocytic Leukemia><Chronic Lymphogenous Leukemia><Clonal Expansion><Clonal Hematopoietic Stem Cell><Collection><Computing Methodologies><Cytogenetic Aberrations><Cytogenetic Abnormalities><DNA><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data><Deoxyribonucleic Acid><Development><Disease><Disease Outcome><Disorder><Environmental Factor><Environmental Risk Factor><Epidemiology><Expression Signature><Female Health><Gene Expression><Gene Expression Profile><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genetic mutation><Genome><Genomic approach><Genomics><Health><Hematology><Hematopoiesis><Hematopoietic Cellular Control Mechanisms><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Host Factor><Host Factor Protein><Human><Immune><Immunes><Individual><Infection><Inflammation><Inflammatory><Integration Host Factors><Intervention><Intervention Strategies><Kidney Diseases><Knowledge><Lead><Learning><Loss of Heterozygosity><Lung Diseases><Lymphoid><Malignant Neoplasms><Malignant Tumor><Maps><Measures><Mediating><Methods><Modeling><Modern Man><Molecular><Molecular Modeling Nucleic Acid Biochemistry><Molecular Modeling Protein/Amino Acid Biochemistry><Molecular Models><Mosaicism><Multi-Ethnic Study of Atherosclerosis><Mutate><Mutation><Myelogenous><Myeloid><NHLBI><NIH><National Heart, Lung, and Blood Institute><National Institutes of Health><Nephropathy><Older Population><Organism><Pathway interactions><Pattern><Pb element><Peripheral Blood Cell><Phenotype><Pneumonia><Point Mutation><Population><Predictive Factor><Predisposing Factor><Process><Pulmonary Diseases><Pulmonary Disorder><RNA Seq><RNA sequencing><RNAseq><Renal Disease><Research Activity><Risk><Risk Factors><Sampling><Sequence Alteration><Site><Somatic Mutation><Survey Instrument><Surveys><TOPMed><Time><Tissues><Trans-Omics for Precision Medicine><United States National Institutes of Health><Women's Health><Work><ages><aging associated disease><aging associated mechanism><aging mechanism><aging pathway><aging related disease><aging related mechanism><biobank><biologic><biological mechanism of age><biological pathways of age><biorepository><blood cell formation><blood cell progenitor><blood fractionation><blood progenitor><blood stem cell><blood-forming stem cell><cardiovascular disease risk><cardiovascular disorder><cardiovascular disorder risk><cardiovascular health><cell type><chromosomal defect><chromosome defect><chronic disorder><chronic lymphoid leukemia><clinical phenotype><clone hematopoietic stem cell><cohort><computational methodology><computational methods><computer based method><computer methods><computing method><developmental><differential expression><differentially expressed><disease of aging><disease of the lung><disease risk><disorder of aging><disorder of the lung><disorder risk><entire genome><environmental risk><epidemiologic><epidemiological><full genome><gene expression pattern><gene expression signature><genome mutation><genomic alteration><genomic data><genomic data-set><genomic dataset><genomic effort><genomic strategy><healthy aging><healthy human aging><heavy metal Pb><heavy metal lead><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><high risk><improved><individualized prevention><insight><interventional strategy><kidney disorder><life span><lifespan><living system><lung disorder><malignancy><molecular modeling><mortality><mosaic><mosaic diseases><mosaic disorders><multidisciplinary><neoplasm/cancer><novel><older groups><older individuals><older person><pathway><personalized prevention><phenome><population health><precision prevention><progenitor cell differentiation><progenitor differentiation><programs><prospective><renal disorder><scRNA-seq><screening><screenings><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><somatic variant><statistics><stem and progenitor differentiation><stem cell differentiation><success><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic agent development><therapeutic development><transcriptional differences><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><whole genome>