# Single cell, whole genome analysis of the aging human cardiomyocyte

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $871,975

## Abstract

Project Summary/Abstract
Recent evidence suggests that environmental factors causing somatic mutations during the lifetime have a
more crucial role, not only in cancer but also in other common diseases, including heart failure. Recent studies
have also shown that somatic single nucleotide variants (sSNV) accumulate even in nondividing cells, such as
neurons in the human cortex, resulting in thousands of sSNV per neuronal genome by old age. However,
genomic DNA changes in aging cardiomyocytes (CM) remain poorly understood. The accumulation of somatic
DNA mutations over time has recently been demonstrated to be a hallmark of aging in many human cell types.
The current study aims to determine the landscape and role of somatic mutations in aging and cardiac disease
by adopting a new technique that allow deep whole-genome sequencing of DNA isolated from single CM taken
from the frozen postmortem heart. The first Aim of this study is to evaluate the somatic mutational burden
(sSNVs) in aging CM genome. We will also compare CM mutational burden with postmitotic cells from another
organ (neurons) to define differences in accumulation rate during aging. In the second Aim, we will ask what
are the mutational signature and the mechanisms of mutation formation in the aging human heart and if the
heart mutational signature is different than the brain mutational signature. Further to recapitulate the mutational
signature and related phenotype in the heart we will directly induce oxidative stress in an in vitro culture model
of primary CMs. The final Aim will focus on evaluating the genotoxic effect of radiation in CMs after childhood
radiation therapy and the role of radiation in premature aging. The proposed research is significant for the
comprehensive, results-based development of strategies for understanding natural aging and disease
progression in the human heart. Together with the planned characterization of mutational signatures, the
anticipated results may provide knowledge to develop new strategies for preventing the heart disease
associated with aging. The proposed study is only possible because of a series of innovations that are, at this
time, uniquely available to our research team, 1) a novel method to isolate single CM nuclei from frozen
myocardium based on CM ploidy and nuclei cardiac troponin T expression. 2) A major breakthrough by
developing “LiRA” and “PhaseDel” algorithm to call sSNV and sSV confidently from tetraploid cells that
considers cell-specific depth distributions of DNA sequencing and allele-dropout rates in scWGS data. For the
first time, our study will reveal the landscape of somatic mutations, genomic changes during aging and after
radiation therapy in human heart muscle cells in a single-cell resolution. In the long term, this study will
provide insights that might allow blocking some of the mutational processes ameliorating age-related
myocardial dysfunction.

## Key facts

- **NIH application ID:** 10326403
- **Project number:** 5R01HL152063-02
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Sangita Choudhury
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $871,975
- **Award type:** 5
- **Project period:** 2021-01-15 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10326403

## Citation

> US National Institutes of Health, RePORTER application 10326403, Single cell, whole genome analysis of the aging human cardiomyocyte (5R01HL152063-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10326403. Licensed CC0.

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