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Deciphering Determinants of Somatic Evolution with Single-Cell Genealogy

Award Number: K99HG013991
ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 02/01/2025
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Deciphering Determinants of Somatic Evolution with Single-Cell Genealogy - Project Summary / Abstract Somatic cells undergo continuous evolution with heritable modifications through genetic and epigenetic changes, influencing cellular competition and selection. Depicted as a detailed branching lineage map, a cellular genealogy provides an essential scaffold to understand the causes and consequences of the somatic evolutionary dynamics. However, the impact of various somatic modifications on genealogical dynamics and cell states remains unclear, due in part to our limited ability to track somatic modifications within genealogical contexts. To address this limitation, I propose to develop a somatic mutation-resolved lineage tracing system that reconstructs a single-cell genealogical tree coupled with joint detection of somatic mutations and epigenetic alterations (Aim1). To demonstrate the biological significance of this system and to advance our understanding of hematopoietic stem cell (HSC) somatic evolution, I will trace the acquisition histories of somatic mutations on HSC genealogical architecture and chart the evolutionary trajectory of normal aging hematopoiesis and the leukemic transformation (Aim2). To tackle the causality in somatic evolution, I will develop a genealogy-resolved massively parallel single-cell CRISPR screen to survey the causative effects of somatic modifications on the genealogical dynamics and cellular functions at a large scale (Aim3). This project will advance the frontier of studying genomic evolution in somatic cells, by revealing how genomic modifications impact cellular dynamics. It paves the way to decipher the driving forces that shape somatic evolution in broad areas essential for human health, including aging hematopoiesis, cancer progression, etc. This project is a critical step for my long-term goal to advance our ability to observe, understand, and control cellular behaviors and cell fate choices. Through the K99 phase of this proposed career development plan, I will further strengthen my expertise and knowledge in mouse modeling, functional genomics, and leukemia biology, as well as professional skills such as leadership, and lab management which are essential for my successful independent career. These training goals will be achieved through joint mentorship between Dr. Jonathan Weissman and Dr. Vijay Sankaran labs together with my advisory committee in a highly enriched cross-institutional environment (Boston Children’s Hospital, Whitehead Institute, Broad Institute). When combining these new skills with my rigorous training in single-cell genomics, stem cell, and computational biology, I will be better prepared to transition into a successful independent research career.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $126,830 )
2026	2026	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	000	2	1/31/2026	NON-COMPETING CONTINUATION	$126,830
														Subtotal = $126,830

Issue Date FY: 2025 ( Subtotal = $126,830 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Human Genome Research	000	1	1/27/2025	NEW	$126,830
														Subtotal = $126,830

Grand Total All Awards = $253,660

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Deciphering Determinants of Somatic Evolution with Single-Cell Genealogy

Award Number: K99HG013991

ORGANIZATION: NATIONAL HUMAN GENOME RESEARCH INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 02/01/2025

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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