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GENETIC HETEROGENEITY AMONG HUMAN SOMATIC CELLS AND ITS ACCUMULATION WITH AGE

Award Number: R56AG067615
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2020
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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GENETIC HETEROGENEITY AMONG HUMAN SOMATIC CELLS AND ITS ACCUMULATION WITH AGE - ABSTRACT Genetic heterogeneity due to the accumulation of mutations in normal tissues increases cancer risk and is likely an important factor in many age-related degenerative and chronic diseases. Somatic mutations can occur due to DNA damage or replication errors. Each single human colon crypt is conventionally viewed as monoclonal, representing a single stem cell lineage based on several previous studies using single genetic markers for lineage tracing. Our WGS study takes advantage of the thousands of genetic differences that can be assessed genome-wide to achieve a much more comprehensive assessment. Using multiple single colon crypts (~1,500 cells per crypt) from each of the 21 individuals ranging in age from 10-month to 90 years of age, our analysis reveals that about half of the human crypts are polyclonal (multi-lineage). A multi-lineage colon crypt will have inflated DNA mutation count and reduced variant allele frequency for each variant in the crypt cell population. This complicates the analysis of mutation rates. Further investigation of the crypts that are monoclonal demonstrates a clear and strong linear dependence of mutation count with age and a mutation accumulation rate of 45 mutations per year. This strongly indicates that an accurate rate of somatic mutation accumulation can and should only be established from monoclonal cell populations as we proposed in the last funding cycle. To achieve this goal with statistical power, we propose to obtain 60X depth WGS data from both existing sequencing libraries and more new single crypt libraries to obtain at least 3 single stem cell lineage crypts from each of the 21 individuals to establish an accurate rate of somatic mutation accumulation in human colon crypts with age in Aim 1. In Aim 2, we propose to analyze sequencing data from multi-lineage crypts to reveal stem cell activity and dynamics and the potential impact of aging on stem cell activity. In Aim 3, we propose to develop a new platform using a second mini-organ, the human hair bulb, that can be easily collected noninvasively from nearly any individual to measure DNA changes with human age and permit comparisons with the crypt findings. Human scalp hair bulbs reside 10-fold deeper than UV light penetration, thus protecting this mini-organ from UV exposure. With the ease of sample collection, hair bulbs can also be used to assess the impact of chronic diseases, environment factors, and lifestyle on human aging. Overall, the efforts from these two mini-organ systems, colon crypt and hair bulb, are important for understanding accumulation of naturally occurring DNA damage and repair with age. This proposed study will also lay the foundation for future work to measure how extrinsic factors, such as diet, lifestyle, and medical treatment, may affect the progression of somatic genetic changes over the human lifespan.


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 = $332,000 )
2026	2026	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Aging Research	000	5	8/10/2026	COMPETING CONTINUATION	$332,000
														Subtotal = $332,000

Grand Total All Awards = $332,000

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GENETIC HETEROGENEITY AMONG HUMAN SOMATIC CELLS AND ITS ACCUMULATION WITH AGE

Award Number: R56AG067615

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2020

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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