# Project 2: Normal Cell Evolution

> **NIH NIH U54** · ARIZONA STATE UNIVERSITY-TEMPE CAMPUS · 2021 · $533,812

## Abstract

Abstract: Somatic Cell Evolution in Small Human Replicative Units
 This Project studies fundamental parameters of evolution (mutation, drift, and selection "MDS") in normal
human and animal cells. Although MDS underlies somatic cell evolution, very little is understood about these
parameters because they are difficult to study in humans. We will translate methods from evolutionary biology
into systems biology. We will study MDS in distinct, small replicative units (intestinal crypts). The
compartmentalization of cells into small replicative units can modify evolution because selection and drift
(random cell turnover) is limited to immediately adjacent cells. The advantages of analyzing small replicative
units are that experimentally they large enough to measure with conventional methods yet small enough to
simulate in detail. Characterizing somatic cell evolution in replicative units can lead to better understanding of
tumor evolution because selection or drift occurs between neighboring cells.
 We will better characterize MDS in crypts based on our existing published (Shibata, Graham) human
crypt simulations. These simulations have already inferred stem cell numbers and dynamics based on
smaller amounts of data. The new sequencing data are a richer resource because more MDS parameters
are encoded by mutations (mutation rates and mechanisms, dN/dS, passenger versus driver, neoantigen
accumulation). The sequencing data is augmented by crypt epigenetic and expression data to more fully
characterize normal somatic cell evolution. We will sample 8 colon and small intestinal crypts from 40 different
aged individuals. For each crypt, we will measure mutations (whole genome sequencing), epigenetic alterations
(ATAC-seq), and expression (NanoString). We will also measure APC+/- crypts to determine whether
somatic cell evolution changes after a gatekeeper mutation. We will also measure crypt somatic cell
evolution in mouse and elephant crypts to determine if their evolution differs.
 We will also determine the DNA damage and stress response in fibroblasts from 57 different mammalian
species. We will determine de novo mutation rates across the same 57 mammalian cell lines through expansion
of single fibroblast cells followed by deep sequencing. We will correlate mutation rates with cancer rates in the
same mammalian species as determined in Project 1. Finally, using prioritized candidate gene lists generated in
Project 1, we will perform gene editing experiments on the top 5 genes from different species most likely to
contribute to their evolution of cancer resistance.
 The significance of these studies is a better characterization of basic MDS evolution parameters. The
species studies will provide perspective on whether MDS parameters are "fixed" or can vary with age or
species, identifying which parameters are more amenable for intervention. A complete systems biology solution
of normal human crypts will facilitate further efforts with much larger groups...

## Key facts

- **NIH application ID:** 10135023
- **Project number:** 5U54CA217376-04
- **Recipient organization:** ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
- **Principal Investigator:** Darryl K Shibata
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $533,812
- **Award type:** 5
- **Project period:** 2018-04-12 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10135023

## Citation

> US National Institutes of Health, RePORTER application 10135023, Project 2: Normal Cell Evolution (5U54CA217376-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10135023. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*