# Constraints and Consequences of Copy Number Variation

> **NIH NIH R01** · NEW YORK UNIVERSITY · 2021 · $305,683

## Abstract

Project Summary/Abstract
Copy number variants (CNVs) – increases and decreases in the number of copies of genomic regions – are a
pervasive class of genetic variation that contribute to rapid adaptive evolution and human phenotypic variation
and disease. Moreover, CNVs are the first step in processes that result in genome evolution such as gene
family expansion and the generation of novel functions through modification of duplicate genes. Despite the
importance of CNVs in human health and evolution, many fundamental questions about their role in evolving
populations and their functional consequences remain unsolved. Experimental microbial evolution in
chemostats is an ideal system for studying the evolutionary constraints and functional consequences of CNVs.
To gain quantitative insights into the role of CNVs in evolving populations, we have developed a novel CNV
reporter system using a constitutively expressed fluorescent protein gene linked to a locus at which CNVs are
known to be repeatedly generated and selected. By coupling this system to a lineage tracking system using
random molecular barcodes we have developed a powerful novel framework for studying the diversity and
dynamics of CNVs in complex populations. We will use this novel system to address three fundamental
questions. In aim 1, we will address the dynamics with which CNVs are selected in fluctuating environments.
Using a combination of two-color CNV reporters and lineage tracking we will investigate the dynamics and
diversity of CNV selection in variable chemostat environments. In aim 2, we will identify the determinants of
CNV fitness effects. We will establish a collection of hundreds of unique CNV alleles that are molecularly
characterized using whole genome sequencing and uniquely marked by DNA barcodes. We will use pooled
fitness assays in a range of environmental conditions to quantify the fitness of each lineage and use these data
to identify determinants of condition dependent and independent fitness fitness costs and benefits of CNVs. In
aim 3, we will test the effect of CNVs on variability of gene expression and phenotypes. Using single cell RNA
sequencing we will test whether CNVs results in increased variation in expression levels of both the genes
contained within a CNV and all genes throughout the genome. We will also test whether CNVs result in
increased variability in phenotypes using a high throughput microcolony growth rate assay. Our study will
make use of the unparalleled efficiency and rigor afforded by the budding yeast model system and the
unprecedented resolution provided by our new method for CNV detection to address fundamental questions of
widespread significance for our understanding of CNVs in evolution and disease. As CNVs are universal in
evolution and disease findings from our study will have a high impact on the field of genomics, evolution, and
human health.

## Key facts

- **NIH application ID:** 10155508
- **Project number:** 5R01GM134066-02
- **Recipient organization:** NEW YORK UNIVERSITY
- **Principal Investigator:** David Gresham
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $305,683
- **Award type:** 5
- **Project period:** 2020-05-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10155508

## Citation

> US National Institutes of Health, RePORTER application 10155508, Constraints and Consequences of Copy Number Variation (5R01GM134066-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10155508. Licensed CC0.

---

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