# The Genetic and Epigenetic Mechanisms of Phenotypic Innovation

> **NIH NIH R35** · ROCKEFELLER UNIVERSITY · 2024 · $457,650

## Abstract

PROJECT SUMMARY
The research proposal aims to investigate the novel regulatory sequences and elements underlying novel
phenotypes, to gain a deeper understanding of the genetic basis of morphological and cellular innovation. The
evolution of morphological structures and traits is complex, and the origins and genetic mechanisms that drive
the development of new cell types, tissues, and organs are not fully understood. Our long-term goal is to uncover
the processes that govern morphological and functional diversity and complexity, which is a crucial step in
understanding the evolution of complex life. Despite progress in this field, our current understanding is still
limited. The goal of this research is to understand the origins of novel regulatory sequences and elements, how
they are integrated into regulatory networks to contribute to genic and phenotypic innovation, and further impact
evolution. To accomplish this, the laboratory has two major focuses: the study of how new genes and
phenotypes, including expression phenotypes, are regulated, and the deciphering of the principles of sex-biased
regulation from an evolutionary biological perspective. The first part of the proposed research aims to investigate
the mechanisms governing the gain of expression of evolutionarily young genes in Drosophila. Specifically, the
project will focus on the regulatory basis of new genes in Drosophila and using scRNA-seq and scATAC-seq to
pinpoint enhancers and promoters for new genes and new expression. Additionally, the project will investigate
the mechanism of pre-meiotic dosage compensation and identify putative novel players. The second part of the
proposed research will focus on the genetic and epigenetic mechanisms for sex-biased novel expression. This
will include using deep learning to reveal the basis of sex-biased chromatin accessibility, investigating the origin
of novel enhancers from poised sequences, and studying the role of distant enhancers in gene expression
novelties and sex-biased novelties. Overall, this project will use cutting-edge techniques and approaches to gain
insight into the mechanisms that drive the evolution of new genes and their expression patterns in Drosophila.
This study will provide important insights into the evolution of transcription regulatory networks and their
contributions to novel traits, including expression phenotypes. Altogether, our integrative approach will help to
elucidate the origination and evolution of novel regulatory circuits and their contributions to phenotypic innovation
and evolution.

## Key facts

- **NIH application ID:** 10765410
- **Project number:** 2R35GM133780-06
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** Li Zhao
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $457,650
- **Award type:** 2
- **Project period:** 2019-09-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765410

## Citation

> US National Institutes of Health, RePORTER application 10765410, The Genetic and Epigenetic Mechanisms of Phenotypic Innovation (2R35GM133780-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10765410. Licensed CC0.

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