# From association to causation: pinpointing the genetic and molecular determinants underlying natural behavioral variations

> **NIH NIH R35** · UNIVERSITY OF PENNSYLVANIA · 2021 · $394,063

## Abstract

PROJECT SUMMARY
Deciphering how natural genetic variations influence complex phenotypic traits is a central goal in human
genetics and evolutionary biology. Over the past decades, empirical studies in model systems have conceptually
advanced the genetic understanding of natural variations in physiological and morphological traits. In contrast,
how natural behavioral variations arise from genetic changes altering neural functions remains a fundamental
mystery. Although numerous correlations between genetic variations and behavioral variations have been
identified across a wide range of species including human, the identity and functional nature of casual genetic
changes are largely out of reach. The evolution of courtship song in closely related Drosophila species provides
a rare opportunity to establish such causal links, by offering extraordinary behavioral diversity and unparalleled
genetic, neuronal and behavioral tractability. The overarching goal of this proposal is to leverage this powerful
system and employ our innovative platforms to identify causal genetic and molecular changes that mediate the
evolution of the nervous system and behaviors. Our research will proceed in two independent but complementary
directions. First, by combining a targeted genetic mapping approach and automated behavioral quantification
with unprecedented throughput, we will perform a gene-resolution dissection of defined trait-associated genomic
regions to delineate the causal genes and mutations underlying a species-specific courtship song trait. Second,
building on our knowledge of relevant neurons in courtship song evolution and our expertise in genetically
labeling these neurons across species, we will exploit possible neural sites of adaptive changes as an entry and
use single-cell transcriptomes to probe gene expression changes, especially cis-regulatory changes, that are
responsible for species-specific neural functions and behaviors. Importantly, for each direction, we will examine
the phenotypic effects of candidate genetic and molecular changes using integrative approaches such as
definitive genetic tests and neuron-specific gene silencing. The two directions are synergistic in connecting the
dots between evolutionary changes at different levels of biological organization. This study will lead to a rich
understanding of how evolution operates on the genes and the nervous system to yield adaptive behavioral
traits, which will allow us to derive principal mechanisms generalizable across species, and in turn, inform the
etiological conditions of behavioral disorders and mental disease in human.

## Key facts

- **NIH application ID:** 10274682
- **Project number:** 1R35GM142678-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Yun Ding
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $394,063
- **Award type:** 1
- **Project period:** 2021-07-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10274682

## Citation

> US National Institutes of Health, RePORTER application 10274682, From association to causation: pinpointing the genetic and molecular determinants underlying natural behavioral variations (1R35GM142678-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10274682. Licensed CC0.

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