# Paternal age effect mutations as selfish drivers of germline stem cell clonality

> **NIH NIH F30** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $39,983

## Abstract

PROJECT SUMMARY
Spermatogonial stem cells (SSCs) maintain male fertility, but not all SSCs are created equal. Here, I propose to
lineage trace the contributions of individual SSCs to sperm production across the fertile lifespan of an animal.
My central hypothesis is that SSCs compete for dominance and that Paternal Age Effect (PAE) mutations in the
RAS-MAPK pathway can confer autonomous advantage to SSCs at the cost of offspring health. In Aim 1, I will
identify the contributions of individually labeled SSC clones to spermatogenesis throughout zebrafish adulthood
using serial sperm sampling of male zebrafish from sexual maturity through the “elderly stage” when fertility
begins to decline. In Aim 2, I will investigate whether PAE mutations drive the selection of individual SSCs. I will
overexpress mutated PAE genes in a subset of SSC clones within the zebrafish testis and determine the
consequences to clonal dynamics, measuring non-neutral clonal competition in a living animal. In Aim 3, I will
determine the potentially “selfish” influence of PAE-containing clonal dominance by measuring mutation
transmission and consequences for the next generation. Together, this proposal will illuminate developmental
mechanisms that underlie male reproductive aging and may aid future efforts to design male-oriented
reproductive interventions that improve birth outcomes.
My interdisciplinary team of mentors will provide training in stem cell population analysis, genetic engineering,
and modeling human disease in animals, complemented by clinical mentorship and shadowing in pediatrics and
reproductive endocrinology. The training plan was developed in collaboration with my Sponsors to complete the
central goals of conducting independent, collaborative research; advancing communication and grant-writing
skills; learning how to effectively mentor and teach trainees in a supportive environment; and honing clinical skills
in preparation for the return to medical school. This training is ideal for a future physician-scientist with the goal
of improving patient care at the intersection of basic research and clinical reproductive interventions.

## Key facts

- **NIH application ID:** 10903616
- **Project number:** 1F30HD115391-01
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Jenna Micole Weber
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $39,983
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903616

## Citation

> US National Institutes of Health, RePORTER application 10903616, Paternal age effect mutations as selfish drivers of germline stem cell clonality (1F30HD115391-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10903616. Licensed CC0.

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