# Patterns and Mechanisms Underlying Somatic Mutations Across Long-Lived Bats

> **NIH NIH K99** · UNIVERSITY OF CALIFORNIA BERKELEY · 2024 · $138,564

## Abstract

Aging is ubiquitous across the tree of life, impacting biology at all levels. Among the hallmarks of aging, the
accumulation of somatic mutations over time has been implicated in many leading causes of death including
cancer10-12, heart disease4, and dementia5. However, most risk factors governing somatic mutation rates and
patterns with age remain unknown. It has recently become possible to study the relationship between somatic
mutation rates and longevity using comparative genomics. Cagan et al. (2022) demonstrated a negative
correlation between somatic mutation rates and longevity, and identified conserved, longevity-associated
mutational spectra across mammals. Yet, this study lacked the power to explore further due to both sparce
taxonomic sampling and low sample sizes per species. Thus, there is an outstanding gap in our knowledge
of how somatic mutational spectra relate to changes in longevity, and the genes involved in longevity-
associated mutational spectra. To properly study the mechanisms governing mutation rates and patterns, one
must sample many individuals from a group of closely-related species spanning a wide range of lifespans.
My central hypothesis is that somatic mutation spectra unique to long-lived mammals are signatures of
enhanced DNA damage repair responses that contribute to their extraordinary longevity. In order to
identify the genetic mechanisms underlying longevity-associated somatic mutational spectra, I have generated
matched skin tissue and cell lines from over 200 individuals across 10 species of a closely related (14 million
years) clade of bats spanning a 3-fold range in lifespans, including the longest-lived bat species in North America.
In Aim 1, to explore how somatic mutation rates co-evolve with longevity and identify longevity-associated
mutational spectra in bats, I will use the highly sensitive NanoSeq to sequence 60 individuals across a trio of
species in skin tissue samples. In Aim 2, using matched cell lines from the same individuals I will identify both
cis and trans regulators of somatic mutation rates and spectra by using the massively parallel CRISPRi screen
Repair-seq. As I transition towards an independent researcher position, in Aim 3 I will expand my functional work
to other tissues and developmental contexts by developing induced pluripotent stem cells (iPSCs) from my
collection of bat cell lines, and combine the cell type diversity of embryoid bodies with the power of Repair-seq
to assess DNA damage repair mechanisms across all cell types simultaneously.
This project is the first to explore how somatic mutation rates and spectra co-evolve with longevity
both mechanistically and at high resolution. The foundations of this project will be the cornerstone of my
research program exploring the evolution of longevity-associated traits in extraordinarily long-lived species
using functional genomics. Using iPSCs from non-lethal skin biopsies will enable us to study aging processes
in internal tiss...

## Key facts

- **NIH application ID:** 10949450
- **Project number:** 1K99AG088361-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Juan Manuel Vazquez
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $138,564
- **Award type:** 1
- **Project period:** 2024-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10949450

## Citation

> US National Institutes of Health, RePORTER application 10949450, Patterns and Mechanisms Underlying Somatic Mutations Across Long-Lived Bats (1K99AG088361-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10949450. Licensed CC0.

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