# Understanding genomic stability betweengenerations by assessing mutational burdens in single sperms

> **NIH NIH K99** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $60,251

## Abstract

PROJECT SUMMARY/ABSTRACT
Mutations during embryonic development, aging, cellular metabolism, and environmental exposure are
permanently recorded in the genomes of each cell and its daughters. Depending upon whether the mutations
can be detected in regular next-generation sequencing, they are recognized as clonal or non-clonal in nature
and present different features. Elucidating the patterns of these mutations and their potential to transmit to
offspring is key to understanding congenital de novo mutation (DNM) disorders and genetic variability across
human generations. As parents age, the number of DNMs in their germ cells increases, and with this, an
increased risk of DNMs and the disease they cause in offspring. Although age-related DNM risks have been
reported in large populations, our understanding of how paternal-specific clonal and non-clonal mosaicism
contribute to offspring and how natural selection shapes the mutation pattern is still limited. During my previous
graduate and postdoctoral research, I established the concept that a considerable portion of DNMs in children
with neurological and psychiatric disorders arise from clonal mosaic mutations in the sperm (Yang, et al. Cell
2021). I developed experimental and computational pipelines to accurately detect clonal mosaic mutations in
bulk samples with deep whole-genome sequencing (Yang, et al. Nature Biotechnology, in press; Breuss, Yang,
co-firsts, et al. Nature 2022). In this K99/R00 application, I aim to unravel the feature of the non-clonal gonadal
mutation burden at the single-cell level, employing multidisciplinary approaches spanning the mentored [K99]
and independent [R00] award phases. I will compare the genomic sequences from 700 single human sperm
from bulk sperm sequences in 35 healthy young men, analyze the genomic positions where the non-clonal
mutations tend to reside compared to the clonal ones, and study the impact of those mutations (Aim 1). I will
develop new computational software to accurately detect mosaic mutations from single cells not only from
haploid and diploid genomes, and develop experimental approaches to accurately validate the somatic mutations
from single-cell amplified DNA (Aim 2). Finally, I will measure the single-cell DNA mutation rate and mutation
patterns using 2300 single sperm from an additional 45 young versus 75 aged donors for clues on age-related
mutational mechanisms and how they will impact the genome stability in the next generation before and after
natural selection (Aim 3). Overall, the results from this proposal will help us to understand the non-clonal mosaic
mutational burden, mutation distributions, as well as mutational functions in human sperm, and the age-related
genetic impacts on the genome stability of the next generation. My career goal is to lead an independent research
group focusing on somatic mutations in the human genome, their causes, and predicting their consequences on
child health. During the K99 phase, I will conti...

## Key facts

- **NIH application ID:** 10885162
- **Project number:** 5K99HD111686-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Xiaoxu Yang
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $60,251
- **Award type:** 5
- **Project period:** 2023-07-15 → 2024-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10885162

## Citation

> US National Institutes of Health, RePORTER application 10885162, Understanding genomic stability betweengenerations by assessing mutational burdens in single sperms (5K99HD111686-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10885162. Licensed CC0.

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