# The evolution and diversity of mutation, molecular fidelity, and genome structure

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA BERKELEY · 2024 · $401,250

## Abstract

Project Summary Abstract
Mutation is the source of all evolutionary novelty and diversity shaping both the structure and sequence of
genomes. Over evolutionary timescales changes to genome structure and content are associated with vast
phenotypic changes between and within species. Throughout the lifetime of an organism individual cells
accumulate somatic mutations that can also confer selective advantages. Our lab is interested in how
mutations emerge and how these changes to genome sequence and structure are maintained and acted on by
selection. We seek to understand at both the cellular and organismal level how cell-type, genotype, selective
pressures, and evolutionary histories influence the structure and sequence of the genome. Ultimately, our
research will further our understanding of the mechanisms underlying why specific cell types are more
susceptible to disease as well as how genome structure influences phenotypic diversity within and between
species. Patterns of somatic mutation have been extensively studied in the context of cancer tumor genomes
in which clonal expansions amplify the signals of mutation to detectable levels. Far less is understood however
about how “normal” cells accumulate mutations through time and how these dynamics are influenced by
factors such as cell type and genotype. Furthermore, somatic mutations have proven challenging to identify
due to the comparably high error rate of standard sequencing approaches. We propose to use novel genomic
methods to investigate how different forms of somatic mutation accumulate and how somatic mutational
processes are impacted by inherited genetic variation. In addition to discerning the contexts in which individual
cells accumulate mutations, we propose to determine how genome structures have evolved in the context of
different evolutionary histories, selective pressures, and life history strategies. While the size and structure of
eukaryotic genomes varies tremendously spanning three orders of magnitude in vertebrates, the evolutionary
and mechanistic bases of this variation remain unknown. We propose to study the evolution of genome
architectures in the explosive adaptive radiation of rockfish to understand how extreme variation in lifespan can
impact mutational processes and genetic diversity. We further propose to study how the structures of human
and chimpanzee genomes have been shaped by local adaptations and the forces of selection. Identifying
signatures of selection and adaption at structurally variable (SV) loci has been challenging in part due the
tendency of SVs to emerge in complex repetitive regions of the genome. We propose to use long-read based
genomics approaches and novel computational methods to assess these loci. Ultimately, our research will
further our understanding of mutation, diversity, and genome structural diversity both within and between
species as well as among the individual cells of organisms.

## Key facts

- **NIH application ID:** 10866523
- **Project number:** 5R35GM142916-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Peter Heshedahl Sudmant
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $401,250
- **Award type:** 5
- **Project period:** 2021-08-06 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10866523

## Citation

> US National Institutes of Health, RePORTER application 10866523, The evolution and diversity of mutation, molecular fidelity, and genome structure (5R35GM142916-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10866523. Licensed CC0.

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