# MUTATIONAL SIGNATURE(S) OF HUMAN GENOMIC REARRANGEMENT MECHANISMS

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $369,698

## Abstract

PROJECT SUMMARY/ABSTRACT
Copy number variation (CNV), too many or too few copies of a segment of the genome, underlies many
important human medical issues. We had predicted that, based on our MMBIR model for the generation of
much CNV by aberrant repair of broken replication forks, that there would be a unidirectional tract of
hypermutation of considerable length extending from the junction of the CNV. We devised a series of
techniques to analyze seven million base-pair tracts of DNA sequence surrounding CNVs on chromosome 17.
With these techniques we were successful in determining the precise structure of, and mutations linked to, 26
CNVs. We also analyzed both parents' genomes. We discovered what we sought: there are tracts of
hypermutation in one direction linked to the CNV extending for up to one million base-pairs from the CNV. This
confirms that our postulated mechanism is responsible for at least half of these CNV events. For the other half
that do not show hypermutation, we will obtain data from a larger sample of parents until we can say whether
these arose by a different mechanism or whether it is the tail of the distribution of the same mechanism.
Because of the very highly detailed resolution of our analyses, we are able to see into the mechanisms that
generate the hypermutation tracts. We find two mechanisms that we can provisionally decipher and possibly a
third whose cause we have not yet found. Near the CNV, a low processivity polymerase makes multiple
template switches and slips on the template that is being replicated. Further away, we see evidence of
processes acting on single-stranded DNA giving clustered mutations of a unique signature. The third signature
might relate to the diminished mismatch repair that is expected when broken replication forks prime replication.
The additional data will make the signatures clearer and allow us to determine the causes. The next step is to
generalize the findings to the rest of the genome. We will do this by whole genome sequencing of CNVs at
other sites. In a third project we are going to use new sequencing technology to decipher the recurrent CNVs
that arise by crossing-over between repeated sequences. This has been an intractable problem with previous
technology because of the numerous copies of the sequence present in the cell. We expect to find the precise
positions of crossovers and gene conversion tracts, indicating the rules that govern where they will fall, and
determine the extent and signature (and therefore the cause) of any new mutations. Together these Aims will
extend understanding of DNA repair events gone wrong that lead to genomic disorders, and potentially
suggest ways to control or avoid this happening.

## Key facts

- **NIH application ID:** 10105331
- **Project number:** 5R01GM106373-07
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** PHILIP John HASTINGS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $369,698
- **Award type:** 5
- **Project period:** 2014-09-05 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10105331

## Citation

> US National Institutes of Health, RePORTER application 10105331, MUTATIONAL SIGNATURE(S) OF HUMAN GENOMIC REARRANGEMENT MECHANISMS (5R01GM106373-07). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10105331. Licensed CC0.

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