# Understanding how structural mutations and individual RNA isoforms are involved in human health and disease

> **NIH NIH R35** · UNIVERSITY OF KENTUCKY · 2022 · $378,658

## Abstract

PROJECT SUMMARY/ABSTRACT
In today’s efforts to personalize medicine, it does not seem reasonable to personalize medicine
without constructing and utilizing an individual’s genome structure for both haplotypes. Current
standards force the reference genome’s structure on each individual. The same principle applies
to understanding the function for individual RNA isoforms. Structural variants are involved in, or
directly cause, a broad range of diseases including cancer, autism, schizophrenia,
neurodegenerative diseases, and Crohn’s disease, among others. We seek to better understand
how structural variants affect disease by helping characterize structural variants and their
downstream effects, combining this information with RNA isoform sequencing (IsoSeq). The
histocompatibility complex, which contains the human leukocyte antigen (HLA) genes, is a
particular region of interest for my lab because this region has been implicated in dozens of
diseases. Similarly, we seek understand the role for individual RNA isoforms for all genes.
Protein-coding human genes average seven RNA isoforms, resulting in unique protein products.
For practical reasons, standard short-read RNA sequencing studies treat all isoforms as a single
‘gene’—an oversimplification of the underlying biology; this is also true when considering sex
differences in human health and disease. While females and males have many similarities, both
sexes have unique biology with clear differences in disease prevalence, therapeutic needs, and
responses. Females, in particular, have not received adequate attention in human health and
disease research. A next critical step in all of biology research, especially in disease research,
will be to determine individual isoform function, and how that changes between sexes. We want
to contribute to this effort, and propose to employ long-read sequencing technologies to
accomplish these goals.

## Key facts

- **NIH application ID:** 10459288
- **Project number:** 5R35GM138636-04
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Mark T W Ebbert
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $378,658
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459288

## Citation

> US National Institutes of Health, RePORTER application 10459288, Understanding how structural mutations and individual RNA isoforms are involved in human health and disease (5R35GM138636-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10459288. Licensed CC0.

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