# Human Genetic Variation and Disease

> **NIH NIH R35** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2024 · $582,963

## Abstract

In this renewal, we will continue our studies of the causes and disease consequences of human
genetic variation. We have generated whole-genome sequence (WGS) data from the three-generation
Utah CEPH pedigrees to longitudinally characterize rates and patterns of de novo mutations (DNMs). We
showed significant differences in the rates of accumulation of mutations among families, and we
demonstrated that 10% of apparent DNMs are actually postzygotic events that result in mosaicism. We
also showed that a higher rate of age-adjusted germline DNM transmission is significantly associated with
a shorter lifespan and earlier menopause. These results imply that one’s germline DNM rate, which
increases with age, is associated with the somatic mutation rate. In the next funding period, we will test
this hypothesis directly using blood-derived DNA samples collected at three different time points in the
same CEPH pedigree members over a 35-year time period. To our knowledge, this is the first long-term
longitudinal study of germline and somatic mutation rates in human pedigrees. We also hypothesize that
DNA repair mechanisms influence variation in both germline and somatic mutation rates. We will test
this hypothesis using whole-genome sequence data (supported by separate funding) and RNA-seq data
from freshly collected whole blood samples. We predict that lower expression of critical DNA repair
genes will result in higher germline and somatic mutation rates.
 To increase our power to detect patterns and disease associations, we will (under separate
funding) expand the CEPH pedigree collection to include more than 700 members of the fourth
generation, who are now adults. We will also resample generations 2 and 3 for a third time. We will
undertake WGS and RNA-seq in these study participants, creating a unique, publicly available repository
of genetic information spanning four generations. More than 180 phenotypic measurements were made
for generations 2 and 3 of the CEPH pedigrees 20 years ago, and the same measurements will be made for
generation 4. These resources will allow us to explore the effects of genetic variation, including mutation
rates and DNA repair, on a broad assortment of phenotypes across several generations.
 In addition, we will continue our work to develop new and improved methods for genome
sequence analysis, including the detection of mobile element insertions. We will analyze WGS and
RNA-seq data from members of large Utah disease pedigrees obtained from the Utah Population
Database, focusing on amyotrophic lateral sclerosis and juvenile idiopathic arthritis. These projects
involve analysis of WGS and RNA-seq data as well as functional analysis in in vitro and in vivo systems.

## Key facts

- **NIH application ID:** 10890659
- **Project number:** 5R35GM118335-09
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Lynn Jorde
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $582,963
- **Award type:** 5
- **Project period:** 2016-07-22 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890659

## Citation

> US National Institutes of Health, RePORTER application 10890659, Human Genetic Variation and Disease (5R35GM118335-09). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10890659. Licensed CC0.

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