# Characterizing and Mapping Deleterious Mutations in Humans

> **NIH NIH F32** · COLUMBIA UNIV NEW YORK MORNINGSIDE · 2020 · $67,446

## Abstract

PROJECT SUMMARY
A fundamental goal of human genetics is to identify and characterize deleterious mutations responsible for
disease. Deleterious disease alleles are introduced by mutation, then increase or decrease in frequency through
the effects of genetic drift and natural selection. Their ultimate fate depends critically on their effects on fitness
in heterozygotes and homozygotes. Although there is clear evidence that humans carry a burden of deleterious
mutations, the total number of such mutations and their typical fitness consequences remain unclear.
Furthermore, it is unknown if mutations responsible for disease when homozygous also have subtle fitness
effects when heterozygous. Minor fitness effects in heterozygotes may not present clinical symptoms, however
can dramatically impact the frequencies of such alleles over evolutionary timescales. Finally, researchers have
traditionally been limited to studying mutations that manifest their deleterious effects after birth and thus
embryonic lethal alleles have remained largely unidentified. A substantial proportion of human genes appear to
be under strong selective constraint, however have no known function, presumably because they are required
for normal embryonic development. The goal of the proposed research is to address these unanswered
questions in characterizing and mapping deleterious mutations in humans. Specifically, the proposed work
combines bioinformatics, population genetics, and human genomics to estimate the burden of strongly
deleterious recessive alleles, determine the fitness and dominance effects of mutations classified as recessive,
and identify dominant and recessive embryonic lethal mutations. The first aim is to take advantage of autozygous
regions in a founder population, the Hutterites, to estimate the deficiency of strongly deleterious genotypes and
compare the result to a colony of vervet monkeys with a similar pedigree structure to understand differences
among populations and species. The second aim is to develop a likelihood framework and use realistic
simulations of human demographic history to test if the frequency distribution of deleterious alleles in genes
annotated as completely recessive is consistent with the absence of any fitness effects in heterozygotes. The
third aim is to sequence miscarriage samples and develop a bioinformatics pipeline to identify candidate
mutations underlying embryonic lethality. Here, the bioinformatics pipeline will be made publically available for
use by the clinical research community interested in understanding mutations responsible for spontaneous
miscarriage. Together, the proposed research will address central questions about the population genetics of
deleterious alleles and provide new insight into the forces that influence the persistence of human genetic
disease.
!

## Key facts

- **NIH application ID:** 9908108
- **Project number:** 5F32GM128318-03
- **Recipient organization:** COLUMBIA UNIV NEW YORK MORNINGSIDE
- **Principal Investigator:** Zachary L Fuller
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $67,446
- **Award type:** 5
- **Project period:** 2018-05-16 → 2021-05-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9908108

## Citation

> US National Institutes of Health, RePORTER application 9908108, Characterizing and Mapping Deleterious Mutations in Humans (5F32GM128318-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9908108. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*