# The origin, the function and the phenotypic impact of human alleles

> **NIH NIH R35** · HARVARD MEDICAL SCHOOL · 2024 · $904,819

## Abstract

Project Summary
All populations are genetically variable, and humans, as well as the populations of somatic cells in their bodies,
are no exception. Genetic variation explains much of phenotype variation and partially determines the risk of
common and rare disease. Analysis of the functional effects of allelic variants opens a unique perspective on
molecular function in the broad organismal context. Study of genetic variation provides understanding of the
actions of evolution over short timescales and helps detect footprints of natural selection that point to
uncharacterized functional elements of the genome. The explosion of sequencing datasets in combination with
new computational and statistical techniques, propel genetic variation research. Our lab plans to be at the
forefront of this endeavor. Our broad research program will analyze genetic variation from multiple angles. We
will study mutagenesis as the origin of genetic variation, and use statistical analysis—in the context of known
DNA replication and repair biology—to infer mutagenic mechanisms. We will develop computational methods
to analyze and predict the effect of human allelic variants on molecular function. We will also study the
evolutionary forces governing the fate of alleles in populations, in order to better understand the persistence of
deleterious variation. Additionally, we will examine the principles of the relationship between genotype and
phenotype, including both polygenic inheritance and the partial penetrance of rare disease variants. These
topics—the origins, persistence, and effects of variants—are intertwined, and their integrated understanding is
critical to the progress of human medical genetics and cancer genomics.

## Key facts

- **NIH application ID:** 10907418
- **Project number:** 5R35GM127131-08
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** SHAMIL SUNYAEV
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $904,819
- **Award type:** 5
- **Project period:** 2018-05-11 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907418

## Citation

> US National Institutes of Health, RePORTER application 10907418, The origin, the function and the phenotypic impact of human alleles (5R35GM127131-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10907418. Licensed CC0.

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