# Genetic and molecular basis for variation in human skin pigmentation

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2021 · $1,076,608

## Abstract

Variation in epidermal pigmentation is one of the most striking features of human populations and is critical for
protection against the harmful effects of ultraviolet radiation. Many genes that control pigmentation have been
identified in animal models, but little is known about the genetic basis of normal human skin pigment variation.
Filling this knowledge gap will likely reveal novel molecular and cellular mechanisms underlying melanocyte
biology, melanoma risk and rare genetic diseases. Because of their high genetic diversity and wide spectrum
of skin tone, African populations are particularly informative for discovering genes that regulate pigmentation.
Accordingly, our team recently used a genome wide association study and scans of natural selection in a
unique dataset from 1600 ethnically diverse Africans to identify genetic variants that affect skin tone in
Africans. These included genes with previously unknown functions in pigmentation such as MFSD12, encoding
a predicted transmembrane transporter that localizes to lysosomes but not to melanosomes and thus regulates
pigmentation by a novel mechanism. Preliminary analyses also identified additional candidate transporters and
regulators of receptor-mediated signaling that were not known to function in pigmentation and that may
regulate melanogenesis in novel ways. Here, employing a multi-PI team headed by experts in human genetics,
membrane trafficking/ organelle biology, and membrane signaling/ ion transport in collaboration with three
additional experts, we propose to identify (i) new pigmentation genes in a larger set of 3,000 Africans for which
we have whole genome sequence data, and (ii) the cellular and molecular mechanisms by which the products
of these genes control human skin pigmentation. We will accomplish our goal by integrating human genomic
and pigmentation data in our unique African cohort, genetic analyses of the impact of non-coding sequence
variants on gene expression, and cell culture studies of melanocyte cell biology and physiology. The three
specific aims will test our hypotheses that variation in pigmentation results from genetic variations in the
regulatory elements of genes encoding proteins that alter either the melanosomal milieu directly or indirectly
via signaling mediated by receptors such as the melanocortin-1 receptor (MC1R). Specifically, we will employ
the following three specific aims:
 1. Identify novel genetic variants influencing skin pigmentation and test whether the variants influence
 gene expression from nearby genes;
 2. Define novel mechanisms by which transporters in lysosomes or melanosomes influence
 pigmentation by defining how MFSD12 and other newly identified transporters impact melanogenesis;
 3. Determine the function of newly identified receptor-mediated signaling proteins that regulate
 pigmentation resulting from our new analyses and test whether and how they influence MC1R signaling.

## Key facts

- **NIH application ID:** 10148642
- **Project number:** 5R01AR076241-02
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Michael S Marks
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,076,608
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148642

## Citation

> US National Institutes of Health, RePORTER application 10148642, Genetic and molecular basis for variation in human skin pigmentation (5R01AR076241-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10148642. Licensed CC0.

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