Corporate Banner
Satellite Banner
Scientific Communities
Become a Member | Sign in
Home>News>This Article

Researchers Identify Genomic Variant Associated with Sun Sensitivity, Freckles

Published: Tuesday, November 26, 2013
Last Updated: Monday, November 25, 2013
Bookmark and Share
NIH-funded work finds genetic switch for pigmentation trait in non-coding, regulatory region of newly associated gene.

Researchers have identified a genomic variant strongly associated with sensitivity to the sun, brown hair, blue eyes - and freckles. In the study of Icelanders the researchers uncovered an intricate pathway involving the interspersed DNA sequence, or non-coding region, of a gene that is among a few dozen that are associated with human pigmentation traits.

The study by an international team including researchers from the National Institutes of Health was reported in the Nov. 21, 2013, online edition of the journal Cell.

It is more common to find people with ancestors from geographic locations farther from the equator, such as Iceland, who have less pigment in their skin, hair and eyes.

People with reduced pigment are more sensitive to the sun, but can more easily draw upon sunlight to generate vitamin D3, a nutrient essential for healthy bones.

The researchers, including scientists from the National Human Genome Research Institute (NHGRI), a part of NIH, analyzed data from a genome-wide association study (GWAS) of 2,230 Icelanders. A GWAS compares hundreds of thousands of common differences across individuals' DNA to see if any of those variants are associated with a known trait.

"Genes involved in skin pigmentation also have important roles in human health and disease," said NHGRI Scientific Director Dan Kastner, M.D., Ph.D. "This study explains a complex molecular pathway that may also contribute insights into skin diseases, such as melanoma, which is caused by the interaction of genetic susceptibility with environmental factors."

The GWAS led the researchers to focus on the interferon regulatory factor 4 (IRF4) gene, previously associated with immunity. IRF4 makes a protein that spurs production of interferons, proteins that fight off viruses or harmful bacteria.

The researchers noted from genomic databases that the IRF4 gene is expressed at high levels only in lymphocytes, a type of white blood cell important in the immune system, and in melanocytes, specialized skin cells that make the pigment melanin. The new study established an association between the IRF4 gene and the pigmentation trait.

"Genome-wide association studies are uncovering many genomic variants that are associated with human traits and most of them are found in non-protein-coding regions of the genome," said William Pavan, Ph.D., co-author and senior investigator, Genetic Disease Research Branch, NHGRI. "Exploring the biological pathways and molecular mechanisms that involve variants in these under-explored portions of the genome is a challenging part of our work. This is one of a few cases where scientists have been able to associate a variant in a non-coding genomic region with a functional mechanism."

The Icelandic GWAS yielded millions of variants among individuals in the study. The researchers narrowed their study to 16,280 variants located in the region around the IRF4 gene. Next, they used an automated fine-mapping process to explore the set of variants in IRF4 in 95,085 people from Iceland. A silicon chip used in the automated process enables a large number of variants to be included in the analysis.

The data revealed that a variant in a non-coding, enhancer region that regulates the IRF4 gene is associated with the combined trait of sunlight sensitivity, brown hair, blue eyes and freckles. The finding places IRF4 among more than 30 genes now associated with pigmentation, including a gene variant previously found in people with freckles and red hair.

Part of the research team, including the NHGRI co-authors, studied the IRF4's role in the pigment-related regulatory pathway. They demonstrated through cell - culture studies and tests in mice and zebrafish that two transcription factors - proteins that turn genes on or off-interact in the gene pathway with IRF4, ultimately activating expression of an enzyme called tyrosinase.

One of the pathway transcription factors, MITF, is known as the melanocyte master regulator. It activates expression of IRF4, but only in the presence of the TFAP2A transcription factor. A greater expression of tyrosinase yields a higher production of the pigment melanin in melanocytes.

"This non-coding sequence harboring the variant displayed many hallmarks of having a function and being involved in gene regulation within melanocyte populations," said Andy McCallion, Ph.D., a co-author at Johns Hopkins University, Baltimore, and collaborator with the NHGRI group.

The newly discovered variant acts like a dimmer switch. When the switch in the IRF4 enhancer is in the on position, ample pigment is made. Melanin pigment gets transferred from melanocytes to keratinocytes, a type of skin cell near the surface of the skin, and protects the skin from UV radiation in sunlight.

If the switch is turned down, as is the case when it contains the discovered variant, the pathway is less effective, resulting in reduced expression of tyrosinase and melanin production. The exact mechanism that generates freckling is not yet known, but Dr. Pavan suggests that epigenetic variation-a layer of instructions in addition to sequence variation-may play a role in the freckling trait.

More research is needed to determine the mechanism by which IRF4 is involved in how melanocytes respond to UV damage, which can induce freckling and is linked to melanoma, the type of skin cancer associated with the highest mortality.

Further Information

Join For Free

Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 3,500+ scientific posters on ePosters
  • More Than 5,100+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Structure of Primary Cannabinoid Receptor is Revealed
The findings provide key insights into how natural and synthetic cannabinoids including tetrahydrocannabinol —a primary chemical in marijuana—bind at the CB1 receptor to produce their effects.
Friday, October 21, 2016
NIH Study Determines Key Differences between Allergic and Non-Allergic Dust Mite Proteins
Researchers at NIH have uncovered factors that lead to the development of dust mite allergy and assist in the design of better allergy therapies.
Thursday, October 20, 2016
NIH Contributes to Global Effort to Prevent and Manage Lung Diseases
The large scale trial will measure health benefits of clean cookstoves.
Thursday, October 20, 2016
Untangling Cause Of Memory Loss In Neurodegenerative Diseases
NIH-funded mouse study identifies a possible therapeutic target for a family of disorders.
Tuesday, October 18, 2016
NIH Scientists Uncover Genetic Explanation for Frustrating Syndrome
Researchers at NIH have suggested that the multiple alpha tryptase gene copies might underlie health issues that affect a substantial number of people.
Tuesday, October 18, 2016
Scientists at NIH and Emory Achieve Sustained SIV Remission in Monkeys
The finding suggest that the immune systems of these animals are controlling SIV replication in the absence of antiretroviral therapy.
Friday, October 14, 2016
Untangling a Cause of Memory Loss in Neurodegenerative Diseases
The mouse study identifies a possible therapeutic target for a family of disorders.
Thursday, October 13, 2016
Visual Cortex Plays Role in Plasticity of Eye Movement Reflex
Researchers at NIH have found that the visual cortex region of the brain known to process sensory information plays a vital role in promoting the plasticity of innate, spontaneous eye movements.
Thursday, October 13, 2016
NIH Commits $6.7 M to Advance DNA, RNA Sequencing Technology
"Can you believe they make DNA sequencers the size of staplers?" asked Meni Wanunu, Ph.D. "Ideas that were crazy twenty years ago are now happening!"
Friday, October 07, 2016
Cone Snail Venom Reveals Insulin Insights
Researchers found that a fast-acting insulin from the cone snail can bind and activate the human insulin receptor.
Wednesday, October 05, 2016
DNA Vaccines Protect Monkeys Against Zika Virus
Two experimental Zika virus DNA vaccines developed by NIH scientists protected monkeys against Zika infection.
Wednesday, October 05, 2016
Targeting Cardiovascular Disease Risk Factors May be Important Across a Lifetime
The study suggests efforts to prevent risk factors should extend to those older than 65.
Tuesday, October 04, 2016
Researchers Find a Gap in the Brain’s Firewall Against Parkinson’s Disease
Researchers at NIH have found mouse study that identified a key player in the progression of the disorder.
Saturday, October 01, 2016
Drug to Treat Alcohol Use Disorder Shows Promise Among Drinkers With High Stress
The findings suggest that potential future studies with drugs targeting vasopressin blockade should focus on populations of people with AUD who also report high levels of stress.
Friday, September 30, 2016
Monkeys Protected by Zika DNA Vaccine
Experimental Zika virus DNA vaccines successfully protected monkeys against Zika infection.
Thursday, September 29, 2016
Scientific News
Integrated Omics Analysis
Studying multi-omics promises to give a more holistic picture of the organism and its place in its ecosystem, however despite the complexities involved those within the field are optimistic.
Unravelling the Role of Key Genes and DNA Methylation in Blood Cell Malignancies
Researchers from the University of Nebraska Medical Center have demonstrated the role of Dnmt3a in safeguarding normal haematopoiesis.
Salford Lung Study - The First Real World Clinical Trial
In this podcast, we learn about the Salford Lung Study and its potential to revolutionize the way we assess new drugs and treatments around the world.
Point of Care Diagnostics - A Cautious Revolution
Advances in molecular biology, coupled with the miniaturization and improved sensitivity of assays and devices in general, have enabled a new wave of point-of-care (POC) or “bedside” diagnostics.
Mass Spec Technology Drives Innovation Across the Biopharma Workflow
With greater resolving power, analytical speed, and accuracy, new mass spectrometry technology and techniques are infiltrating the biopharmaceuticals workflow.
Structure of Primary Cannabinoid Receptor is Revealed
The findings provide key insights into how natural and synthetic cannabinoids including tetrahydrocannabinol —a primary chemical in marijuana—bind at the CB1 receptor to produce their effects.
Overlooked Molecules Could Revolutionise our Understanding of the Immune System
Researchers have discovered that around one third of all the epitopes displayed for scanning by the immune system are a type known as ‘spliced’ epitopes.
Illumina Contributes to ClinVar Database
The contribution includes variants of all classifications, from pathogenic to benign, identified during interpretation of whole genome sequences generated in the CLIA-certified, CAP-accredited Illumina Clinical Services Laboratory.
Agilent Presents Early Career Professor Award to Dr. Roeland Verhaak
JAX professor recognized for the development and implementation of workflows for the analysis of big-data from transcriptomics to next generation sequencing approaches.
NIH Study Determines Key Differences between Allergic and Non-Allergic Dust Mite Proteins
Researchers at NIH have uncovered factors that lead to the development of dust mite allergy and assist in the design of better allergy therapies.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,500+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
5,100+ scientific videos