Genetic Variant Linked To Freckling, Sun Sensitivity Discovered

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April Flowers
for – Your Universe Online

A genomic variant strongly associated with sensitivity to the sun, brown hair, blue eyes and freckles has been identified by a new study.
Researchers studying Icelanders discovered 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 findings were published in a recent issue of the journal Cell.
People with ancestors from geographic locations farther from the equator, such as Iceland, are more likely to have less pigmentation in their skin, hair and eyes. A reduction in pigment makes individuals more sensitive to the sun, but allows them to more easily draw upon sunlight to generate vitamin D3, which is essential for healthy bones.
The international research team — including scientists from the National Human Genome Research Institute (NHGRI), a part of the National Institutes of Health (NIH) — analyzed data from a genome-wide association study (GWAS) of 2,230 Icelanders. Hundreds of thousands of common differences across individuals’ DNA are compared during a GWAS 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, MD, PhD.  “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 data helped the team to focus on the interferon regulatory factor 4 (IRF4) that had previously been associated with immunity. The production of interferons — proteins that fight off viruses or harmful bacteria — is spurred by a protein generated by IRF4. Genomic databases revealed 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. An association between the IRF4 gene and the pigmentation trait was established by the current study results.
“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, PhD, 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.”
Millions of variants were revealed among the individuals in the Icelandic GWAS. To make the study more manageable, the researchers narrowed their focus to 16,280 variants located in the region around the IRF4 gene, then they used an automated fine-mapping process to explore the set of variants in IRF4 in 95,085 people from Iceland. The automated process uses a silicon chip that enables a large number of variants to be included in the analysis.
The new data allowed the researchers to discover a variant in a non-coding, enhancer region which regulates IRF4 that is associated with the combined trait of sunlight sensitivity, brown hair, blue eyes and freckles — placing IRF4 among more than 30 genes now associated with pigmentation. This group includes a gene variant previously found in people with freckles and red hair.
The NHGRI researchers studied the IRF4’s role in the pigment-related regulatory pathway. Using cell-culture studies and tests in mice and zebrafish, they demonstrated 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. MITF activates expression of IRF4, but only in the presence of the TFAP2A transcription factor. A higher production of the pigment melanin in melanocytes is caused by a greater expression of tyrosinase.
“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, PhD, from Johns Hopkins University and collaborator with the NHGRI group.
The new variant acts like a dimmer switch for pigment production. When the switch in the IRF enhancer is in the “on” position, more pigment is produced. Melanin pigment is transferred from melanocytes to keratinocytes — a type of skin cell near the surface of the skin — where it protects the skin from UV radiation in sunlight.
If the switch in the IRF4 enhancer is turned “off,” as is the case in the newly discovered variant, the pathway is less effective and the expression of tyrosinase and melanin production is reduced. The researchers haven’t isolated the exact mechanism that generates freckling yet, but Dr. Pavan suggests that epigenetic variation — a layer of instructions in addition to sequence variation — may play a role in the freckling trait.
The researchers say more investigation 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.