@@ One more human skin color variation gene found @@

Pennsylvania State University
December 16, 2005

Fish gene sheds light on human skin color variation

Megan Walde Manlove
mmanlove[AT]hmc.psu.edu

University Park, Pennsylvania -- With help from a common aquarium pet and a recently
released online database of human genetic variation, a collaborative team of Penn
State researchers has found what could be the most important skin color gene
identified to date.

The team, led by cancer geneticist Keith Cheng
(http://www.hmc.psu.edu/pathology/residency/experimental/cheng.htm), in collaboration
with anthropologist Mark Shriver (http://www.anthro.psu.edu/shriver.html), found that
a change in just one amino acid in one gene plays a major role in determining why
people of European descent have lighter skin than people of African descent.

The find could lead to further research using the protein coded by the pigmentation
gene as a target for treatment of malignant melanoma, the most deadly form of skin
cancer, as well as to research on ways to modify skin color without damaging it by
tanning or using harsh chemical lighteners.

The findings will be published as the cover story
(http://www.sciencemag.org/content/vol310/issue5755/cover.dtl) in the December 16
edition of Science magazine. [SLC24A5, a Putative Cation Exchanger, Affects
Pigmentation in Zebrafish and Humans]

The genetic determination of human skin color is one of biology's enduring mysteries.

Previous studies on pigmentation have identified more than 100 genes involved in
pigment production. Alterations in some of these genes are associated with disorders
such as albinism, which causes very light skin, but also vision problems. However,
most of the genes responsible for normal differences in skin pigmentation remained
unknown. The gene identified by Cheng's team -- called SLC24A5 -- previously had not
been suspected to be involved in pigmentation.

The pigmentation discovery was an unexpected offshoot of cancer research Cheng began
a decade ago using zebrafish, a common aquarium pet that is widely used as a model
organism for studying the genetics of development. The zebrafish reproduces rapidly,
and many of its genes are similar to humans, which makes it a good model for studying
genetic alterations and their roles in cancer, Cheng said.

The similarities between fish and humans extend to the pigment cells, which contain
pigment granules called melanosomes. In people of European descent, the melanosomes
are fewer, smaller, and lighter than those from people of West African ancestry,
while the melanosomes of East Asians show intermediate properties. Cheng's team found
that a zebrafish variant called "golden" also had fewer, smaller and less-heavily
pigmented melanosomes than normal fish.

This clue suggested the gene mechanisms responsible for the change in zebrafish also
might be involved in variation in human skin color.

The researchers found that the lighter pigmentation of golden zebrafish is caused by
a mutation that cuts short a certain protein -- referred to as SLC24A5. Adding the
normal zebrafish protein to the golden version resulted in fish with darker coloring.

Victor Canfield (http://fred.hmc.psu.edu/ds/retrieve/fred/investigator/vcanfield),
assistant professor of pharmacology in the College of Medicine, found that the
closely related genes were present in all vertebrates. The team asked whether the
human version of the gene also could work in zebrafish and found that it did.

Keith Cheng then sought Mark Shriver's help in determining whether this gene plays a
role in human pigmentation. Shriver's group has been focused for the past eight years
on the evolutionary genetics and physiology of normal variation in human
pigmentation.

The importance of the work extends beyond pigmentation, Cheng and Shriver say.

"We know so little about the genetic and evolutionary architecture of human traits",
said Mark Shriver, associate professor of anthropology. "We can not expect to use
human genetics to understand complex diseases most effectively without first working
out how fundamental characteristics, such as eye, hair and skin color, are
determined".

"Working out the details of pigmentation with help from model systems like zebrafish
is a great paradigm for seeking understanding of diseases such as diabetes or heart
disease", Cheng said.

The team started with the recently released HapMap (http://www.hapmap.org) -- a free
and publicly accessible database of DNA sequence variation in the human genome. When
researchers looked at variations within the human SLC24A5 gene, they found that the
protein specified by the gene was identical in all populations studied, except for
the amino acid at one position. At that position, West Africans and East Asians
shared the same ancestral sequence with other vertebrates, including zebrafish and
chimpanzees. In contrast, all individuals in the European population tested showed a
change in one amino acid.

According to Mark Shriver, the results are indicative of a "selective sweep", which
is a signal of selection for a particular gene variant.

Either a variant is selected for because the trait produced is better suited to the
current environment than other traits and other traits are less capable of competing,
or the variant is sexually selected. Sexual selection occurs because individuals
choose mates with certain characteristics that are more attractive or that indicate
better reproductive potential.

To verify the importance of the amino acid change, Mark Shriver examined the SLC24A5
gene in populations of mixed European and West African ancestry. Individuals with the
European form of SLC24A5 tended to have lighter skin than those with the ancestral
form of the gene. Those findings suggested that this variation contributes between
25% and 38% of the range of skin color in this population.

The team speculates that well-known variations in European eye and hair color may
have been made possible by the alteration in SLC24A5. However, they say that the
patterns of DNA variation indicate that the lighter skin color of East Asians is due
to variation in genes that have yet to be identified.

Scientists have long hypothesized that decreased skin pigmentation was an adaptive
change that made it possible for humans to live outside the tropics, since sunlight
is essential to generate the vitamin D required to prevent rickets, a condition
causing bones to become weak. Team members suggest that the gene they have identified
played an important role in that adaptation in Europeans.
http://live.psu.edu/story/15166

Related:

The Scientist: Gene implicated in human pigment variation
http://www.the-scientist.com/news/20051216/01

Professor John Hawks blog: Hunting the genes of the golden zebrafish
http://johnhawks.net/weblog/reviews/genetics/populations/lamason_2005_slc24a5_skin_color.html

Gene Expression blog: Race is skin deep
http://www.gnxp.com/blog/2005/12/race-is-skin-deep.php


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