SLC24A5
Encyclopedia
Sodium/potassium/calcium exchanger 5 (NCKX5) also known as solute carrier family 24 member 5 (SLC24A5) is a protein
that in humans is encoded by the SLC24A5 gene
that has a major influence on natural skin colour variation. The NCKX5 protein is a member of the potassium-dependent sodium/calcium exchanger
family. Sequence variation in the SLC24A5 gene, particularly a non-synomyous SNP changing the amino acid
at position 111 in NCKX5 from alanine
to threonine
, has been associated with differences in skin pigmentation
.
on position 21.1, from base pair
46,200,461 to base pair 46,221,881.
protein that is partially localized to the trans-Golgi network
in melanocyte
s. Removal of the NCKX5 protein disrupts melanogenesis in human and mouse melanocytes, causing a significant reduction in melanin
pigment production. Site-directed mutagenesis
corresponding to a non-synonymous single nucleotide polymorphism in SLC24A5 alters a residue in NCKX5 (A111T) that is important for NCKX5 sodium-calcium exchanger activity.
s (pigment cells) in those lighter-skinned fish and lighter-skinned humans (in particular, Europeans). This led Cheng to ask his Pennsylvania State University
colleague, anthropologist Mark D. Shriver
, whether he had human DNA linked to skin color measurements. Shriver, who collaborates internationally to study the basis of variation in human skin color and other features in human populations, pointed to the then-new International HapMap Project
database of genetic variation in human populations, and found that the gene has a single "coding" polymorphism - one that changes an amino acid. The two primary allele
s differ in only one nucleotide
, changing the 111th amino acid
from alanine
to threonine
, abbreviated "A111T".
The threonine allele was present in 98.7 to 100% among several European samples, while the alanine form was found in 93 to 100% of samples of Africans, East Asians and Indigenous Americans. The variation is a SNP
polymorphism rs1426654, which had been previously shown to be second among 3011 tabulated SNPs ranked as ancestry-informative marker
s. Collaborator Victor Canfield plotted the human data to estimate that this single change in SLC24A5 explains between 25 and 38% of the difference in skin melanin
index between peoples of West African vs. European Ancestry.
The discovery of this gene has interesting social implications because the "derived" European allele was derived by mutation from the ancestral gene sequence. As noted by Penn State's Victor Canfield, the ancestral alanine is conserved in all vertebrates sequenced to date, mutant only in the European allele, but only rarely in West African or East Asian (primarily Chinese, Japanese and Korean) populations (presumably by admixture). Furthermore, the European mutation is associated with the largest region of diminished genetic variation in the CEU HapMap population, suggesting the possibility that the A111T mutation may be the subject of the single largest degree of selection in human populations of European ancestry. Selection for the derived allele is based on the need for sunlight to produce the essential nutrient, vitamin D
. In northerly latitudes, there is less sun, greater requirement for body coverage due to colder climate, and frequently, diets poor in vitamin D, making lighter skin necessary for survival. Tests for this variation has obvious application to forensic science.
It has been estimated that the threonine allele became predominant amongst Europeans 5,300 to 6,000 years ago .
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the SLC24A5 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
that has a major influence on natural skin colour variation. The NCKX5 protein is a member of the potassium-dependent sodium/calcium exchanger
Potassium-dependent sodium-calcium exchanger
Potassium-dependent sodium-calcium exchanger also known as solute carrier family 24 is a type of sodium-calcium exchanger that requires potassium to function.- Family members :...
family. Sequence variation in the SLC24A5 gene, particularly a non-synomyous SNP changing the amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
at position 111 in NCKX5 from alanine
Alanine
Alanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...
to threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
, has been associated with differences in skin pigmentation
Human skin color
Human skin color is primarily due to the presence of melanin in the skin. Skin color ranges from almost black to white with a pinkish tinge due to blood vessels underneath. Variation in natural skin color is mainly due to genetics, although the evolutionary causes are not completely certain...
.
Gene
The SLC24A5 gene, in humans, is located on the long (q) arm of chromosome 15Chromosome 15 (human)
right|frame|Human chromosome 15Chromosome 15 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 15 spans about 106 million base pairs and represents between 3% and 3.5% of the total DNA in cells.Identifying genes on each chromosome is an...
on position 21.1, from base pair
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
46,200,461 to base pair 46,221,881.
Protein
NCKX5 is 43 kDaAtomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
protein that is partially localized to the trans-Golgi network
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
in melanocyte
Melanocyte
-External links: - "Eye: fovea, RPE" - "Integument: pigmented skin"...
s. Removal of the NCKX5 protein disrupts melanogenesis in human and mouse melanocytes, causing a significant reduction in melanin
Melanin
Melanin is a pigment that is ubiquitous in nature, being found in most organisms . In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms...
pigment production. Site-directed mutagenesis
Site-directed mutagenesis
Site-directed mutagenesis, also called site-specific mutagenesis or oligonucleotide-directed mutagenesis, is a molecular biology technique in which a mutation is created at a defined site in a DNA molecule. In general, this form of mutagenesis requires that the wild type gene sequence be known...
corresponding to a non-synonymous single nucleotide polymorphism in SLC24A5 alters a residue in NCKX5 (A111T) that is important for NCKX5 sodium-calcium exchanger activity.
Effect on skin color
SLC24A5 appears to have played a key role in the evolution of light skin in humans of European ancestry. The gene's function in pigmentation was discovered in zebrafish as a result of the positional cloning of the gene responsible for the "golden" variety of this common pet store fish. In this work, cancer geneticist Keith Cheng used electron microscopy to probe the cellular mechanism underlying the lighter color of golden zebrafish, and noted a striking similarity between the changes of melanocyteMelanocyte
-External links: - "Eye: fovea, RPE" - "Integument: pigmented skin"...
s (pigment cells) in those lighter-skinned fish and lighter-skinned humans (in particular, Europeans). This led Cheng to ask his Pennsylvania State University
Pennsylvania State University
The Pennsylvania State University, commonly referred to as Penn State or PSU, is a public research university with campuses and facilities throughout the state of Pennsylvania, United States. Founded in 1855, the university has a threefold mission of teaching, research, and public service...
colleague, anthropologist Mark D. Shriver
Mark D. Shriver
Mark D. Shriver is an American population geneticist. His research is focused on admixture mapping, signatures of natural selection, and phenotypic variability in common trait variation. A major goal of his work is to apply these methods and understanding of genomic variation to studies of common...
, whether he had human DNA linked to skin color measurements. Shriver, who collaborates internationally to study the basis of variation in human skin color and other features in human populations, pointed to the then-new International HapMap Project
International HapMap Project
The International HapMap Project is an organization that aims to develop a haplotype map of the human genome, which will describe the common patterns of human genetic variation. HapMap is a key resource for researchers to find genetic variants affecting health, disease and responses to drugs and...
database of genetic variation in human populations, and found that the gene has a single "coding" polymorphism - one that changes an amino acid. The two primary allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
s differ in only one nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
, changing the 111th amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
from alanine
Alanine
Alanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...
to threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
, abbreviated "A111T".
The threonine allele was present in 98.7 to 100% among several European samples, while the alanine form was found in 93 to 100% of samples of Africans, East Asians and Indigenous Americans. The variation is a SNP
Single nucleotide polymorphism
A single-nucleotide polymorphism is a DNA sequence variation occurring when a single nucleotide — A, T, C or G — in the genome differs between members of a biological species or paired chromosomes in an individual...
polymorphism rs1426654, which had been previously shown to be second among 3011 tabulated SNPs ranked as ancestry-informative marker
Ancestry-informative marker
An ancestry-informative marker is a set of polymorphisms for a locus, generally from humans, which exhibits substantially different frequencies between populations from different geographical regions....
s. Collaborator Victor Canfield plotted the human data to estimate that this single change in SLC24A5 explains between 25 and 38% of the difference in skin melanin
Melanin
Melanin is a pigment that is ubiquitous in nature, being found in most organisms . In animals melanin pigments are derivatives of the amino acid tyrosine. The most common form of biological melanin is eumelanin, a brown-black polymer of dihydroxyindole carboxylic acids, and their reduced forms...
index between peoples of West African vs. European Ancestry.
The discovery of this gene has interesting social implications because the "derived" European allele was derived by mutation from the ancestral gene sequence. As noted by Penn State's Victor Canfield, the ancestral alanine is conserved in all vertebrates sequenced to date, mutant only in the European allele, but only rarely in West African or East Asian (primarily Chinese, Japanese and Korean) populations (presumably by admixture). Furthermore, the European mutation is associated with the largest region of diminished genetic variation in the CEU HapMap population, suggesting the possibility that the A111T mutation may be the subject of the single largest degree of selection in human populations of European ancestry. Selection for the derived allele is based on the need for sunlight to produce the essential nutrient, vitamin D
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
. In northerly latitudes, there is less sun, greater requirement for body coverage due to colder climate, and frequently, diets poor in vitamin D, making lighter skin necessary for survival. Tests for this variation has obvious application to forensic science.
It has been estimated that the threonine allele became predominant amongst Europeans 5,300 to 6,000 years ago .