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Nicholas Crawford and Sarah Tishkoff at the University of Pennsylvania in Philadelphia recruited around 1500 ethnically and genetically diverse volunteers living in Ethiopia, Tanzania and Botswana for their study. Each person agreed to provide a DNA sample and have their skin pigmentation measured (pictured above).
The combined data allowed the team to find eight sites in the human genome that are particularly associated with the level of skin pigmentation. Together, these sites account for about 30 per cent of the variation they found in skin pigmentation among the volunteers.
For each of the eight sites of variation, there existed a genetic variant associated with paler skin, and a variant linked to darker skin. Seven of the paler skin variants emerged at least 270,000 years ago. Four of these arose more than 900,000 years ago.
Plenty of variation
The latest thinking is that Homo sapiens emerged in Africa about 300,000 years ago. The new findings mean that relatively pale skin tone variants predate the appearance of our species and have been retained in some parts of Africa ever since.
This might surprise some geneticists, says Tishkoff. Previous studies of a skin pigmentation gene called MC1R had led many geneticists to think that dark skin colour – which is thought to protect against UV damage – is a fixed and consistent trait in all people of African descent.
“They thought [MC1R] shows that there has been selection for dark skin in Africa and therefore there’s no variation,” says Tishkoff.
But in retrospect, it’s obvious that the story of skin pigmentation in sub-Saharan Africa is more complicated than that, as there is huge variation in skin colour across the continent today. The San hunter-gatherer populations of southern Africa often have lightly pigmented skin, and belong to one of the most ancient branches of the Homo sapiens family tree.
“I think the most interesting observation is that some ancestral light skin alleles are shared between the San and archaic hominins such as Neanderthals and Denisovans,” says Carles Lalueza-Fox at the Institute of Evolutionary Biology in Barcelona, Spain. “This suggests a shared, common ancestry for this trait before the split of these three hominin lineages.”
Of the darker-skin gene variants, three appear to have evolved from less pigmented variants. This means that some people with particularly dark skin – such as the Nilo-Saharan pastoralists of East Africa – gained the trait relatively recently, from paler-skinned ancestors. “People have thought it was just light skin that has been evolving,” says Tishkoff. “I think dark skin continues to evolve as well.”
No single “African race”
Research into the genetics of skin tone and other traits has a significance beyond understanding our species’ evolutionary history. “There are racists who want to associate skin pigmentation with intellectual traits or traits dealing with moral behaviour,” says Nina Jablonski at Pennsylvania State University.
But there is no justification for white supremacist arguments that people of European descent with typically paler skin are inherently superior or more evolved. “We see these variants associated with whiter skin actually came from Africa,” says Tishkoff.
“There is no homogeneous ‘African race’,” says Tishkoff. In fact, recent surveys of the views of physical anthropologists suggest that most of them flatly reject the idea that humans can be divided into biological races at all.
Journal reference: Science, DOI: 10.1126/science.aan8433
Hum Genet. 2005 Apr;116(5):402-6. doi: 10.1007/s00439-004-1251-2. Epub 2005 Feb 22.
The 8818G allele of the agouti signaling protein (ASIP) gene is ancestral and is associated with darker skin color in African Americans
Carolina Bonilla 1, Lesley-Anne Boxill, Stacey Ann Mc Donald, Tyisha Williams, Nadeje Sylvester, Esteban J Parra, Sonia Dios, Heather L Norton, Mark D Shriver, Rick A Kittles
A single change in an amino acid lowers MC1R’s affinity for α-MSH. The result is the synthesis of the pigment pheomelanin instead of eumelanin and lighter skin. There are many alleles of the MC1R gene. Agouti Signaling Protein (ASIP, coded by the ASIP gene) is an antagonist to MC1R, shutting down the pathway of eumelanin synthesis.
Abstract
Skin color, a predictor of social interactions and risk factor for several types of cancer, is due to two contrasting forms of melanin, the darker eumelanin and lighter phaeomelanin. The lighter pigment phaeomelanin is the product of the antagonistic function of the agouti signaling protein (ASIP) on the alpha-melanocyte stimulating hormone receptor (MC1R). Studies have shown that a single-nucleotide polymorphism (SNP) in the 3'UTR of the ASIP gene is associated with dark hair and eyes; however, little is known about its role in inter-individual variation in skin color. Here we examine the relationship between the ASIP g.8818A>G SNP and skin color (M index) as assessed by reflectometry in 234 African Americans. Analyses of variance (ANOVA) were performed to evaluate the effects of ASIP genotypes, age, individual ancestry, and sex on skin color variation. Significant effects on M index variation were observed for ASIP genotypes (F(2,236)=4.37, P=0.01), ancestry (F(1,243)=37.2, P<0.001), and sex (F(1,244)=4.08, P=0.05). Subsequent analyses revealed a strong effect on M index from ASIP genotypes in African American females (P<0.001). Our study suggests that the ASIP G>A polymorphism exhibits a dominant effect leading to lighter skin color and that variation in the ASIP gene may have been one of several factors contributing to reductions in pigmentation in some populations. Further study is needed to reveal how interactions between ASIP and several other genes, such as MC1R and P, predict human pigmentation.
Introduction
Skin, hair, and eye pigmentation is due to melanin, a
biopolymer produced by cells called melanocytes. Melanin
plays an important role in shielding the body from
ultraviolet (UV) radiation. There are two classes of
melanin: eumelanin, which is associated with brown/
black color, and phaeomelanin, associated with yellow/
red coloration. Tyrosinase is the rate-limiting enzyme
essential for the production of melanin, and the quantity
of melanin synthesized is proportional to the tyrosinase
activity in the cells (Robins 1991). The pathway by
which eumelanin is produced is initiated by the binding
of a-melanocyte stimulating hormone (a-MSH) to the
melanocyte stimulating hormone receptor, also called
melanocortin-1 receptor (MC1R) (MIM 155555). The
binding of a-MSH to its receptor leads to increased
intracellular levels of cyclic adenosine monophosphate
(cAMP), increased expression of tyrosinase (TYR)
(MIM 606933), which catalyzes the hydroxylation of
tyrosine, and the production of eumelanin (Hunt et al.
1994). Phaeomelanin, on the other hand, is stimulated
through the antagonism of a-MSH through MC1R by
the agouti signaling protein (Lu et al. 1994).
In mice, the agouti signaling protein gene (ASP) is
one of the main genes that regulates pigmentation
(Suzuki et al. 1997). Loss of function mutations in mouse
ASP produce eumelanin, while gain of function mutations
lead to phaeomelanin production. A variety of coat
colors in mice appear as a result of these alterations
(Voisey and Van Daal 2002). In humans, the ASPencoding
(MIM 600201) gene, ASIP, homologue to
mouse ASP, is located on chromosome 20q11.2-q12,
and encodes a 132-amino-acid protein (Wilson et al.
1995). Given that ASIP is conserved among species
(Voisey and Van Daal 2002), it is likely that ASIP
contributes to variation in human pigmentation as well.
However, the precise role of ASIP in the human pigmentation
pathway remains to be defined, as few studies
have been conducted to date. A single-nucleotide polymorphism
(SNP) in the 3¢-untranslated region (UTR) of
ASIP (noted as g.8818A>G in the literature, dbSNP#
rs6058017) has been reported to be associated with dark
hair and brown eyes in European Americans (Kanetsky
et al. 2002) and was found to occur at different frequencies
in European Americans, East Asians, African
Americans and West Africans (Zeigler-Johnson et al.
2004). The proposed mechanism of action for the ASIP
SNP involves reduced mRNA stability and premature
degradation of the transcript when the G allele is present.
As a consequence, binding to MC1R is biased towards a-MSH,
leading to eumelanogenesis and
subsequently darker pigmentation (Kanetsky et al. 2002;
Zeigler-Johnson et al. 2004).
Previously, we have reported on the involvement of
two other pigmentation candidate genes, namely TYR
and the P gene (OCA2) (MIM 203200), in skin pigmentation
differences between populations of European
and West African descent (Shriver et al. 2003). To
further explore the genetic contribution to skin color we
examined the relationship between the ASIP 8818G allele and
skin pigmentation in a sample of African
Americans whose skin color was objectively measured
using reflectometry.
The combined data allowed the team to find eight sites in the human genome that are particularly associated with the level of skin pigmentation. Together, these sites account for about 30 per cent of the variation they found in skin pigmentation among the volunteers.
For each of the eight sites of variation, there existed a genetic variant associated with paler skin, and a variant linked to darker skin. Seven of the paler skin variants emerged at least 270,000 years ago. Four of these arose more than 900,000 years ago.
Plenty of variation
The latest thinking is that Homo sapiens emerged in Africa about 300,000 years ago. The new findings mean that relatively pale skin tone variants predate the appearance of our species and have been retained in some parts of Africa ever since.
This might surprise some geneticists, says Tishkoff. Previous studies of a skin pigmentation gene called MC1R had led many geneticists to think that dark skin colour – which is thought to protect against UV damage – is a fixed and consistent trait in all people of African descent.
“They thought [MC1R] shows that there has been selection for dark skin in Africa and therefore there’s no variation,” says Tishkoff.
But in retrospect, it’s obvious that the story of skin pigmentation in sub-Saharan Africa is more complicated than that, as there is huge variation in skin colour across the continent today. The San hunter-gatherer populations of southern Africa often have lightly pigmented skin, and belong to one of the most ancient branches of the Homo sapiens family tree.
“I think the most interesting observation is that some ancestral light skin alleles are shared between the San and archaic hominins such as Neanderthals and Denisovans,” says Carles Lalueza-Fox at the Institute of Evolutionary Biology in Barcelona, Spain. “This suggests a shared, common ancestry for this trait before the split of these three hominin lineages.”
Of the darker-skin gene variants, three appear to have evolved from less pigmented variants. This means that some people with particularly dark skin – such as the Nilo-Saharan pastoralists of East Africa – gained the trait relatively recently, from paler-skinned ancestors. “People have thought it was just light skin that has been evolving,” says Tishkoff. “I think dark skin continues to evolve as well.”
No single “African race”
Research into the genetics of skin tone and other traits has a significance beyond understanding our species’ evolutionary history. “There are racists who want to associate skin pigmentation with intellectual traits or traits dealing with moral behaviour,” says Nina Jablonski at Pennsylvania State University.
But there is no justification for white supremacist arguments that people of European descent with typically paler skin are inherently superior or more evolved. “We see these variants associated with whiter skin actually came from Africa,” says Tishkoff.
“There is no homogeneous ‘African race’,” says Tishkoff. In fact, recent surveys of the views of physical anthropologists suggest that most of them flatly reject the idea that humans can be divided into biological races at all.
Journal reference: Science, DOI: 10.1126/science.aan8433
Hum Genet. 2005 Apr;116(5):402-6. doi: 10.1007/s00439-004-1251-2. Epub 2005 Feb 22.
The 8818G allele of the agouti signaling protein (ASIP) gene is ancestral and is associated with darker skin color in African Americans
Carolina Bonilla 1, Lesley-Anne Boxill, Stacey Ann Mc Donald, Tyisha Williams, Nadeje Sylvester, Esteban J Parra, Sonia Dios, Heather L Norton, Mark D Shriver, Rick A Kittles
A single change in an amino acid lowers MC1R’s affinity for α-MSH. The result is the synthesis of the pigment pheomelanin instead of eumelanin and lighter skin. There are many alleles of the MC1R gene. Agouti Signaling Protein (ASIP, coded by the ASIP gene) is an antagonist to MC1R, shutting down the pathway of eumelanin synthesis.
Abstract
Skin color, a predictor of social interactions and risk factor for several types of cancer, is due to two contrasting forms of melanin, the darker eumelanin and lighter phaeomelanin. The lighter pigment phaeomelanin is the product of the antagonistic function of the agouti signaling protein (ASIP) on the alpha-melanocyte stimulating hormone receptor (MC1R). Studies have shown that a single-nucleotide polymorphism (SNP) in the 3'UTR of the ASIP gene is associated with dark hair and eyes; however, little is known about its role in inter-individual variation in skin color. Here we examine the relationship between the ASIP g.8818A>G SNP and skin color (M index) as assessed by reflectometry in 234 African Americans. Analyses of variance (ANOVA) were performed to evaluate the effects of ASIP genotypes, age, individual ancestry, and sex on skin color variation. Significant effects on M index variation were observed for ASIP genotypes (F(2,236)=4.37, P=0.01), ancestry (F(1,243)=37.2, P<0.001), and sex (F(1,244)=4.08, P=0.05). Subsequent analyses revealed a strong effect on M index from ASIP genotypes in African American females (P<0.001). Our study suggests that the ASIP G>A polymorphism exhibits a dominant effect leading to lighter skin color and that variation in the ASIP gene may have been one of several factors contributing to reductions in pigmentation in some populations. Further study is needed to reveal how interactions between ASIP and several other genes, such as MC1R and P, predict human pigmentation.
Introduction
Skin, hair, and eye pigmentation is due to melanin, a
biopolymer produced by cells called melanocytes. Melanin
plays an important role in shielding the body from
ultraviolet (UV) radiation. There are two classes of
melanin: eumelanin, which is associated with brown/
black color, and phaeomelanin, associated with yellow/
red coloration. Tyrosinase is the rate-limiting enzyme
essential for the production of melanin, and the quantity
of melanin synthesized is proportional to the tyrosinase
activity in the cells (Robins 1991). The pathway by
which eumelanin is produced is initiated by the binding
of a-melanocyte stimulating hormone (a-MSH) to the
melanocyte stimulating hormone receptor, also called
melanocortin-1 receptor (MC1R) (MIM 155555). The
binding of a-MSH to its receptor leads to increased
intracellular levels of cyclic adenosine monophosphate
(cAMP), increased expression of tyrosinase (TYR)
(MIM 606933), which catalyzes the hydroxylation of
tyrosine, and the production of eumelanin (Hunt et al.
1994). Phaeomelanin, on the other hand, is stimulated
through the antagonism of a-MSH through MC1R by
the agouti signaling protein (Lu et al. 1994).
In mice, the agouti signaling protein gene (ASP) is
one of the main genes that regulates pigmentation
(Suzuki et al. 1997). Loss of function mutations in mouse
ASP produce eumelanin, while gain of function mutations
lead to phaeomelanin production. A variety of coat
colors in mice appear as a result of these alterations
(Voisey and Van Daal 2002). In humans, the ASPencoding
(MIM 600201) gene, ASIP, homologue to
mouse ASP, is located on chromosome 20q11.2-q12,
and encodes a 132-amino-acid protein (Wilson et al.
1995). Given that ASIP is conserved among species
(Voisey and Van Daal 2002), it is likely that ASIP
contributes to variation in human pigmentation as well.
However, the precise role of ASIP in the human pigmentation
pathway remains to be defined, as few studies
have been conducted to date. A single-nucleotide polymorphism
(SNP) in the 3¢-untranslated region (UTR) of
ASIP (noted as g.8818A>G in the literature, dbSNP#
rs6058017) has been reported to be associated with dark
hair and brown eyes in European Americans (Kanetsky
et al. 2002) and was found to occur at different frequencies
in European Americans, East Asians, African
Americans and West Africans (Zeigler-Johnson et al.
2004). The proposed mechanism of action for the ASIP
SNP involves reduced mRNA stability and premature
degradation of the transcript when the G allele is present.
As a consequence, binding to MC1R is biased towards a-MSH,
leading to eumelanogenesis and
subsequently darker pigmentation (Kanetsky et al. 2002;
Zeigler-Johnson et al. 2004).
Previously, we have reported on the involvement of
two other pigmentation candidate genes, namely TYR
and the P gene (OCA2) (MIM 203200), in skin pigmentation
differences between populations of European
and West African descent (Shriver et al. 2003). To
further explore the genetic contribution to skin color we
examined the relationship between the ASIP 8818G allele and
skin pigmentation in a sample of African
Americans whose skin color was objectively measured
using reflectometry.