Re: Why do Caucasians have the color variations in their hair?
From: Michael Ragland (ragland37_at_webtv.net)
Date: 10/06/04
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Date: Wed, 6 Oct 2004 15:38:07 +0000 (UTC)
If it were solely from climate, wouldnt some Asian cultures also have
groups of people with natural blond or red hair?? Anybody know if any
study has been done on this, any ideas? Any insight would be greatly
appreciated.
Aquatic Dubmonkey
Here are two articles. It is complicated subject.
Cell Research, (2001); 11(1):81-84
Melanocortin-1 receptor gene variants in four Chinese ethnic populations
SHI Peng, Xue Mei LU, Huai Rong LUO, Jin-Gong XIANG-YU, Ya Ping ZHANG*
Laboratory of Cellular and Molecular Evolution, Kunming Institute of
Zoology, the Chinese Academy of Sciences, Kunming 650223, China
ABSTRACT
There is strong relationship between melanocortin-1 receptor
(MC1R) gene variants and human hair color and skin type. Based on a
sequencing study of MC1R gene in 50 individuals from the Uygur, Tibetan,
Wa and Dai ethnic populations, we discuss the occurrence of 7 mc1r
variants consisting of 5 nonsynonymous sites (Val60Leu, Arg67Gln,
Val92Met, Arg163Gln and Ala299Val) and 2 synonymous sites (C414T and
A942G), among which C414T and Ala299Val were reported for the first
time. Confirmation and analysis were also made of 122 individuals at
three common point mutations (Val92Met, Arg163Gln, A942G) using
PCR-SSCP. The frequency of Arg163Gln variant varies in the four ethnic
populations, with percentage of 40%, 85.0%, 66.2% and 72.7%,
respectively, while those of Val92Met and A942G are roughly similar in
these four populations. The different environments, migration and
admixture of various ethnic groups in China might have impact on the
observed frequency of Arg163Gln.
Key words: MC1R gene, ethnic populations, nonsynonymous site, synonymous
site.
INTRODUCTION
The variation in human hair and skin color in different
geographic regions of the world is the result of differences in two
principal forms of melanin, the red-yellow phaeomelanins and the
black-brown eumelanins, which are present in the epidermal layer of
human skin and hair[1],[2]. The type of melanin produced is under the
control of two genes, identified initially by the mouse mutation,
extension and agouti. The extension gene is expressed in melanocytes,
producing the melanocyte stimulating hormone receptor (MSHR) or
melanocortin-1 receptor ( MC1R)[3],[4]. The human MC1R gene, homologous
to the mouse extension locus, was cloned[3],[5],[6], located to
chromosome 16q24[7] and shown to encode the MC1R protein. Expressed on
cutaneous melanocytes[3], MC1R is a seven transmembrane domain G
protein-coupled receptor of 317 amino acids belonging to the melanocotin
receptor subfamily and has high binding affinity for MSH and ACTH[8, 9].
In addition, some other studies show that MC1R variants are associated
with the coat colors in cattle[10],[11], fox[12], and horse[13].
Studies of MC1R polymorphism have been made in European,
African and Asian populations. Valverde et al[14], Box et al[15] and
Smith et al[16] reported 18 variants of MC1R in red hair/fair skin
individuals. In a recent study by Rana et al[4], Africans were reported
to be lack of variation while six variants were found in Asian
populations. However, little is known about the variants of MC1R gene in
Chinese populations, let alone data in Chinese ethnic populations. In
this paper we examined the polymorphism of the human MC1R gene in four
Chinese ethnic populations.
SAMPLES AND METHODS
Human samples
A total of 122 individuals from 4 Chinese ethnic populations
(35 Uygur from Xinjiang Province, 20 Tibetans from Qinghai Province, 34
Was and 33 Dais from Yunnan Province.) volunteered as samples for the
study. Genetically, none of them was known to be related to any other
volunteer and all of their parents and grandparents were descendants of
the mentioned nationality.
Amplification and sequencing
Genomic DNA from blood was amplified by PCR to obtain the
entire coding region of human MC1R gene according to Rana et al[4]. PCR
products were purified with gel extraction kits (Watson BioMedicals,
Inc.) and sequenced with an Applied Biosystem ABI 377 sequencer (PE
Biosystems) using BigDyeTM Terminator Cycle Sequencing Kit
(Perkin-Elmer) under the manufacturer's instructions.
Identification of variants
Both sequencing and SSCP (single-strand conformation
polymorphism) analysis were used to identify the MC1R variants. In our
preliminary study, 10 Dais, 15 Tibetans, 15 Uygurs and 10 Was were
sampled randomly for sequencing. Three variants (Val92Met, Arg163Gln and
A942G) were chosen for PCR-SSCP analysis and gene frequency calculation
in 122 individuals. PCR-SSCP was performed with three sets of primers to
yield three 200-300bp products using the method in reference[17].
Calculation of allele frequency
The mathematical equations of the allele frequencies and the
genotype are given by:
p=(2NAA+NAa)/2N q=(2Naa+NAa)/2N.
In which p and q are the allele frequencies of A and a; NAA, NAa and Naa
are the numbers of AA (wild-genotype), Aa (heterozygous
variant-genotype) and aa (homozygous variant-genotype).
RESULTS
MC1R variants
The entire coding sequence of the MC1R gene was sequenced in
50 individuals from the Urgur, Tibeten, Dai, and Wa nationalities.
Compared to the published sequences[3-6], [18], sequences of our samples
differed from the human consensus sequence at five nonsynonymous sites
(at codon 60, 67, 92, 163 and 299) and at two synonymous sites (at
nucleotide 414 and 942) (Tab 1). In the previous study of MC1R variants,
Val92Met and Val60Leu were reported to be frequent in the red hair/fair
skin samples[14]. In this study, heterozygous Val60Leu was found only in
one Uygur individual; whereas the Val92Met variant was found in Uygur,
Dai, Wa ethnic populations, but no homozygote in Tibetan. Furthermore,
the Val92Met variant always went with the A942G variant in our samples.
The number of individual alleles genotype: AA=homozy- gous wild-type,
Aa=heterozygous variant, aa=homozygous variant.
bp represents the frequency of the A allele; q represents the frequency
of the a allele
Rana et al[4] reported the Arg163Gln variant to be associated
with the East and Southeast Asian populations. In this study, a very
common Arg163Gln variant was also found in the four ethnic groups
concerned, including 21 of 35 Uygurs, 19 of 20 Tibetans, 29 of 34 Was
and 27 of 33 Dais. The Arg67Gln/Arg163 variant in one Dai individual was
also observed in other East and Southeast Asian populations (Rana et al,
1999), which is a combination of the Arg163Gln variant. Besides,
one synonymous mutation and one nonsynonymous mutation were
first found in Uygur (C414T and Ala299Val).
Gene frequency
The PCR-SSCP analysis was used to genotype the three variants,
Val92Met, Arg163Gln and A942G in 122 individuals. The gene frequency of
the Arg163Gln variant was found to be significantly different in the
four ethnic groups, with the highest (85.0%) in Tibetan, the lowest
(40%) in Uygur, and the intermediate in Dai (72.7%) and Wa (66.2%). The
gene frequency of the Val92Met differed in the Dai (31. 8%), the
Tibetans (10%), the Wa (11.8%) and the Uygur (11.4%). The A942G and
Val92Met variant gene frequency for each of the four ethnic groups
remained roughly similar, as listed in Tab 2. Hardy-Weinberg equilibrium
was not rejected in all these ethnic groups (Data not shown).
DISCUSSION
MC1R is a regulator of eumelanin and phaeomelanin production,
and its mutations might cause the changes in human hair and skin
color[1],[2].
Three alleles (Arg151Cys, Arg160Trp and Asp294His) that are
associated with red hair/fair skin phenotype have been reported in
European individuals[5],[16]. Recently, Franderberg et al[19] found new
evidence that the Arg151Cys mutation of MC1R can cause the synthesis of
the red pigment. This evidence explains why the red hair person carries
the Arg151Cys mutation. The Arg163Gln variant is present with relatively
high frequency in the East and Southeast Asian populations[4],[20]. In
consistent with those reports, our result shows a very common Arg163Gln
variant in the four ethnic groups. It might suggest that the Arg163Gln
polymorphism is associated with phaemomelanin-rich skin. But further
functional study is required to confirm our expectation.
The Arg163Gln variant is found in American Indians as well as
in East and Southeast Asian populations, while the allele appears at a
very low frequency or even disappears in both Europeans and Africans.
Rana et al[4] considered that the allele has increased rapidly in
frequency in East Asians by positive Darwinian selection. We suggest
that the random genetic drift, migration and the admixture of various
ethnic groups might have impact on the frequency of the Arg163Gln
variant in different populations. Firstly, the highest frequency and the
most homozygous state in Tibetans might arise from genetic drift and
little possibility of gene flows among different ethnic groups. The
positive Darwinian selection is also a possible explanation. Secondly,
the lowest frequency in Uygurs might be the result of their genetic
admixture with Caucasians. This assumption can be further supported by
results from other reports[17],[22]. On the other hand, considering the
genetic admixture, it is explicable that an European specific allele,
Val60Leu, is present in one Uygur individual. Lastly, the similar
frequencies in the Dai and the Wa might be explained by their similar
geographic locations and living environments.
Tab 2 shows that the gene frequency of A942G in the Dai and
the Wa originating in southern China is 20% and the frequency in the
Tibetan and the Uygur is 10% and 12%, respectively; whereas Rana et
al[4] reported a 42% gene frequency in the Africans, 23% in east and
southeast Asians and the absence in American Indians. It seems that the
gene frequency of A942G decreases with increasing latitude.
Nevertheless, more data are needed to examine this possibility.
In addition to the three variants (Val92Met, Arg163Gln and
A942G), two new mutations are found in two Uygur individuals, one with
C414T in homozygous state and the other with Ala299Val in heterozygous
state. The occurrence of two new mutations and the question whether the
differences can suggest the genetic divergences in these four ethnic
groups or not, require further investigation.
ACKNOWLEDGMENTS
We are grateful to Prof. Wen Hsiung LI for his constructive
suggestions; to Yong Gang YAO for discussion; to Prof. JL REES for help.
This work was supported by Natural Sciences Foundation of China, the
Chinese Academy of Sciences and NSF of Yunnan Province to Ya Ping ZHANG.
References
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eumelani is present in human epidermis. J Invest Dermator 1991;
97:340-4.
[2] Prota G. Recent advance in the chemistry of melanogenesis in
mammals. J Invest Dermatol 1980; 75:122-7.
[3] Mountjoy KG, Robbins LS, MT Nortrud, Cone RD. The cloning of a
family of genes that encode the melanocortin receptors. Science 1992;
257:1248-51.
[4] Rana BK, Hewett- Emmett D, Jin L et al. High polymorphism at the
human melanocortin 1 receptor locus. Genetics 1999; 151:1547-7.
[5] Chhajlani V, Wiaberg JES. Molecular cloning and expression of the
human melanocyte stimulating hormone receptor cDNA. FEBS Lett 1992;
309:417-20.
[6] Gantz I, Konda Y, Tashiro T et al. Molecular cloning of a novel
melanocortin receptor. J Biol Chem 1993; 268:8246-50.
[7] Magenis RE, Smith L, Nadeau JH et al. Mapping of the ACTH, MSH, and
neural (MC3 and MC4) melanocortin receptors in the mouse and human. Mamm
Genome 1994; 5:503-8.
[8] Robbins LS, Nadeau JH, Johnson KR et al. Pigmentation phenotypes of
variant extension locus alleles result from point mutations that alter
MSH receptor function. Cell 1993; 72:827-34.
[9] Mountjoy KG. The human melanocyte stimulating hormone receptor has
evolved to become ``super-sensitive" to melanocortin peptides. Mol Cell
Endocrinol 1994; 102:R7-11.
[10] Klungland H, Vieira WD, Gomez-Raya L, Adalsteinsson S, Lien S. The
role of melanocyte stimulating hormone (MSH) receptor in bovine coat
color determination. Mamm Genome 1995; 6:636-9.
[11] Joerg H, Fries HR, E Meijernik, Stranzinger GF. Red coat color in
holstein cattle is associated with a deletion in the MSHR gene. Mamm
Genome 1996; 7:317-9.
[12] Vage DG, Lu D, Klungland H et al. A non-epistatic interaction of
agouti and extension in the fox, Vulpes vulpes. Nat Genet 1997;
15:311-5.
[13] Johansson M, Marklund L, Sandber GK, Andersson L. Cosegregation
between the chestnut coat colour in horses and polymorphisms at the
melanocyte-stumulation hormone (MSH) receptor locus. Anim Genet 1994;
25:35.
[14] Valverde P, Healy E, Jackson I, Rees JL, Thody AJ. Variants of the
melanocyte stimulating hormone receptor gene are associated with red
hair and fair skin in humans. Nat Genet 1995; 11:328-30.
[15] Box NF, Wyeth JR, O'Gorman LE et al. Characterization of melanocye
stimulating hormone receptor variant alleles in twins with red hair. Hum
Mol Genet 1997; 11:1891-7.
[16] Smith R, Healy E, Siddiqui S et al. Melanocortin 1 receptor
variants in an Irish population. J Invest Dermatology 1998; 111:119-22.
[17] Yao Y-G, LU X-M, Luo H-R, Li W-H, Zhang Y-P. Gene admixture in the
Silk Road region of China -evidence from mtDNA and melanocortin 1
receptor polymorphism. Genes and Genetic Systems 2000; 75:173-8.
[18] Cone RD, Lu D, Koppula S et al. The melanocortin receptors:
agonsis, antaagonista, and the hormonal control of pigmentation. Recent
Prog Horm Res 1996; 51:287-318.
[19] Frandberg PA, Doufexis M, Kapas S, et al. Human pigmentation
phenotype: a point mutation generates nonfunctional MSH receptor.
Biochem Biophys Res Commun 1998; 245:490-2.
[20] Harding RM, Healy E, Ray AJ et al. Evidence for variable selective
pressures at MC1R . Am J Hum Genet 2000; 66:1351-61.
[21] Cavalli-Sforz LL, Menozzi P, Piazza A. In: The History and
Geography of Human Genes. Princeton University Press: Princeton
1994:304-8.
[22] Chen RB, Ye GY, Geng, ZC et al. Revelation of the origin of Chinese
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Genetica Sinica 1993; 20(5):389-93.
¡¡
*Corresponding author: Ya Ping ZHANG, Tel: 0871-5198993
Fax: 0871-5195430, E-mail: zhangyp@public.km.yn.cn
Received May-31-2000 Revised Oct-23-2000 Accepted Jan-9-2001
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August 19, 2003
Hair color
I spent a little time doing research on hair color in PubMED and many of
the leads seem to end up at the Melanocortin 1 receptor (MC1R). This is
what I was curious about, is the "recessive" vs. "dominant" dichotomy
illustrated in blonde & brunette inheritance patterns among whites that
is taught in introductory high school genetics just an illusion? This is
why I ask: most of the children who I have seen who have a non-white
black-haired parent and a blonde white parent do not have black hair,
rather, their hair tends to be dark brown on average, though sometimes
you will see someone with auburn hair. Quite often the children might
even be blonde as infants [1].
My question, is there a clear way to measure the amount of melanin
present in hair that can be quantitized? I assume there is-though
unfortunately I don't have the time to do any more googling on this
topic (so someone can hopefully comment on how this is done). And would
one find that the children of two individuals who have extreme
phenotypes would have values that show that hair color is a continuous,
rather than discrete, trait? [2] I wonder if in fact some brown-haired
Eurasians may have melanin levels somewhere between their blonde white
parent and black-haired Asian parent, but are classified with the latter
because of the dichotomy that our classification system imposes.
Here is an excerpt from the abstract of one of the articles I found:
Recent work suggests that the MC1R also shows a clear heterozygote
effect on skin type, with up to 30% of the population harbouring
loss-of-function mutations....In particular, study of the MC1R may
provide insights into the lightening of skin colour observed in most
European populations. The world wide pattern of MC1R diversity is
compatible with functional constraint operating in Africa, whereas the
greater allelic diversity seen in non-African populations is consistent
with neutral predictions rather than selection....
Here is another abstract snippet:
We found variation at five nonsynonymous sites...but at only one
synonymous site (A942G)...The Arg163Gln variant is absent in the
Africans studied, almost absent in Europeans, and at a low frequency
(7%) in Indians, but is at an exceptionally high frequency (70%) in East
and Southeast Asians...the nucleotide diversity at the MC1R locus is
shown to be several times higher than the average nucleotide diversity
in human populations, possibly due to diversifying selection.
Here are some related articles-I haven't had time to sort through all of
this. Also, I found that the journal GENETICS seems to offer full access
for articles before June of 2003 in their archives.
Update:
Why Humans and Their Fur Parted Ways shouts the headline in The New York
Times. Turns out our friend, the MC1R gene, shows up again. Dr. Mark
Stoneking conjectures that the version of MC1R that produces dark skin
among African people must have swept through the human population after
we lost our fur. He notes chimpanzees are relatively light-skinned and
tan on their faces as they age. Stoneking found that the version of MC1R
that causes dark skin became dominant in Africa about 1.2 million years
ago, ergo, that is when humans lost their fur. Furthermore, Stoneking
hypothesizes that the reason humans lost their fur is to avoid parasitic
infestation. He caps his theory off with the assertion that humans have
only been clothed for 50,000 years because that is the point of
divergence between the human body louse (which resides in clothing) and
the chimpanzee louse-which dovetails well with the "cultural explosion"
that putatively occurred at that time, The Great Leap that some
palaeoanthropologists speak of.
[1] Bruce Lee would joke to his wife that his son Brandon, who was
dark-haired as an adult, was the "first blonde Chinamen" when he was an
infant.
[2] After I re-read this sentence, it seemed stupid, of course hair
color is a continuous trait to some extent (ah, weasel words, I know),
but our terminology tends to shoe-horn it into discrete classes,
sometimes ones that don't map well onto reality ("Hung-Mao" = "Red
Haired Folk", in other words, Europoid, but most Europeans don't have
red hair). But what I am more interested in is how the genes interact
and express the phenotype, and whether those that effect hair color (and
other pigmentation), are additive, assuming it is a polygenic (multiple
genes effect it) trait. Additionally, I have read that MC1R is
pleiotropic, it is a multi-functional spot in the genome. Getting
complicated....
Posted by razib at 03:48 PM
Comment (0)
I read something about this online not long ago (of intermediate
complexity) - my vague memory of it was that there were four sites where
mc1r could be expressed and one additional one for the redhead mutation,
and each of these five could be hetero or homozygous. The amount of hair
pigment depended on the number of functional pigment genes... so if you
had a very simple model where a given allele of mc1r either produced
eumelanin or didn't, you'd still have anywhere from zero to eight
functioning copies of the gene with a light-to-dark coloration spectrum.
So blondeness involves having just a few (zero to two? I don't know)
functioning mc1r genes. The redheadedness is independent but of course
can't be seen if too much eumelanin is present, so for redheadedness you
need both blondeness (few functional eumelanin genes) and either one or
two phomelanin (red pigment) genes, resulting in either reddish hair or
really red hair.
Of course as you point out it's much more complicated due to the
profusion of alleles - I think asians have a different set of mc1r
alleles than westerners.
One final point: even though hair color is not really mendelian, the
greater blondeness of children would support the illusion that it is. If
both parents have a small number of eumelanin-producing genes (are
blond), the child could end up with more than either and have darker
hair in adulthood. But it would be very unlikely that his hair would be
darker as a child.
Posted by: bbartlog at August 19, 2003 05:44 PM
Interesting - so we can figure out when humans lost their fur from the
diversity of the mc1r gene. Pretty neat! Stoneking's notion that this
happened as a way of dealing with parasites is plausible. But if you're
a fan of Leakey's 'man the cursorial hunter' idea, then I think another
hypothesis presents itself, namely that we would have lost our fur in
order to sweat more efficiently.
"It's uncertain whether intelligence has any long term survival value.
Bacteria do quite well without it."
Stephen Hawking
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