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Population distribution of the human vitamin D binding protein Anthropological considerations.

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AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY 68:107-122 (1985)
Population Distribution of the Human Vitamin D Binding Protein:
Anthropological Considerations
J. CONSTANS, S. HAZOUT, R.M.GARRUTO, D.C. GAJDUSEK,
E.K. SPEES
Centre d’Hkmotypobgie C.N.R.S., CHU Purpan, 31300 Toulouse (J.C.),
AND
Unite de Recherche5 Bwmathkmatiques et Biostatistiques, U.263 INSERM,
Uniuersitk Paris 7, Paris (S. H.), France; National Institutes of Health,
Bethesda (R.M. G., D. C.G.), Diuiswn of Transplantation Surgery, Baltimore
City, Baltimore (E.K.S.)
DBP subtypes, Rare alleles, Worldwide distribution,
KEY WORDS
Migrations, Heterogeneity, Clusters
ABSTRACT
The polymorphism of the serum vitamin D binding rotein
(DBP) in humans is based on the existence of three common alleles, Gclf, Gc”,
and Gc2, and 84 rare alleles. The geographical distribution of GdF, Gc”, and
Gc2 alleles shows north to south clines, together with a balanced equilibrium
between the GclF or GclS allele frequency and the Gc2 frequency.
The distribution of the FSTvalues shows high variability within a geographical area. For European and North Asiatic groups, the FSTvalues are the
lowest observed, and the reason may be a long process of homogenization.
Aboriginal populations from Australia and New Guinea and groups from both
North Africa and South America show the greatest heterogeneity of their
allele frequencies. Systematic factors such as genetic drift and selection may
account for this distribution.
In contrast with the three main DBP alleles, the distribution of the rare
alleles corresponds to patterns of human migrations that occurred during
prehistoric and historic periods. Thus, the rare mutants are of particular
relevance to anthropological and genetical investigations.
The polymorphism of the vitamin D binding protein (DBP) also called group-specific
component, had been restricted to three
phenotypes, Gcl-1, Gc2-1 and Gc2-2, and to
six rare mutants (Constans and Viau, 1977).
The electrophoretic methods used were immunoelectrophoresis, agarose electrophoresis, and immunofixation (Hirschfeld et al.,
1960; Johnson et al., 1975).
In recent years, the electrophoretic procedures employed in the study of protein polymorphism in human groups and animal
species have significantly improved with the
development of the techniques of isoelectric
focusing (IEF on polyacrylamide and agarose
gels) (Righetti, 1979; Radola, 1980). Since its
first description, IEF itself has been improved, and further advances are expected
(Gorg et al., 1983). Despite IEF’s being a n
indispensable tool, such traditional procedures as horizontal or vertical electrophoresis on agarose and polyacrylamide gels are
‘c
1985 ALAN R LISS, INC
still useful for the standardization of new
data, and their use complements IEF (Constans and Cleve, 1979; Cox, 1981). The proteins are known t o differ in charge, conformation, or both, and the charges distributed on the protein surface are those that
contribute the most to electrophoretic mobilities. Detergents, such as urea and SDS, are
now more frequently introduced when studying tissue and serum protein polymorphisms
in order to reveal charge differences concealed by the three-dimensional configuration of the proteins (Aquadro and Avise,
1981).
These different procedures were used in
various combinations when investigating the
polymorphism of the serum DBP in human
populations. In addition to three main alleles, GdF, Gc“, and Gc2, 84 rare mutants
Received August 9, 1983; revised April 3, 1985; accepted April
29, 1985.
108
J. CONSTANS ET AL
were detected and defined (Constans et al.,
1983). This study presents the results of the
analysis of the polymorphism of the serum
DBP determined on more than 9,000 serum
specimens from French, African, Indian,
Asiatic, and Amerindian groups. Unpublished data on western and southern Pacific
regions are also included; altogether 54 populations have been investigated.
am*
m m m
t-t-hrn
0t-e-l
mNNm
000
0000
m
ro
m
ro
N*Ln
m
0
0
t-
*0
9
0
MATERIALS AND METHODS
Electrophoresis in the form of isoelectric
focusing electrophoresis was performed on a
polyacrylamide gel using a 4-6.5 pH range
ampholyte solution, as previously described
(Constans and Viau, 1977). After migration,
the DBP phenotypes were determined using
the technique of print-immunofixation.
The Gc frequences given in this study for
French groups, including a n additional sample of 190 Spanish Basques (Table 1) and
some African populations, were published
elsewhere (Constans et al., 1980al.
The materials are composed of four series.
The first series consisted of a total of 647
sera (Table 2) obtained from the following
groups:
three samples from Africa: (1) Erythreans
(Ethiopia),(2) a Bantu-speaking group from
Cameroon (Bamilikk tribe), and (3) a limited sample of Bushmen from South-Africa;
samples from two tribes living on the
southeast and the west coasts of Malagasy;
and
a sample of blacks from Baltimore,
Maryland.
C
N
z
W
u3*
00
8
88
0
0
t-
*
N
x x
mww
* o w
d
c
met-?
rnrnrod
000
gqgc
oooc
m*m
wt-ma
gwg
The second series included a total of 1,530
sera (Table 3) from the following groups:
one tribe, the Jirel-Sherpa of Nepal;
one sample obtained among the Dogpa tribe
of Tibet;
Tamil individuals living in Pondicherry,
India;
a sample collected from Bangkok blood donors in Thailand;
South Vietnamese refugees sampled a t
random on the occasion of a medical examination for a n epidemiological survey;
a group of refugees belonging to a H’Mong
tribe from Laos; and
the people of the Karangasem community
from Bali.
The third series, a total of 1,870 sera, had
been collected among the following groups:
h
N
25
24
23
21
22
20
19
18
17
15
16
14
13
12
11
10
Algeria
Harratin and
M' Rabtin
(Saoura)
Tuareg
Isseqamaren
(Hoggar)
Mali
Tuareg
Kel-Kummer
(Menaka)
Ethiopia
Erythrean
Djibouti
Afar
Issa
North Yemen:
Bedouins
Iraq:
Kurds
Senegal
Peulh
Fula
Cameron
Bantu
Bamileke
Central Africa
Pygmies
Bi-Aka
Sara
South Africa
Bushmen
Malagasy
West coast
East coast
United States
(Black people, Baltimore)
0.629
31
0.727
0.641
0.667
0.835
291
120
121
126
0.608
0.825
914
123
0.780
0.270
0.224
135
58
357
0.463
0.430
0.500
0.315
0.425
0.083
0.150
0.167
0.306
0.091
0.185
0.077
0.115
0.589
0.596
0.358
0.430
0.357
0.677
0.541
GC'F __
0.446
0.482
95
92
126
260
160
N
161
Population
0.029
0.030
0.032
0.005
0.034
0.004
0.027
0.004
0.008
0.005
0.004
0.004
0.010
0.004
0.010
0.005
0.008
0.016
0.008
0.008
0.008
0.004
0.004
0.090
0.005
TABLE 2. DBP allele frequencies among North African and West African groups, Malagasy, and Middle East populations
0.015
0.008
0.003
0.149
0.171
0.130
0.065
0.069
0.083
0.086
0.053
0.137
0.172
0.179
0.125
0.131
0
0.015
0.054
110
J. CONSTANS ET AL.
TABLE 3. DBP allele frequencies in Asiatic groups
Population
26
27
28
29
30
31
32
Nepal (Jirel Sherpa)
Tibet (Dogpa)
India (Pondicherry Tamil)
Thailand (Bangkok Thais)
South Vietnam
Laos (H-mong)
Bali (Karangasem)
N
a l F
a l S
195
231
112
199
186
293
294
0.251
0.364
0.143
0.405
0.492
0.469
0.677
0.518
0.376
0.625
0.354
0.271 0.003
0.377
0.252
&'A2
&'A3
&'A9
a l C 7
a
2
0.005
0.226
0.009 0.002 0.249
0.232
0.005
0.236
0.234
0.154
0.071
*two tribes (Pima and Lumbees) living; in
Arizona and in North Carolina respectively;
one tribe from Guatemala, the Ixils;
a Quechua-speaking group living in Tarabuco (Bolivia) and a cross-bred Indian
(Spanish-Quechua) group from Auchapata
(Bolivia); and
different groups from Brazil: to the ones
already published (Constans and Salzano,
198Ocbthe Gorotire, Kraho, and Gaingang-to samples were added-a Caraibspeaking tribe, the Macushi; and the ICana
River Indians, now speaking a Tupi language, Nyengatu, introduced by missionaries (Salzano, 1980).
FSTIover all loci is by convention simply the
arithmetic mean:
The fourth series was made up of a total of
855 samples from both Southeast Asia and
South Pacific Islands (Table 5). This series
came from the following groups:
Principal component analysis
The method described by Morrison (1976)
was used to represent the distribution of the
different populations investigated according
to their GclF, Gc", and Gc2 allele frequencies. The two F1 and F2 axes summarized
98% of the total variability of the allele frequencies and represent, respectively, the opposite distribution of the samples according
to GclF and Gels and to (GclF, GclS)and G c ~ .
The relations used to locate the points on
Figure 1are as follows:
individuals from Australia, Papua New
Guinea (Fore-speaking group), and from Irian Jaya (a Moni-speaking group);
individuals from the New Hebrides, Banks,
and Torres Islands and from Anuta in the
Solomon Islands (the samples from the Solomon, Banks, and Torres Islands, collected
in the course of a multidisciplinary survey,
were previously described by Blake et al.,
1983);
people living in Ifalik and Fais Islands and
also Chamorros from Guam, Micronesia;
two additional samples came from people
living in the Marquesas and the Cook Islands, Polynesia.
FST analysis
The FSTparameter (Wright, 1969) is used
to measure the level of differentiation between the geographical groups studied. In
the case of the three alleles, we choose to use
the formulation proposed by Wright (1978).
where g equals the number of loci.
Since all variable forms of the DBP have
been shown to be the products of codominant
alleles a t the same locus, gene counting was
used to assess the frequency of the alleles
assuming a distribution of these alleles in
the samples according to Hardy Weinberg
equilibrium.
F1 = 0.776 x GclF - 0.60 X Gels - 0.192
x Cic2 - 0.0095
Fs = 0.240 X GclF + 0.563 x Gels - 0.791
x &2 - 0.01581
Correlation coefficients were also calculated between the frequencies of the three
alleles. To compare the variation of the Gels
and Gc2 allele frequencies in the populations
investigated, the frequency of the GclF being
considered as constant, the partial correlation coefficient was calculated according to
the following relation:
42
43
44
37
38
39
40
41
36
35
33
34
53
54
50
51
52
49
48
47
45
46
0.231
0.178
0.277
0.197
0.330
0.200
0.321
0.448
0.135
0.365
0.474
0.198
&lF
0.637
0.714
0.540
0.426
0.290
0.480
0.464
0.453
0.610
0.510
0.414
0.475
&lS
~ 1 A 2
~ 1 A 3
&'A4
0.082
~ 1 A 8
TABLE 4. DBP allele frequencies in Amerindian groups
Oceanic Groups
Australia: Aborigines
Melanesia
Papua New Guinea: Fore (Kuru Area)
Irian Jaya: Moni
New Hebrides
Banks Islands
Torres Islands
Solomon Islands: Anuta Island
Micronesia: Western Caroline Islands
Ifaluk Island
Fais Island
Mariana Islands: Guam (Chamoros)
Polynesia
Marquesas Islands
Cook Islands
(Mauke moun)
Population
253
171
161
155
136
106
165
211
104
108
58
242
N
0.009
0.003
a l A 9
0.443
0.398
0.592
0.538
0.375
39
131
88
166
49
0.288
0.385
0.244
0.379
80
66
141
66
0.311
GC'F
29
N
0.298
0.316
0.214
0.187
0.364
0.386
0.303
0.250
0.364
0.587
GC'S
0.042
0.163
0.030
0.034
&A1
0.034
GlC2
TABLE 5. DBP allele frequencies among Melanesian, Micronesian, and Polynesian samples
North America (U.S.)
Pima
Lumbee
Central America (Guatemala):
Ixil
Guyana (F): South America
Palikour
Brazil
Gorotire
Kraho
Caingang
Iqana River
Macushi
Bolivia
Aymara (Altiplano)
Quechua (Tarabuco)
Metis (Auchapata)
Population
0.011
~ 2 A 1 0
0.026
~ l C 7
0.259
0.286
0.194
0.275
0.250
0.284
0.311
0.343
0.227
0.034
GC2
0.002
&ClO
0.123
0.105
0.183
0.351
0.380
0.320
0.215
0.099
0.173
0.125
0.112
0.325
2
112
J.CONSTANS ET AL
EAST and
NORTH AFRICA
SUNDA ISLAND
-0.4
-0.3
EUROPE
/
-0.1
-0:
0.1
0.5
0.2
I
0.b
w
AXE 1
+
y
ABORIGINES
--I
f-0.3
Fig. 1. Eigenveckor diagram for the populations investigated in this study using the two
principal axes F1 and F2(refer to Materials and Methods).
GEOGRAPHICAL DISTRIBUTION OF THE
Gc", Gc2 ALLELES
a'*,
Student's test was used with a df equal to
n - 2.
RESULTS AND DISCUSSION
The gene frequencies obtained in this study
and those already published are assembled
in five tables (Tables 1-5). The frequencies
for alleles GclF, GclS, and Gc2 are summarized in Figure 1.The different samples are
represented in a diagram that reveals three
axes and several clusters (Fig. 1).The distribution of the rare mutants is represented in
two maps (Figs. 2,3).
The results show two main features of the
DBP polymorphism: (1)the worldwide presence of the three &IF,
and Gc2 alleles,
except in one isolated group; (2) the existence
of more than 84 rare mutants. Their distribution coincides with historic and prehistoric
isolation and human migration patterns.
European and african groups (Fig. 1)
The French groups are characterized by a
Gc2 frequency of 0.20 to 0.30, a GclF frequency of 0.10 to 0.20, and a Gels frequency
of 0.55 to 0.60 (Table 1).Similar values are
found among Danish (Thymann, 1979), German (Weidinger, 1981), Belgian and English
groups (Papiha, 1982a), as well as among Europeans living abroad (Dykes et al., 1981;
Nicholls, 1982). The Basques are of a particular interest with the highest Gc2 and the
lowest GclF gene frequencies. In general, European values tend to cluster tightly (Fig. 1)
with high Gc2 and low GclF frequencies.
Populations from the Middle East, such as
the Bedouins from North Yemen and the
Kurds from Iraq, are characterized by lower
Gc2 and markedly higher GclF allele frequencies than are found in Europeans. They
constitute a different cluster in which the
Druses from Israel (Cleve et al., 1978) and
Fig. 2. Distribution of rare Gc mutants among Asiatic and Amerindian groups.
Fig. 3. Distribution of the rare mutants among African groups and Black people living in the United
States. The Aboriginal populations living in Australia New Guinea, and New Hebrides (Vanuatu) are
located on this map as a result of the presence of the GciA1mutant.
DBP POLYMORPHISM IN HUMANS
the Berbers from Tunisia (Lefranc et al.,
1981) could be included. In contrast with
other North Africans, the Berbers are genetically related to Middle Eastern Groups. This
observation is in agreement with their assumed anthropological origins.
The main difference betwen North Africans and Middle Eastern groups is a lower
Gc2 and a higher GclS allele frequencies (Table 2). Populations from North Africa are
located in the diagram (Fig. 1)in an intermediate position between the two clusters of
Europe and Africa. A similar genetic pattern
is observed for the Tuareg from Algeria or
Mali, the Erythreans, and the two tribes from
Djibouti. This occurs in spite of their cultural
differences and their geographical locations.
In this cluster the influence of the Gc2 allele
is so weak that it may disappear under an
important founder effect, as in the Kel Kummer Tuareg.
African populations are characterized by
the highest GclF frequencies observed and a
Gc2frequency not very different from the one
present among Saharan groups. Africans
make up one cluster, but they can be divided
into two subgroups-one represented by the
populations living in West or Central Africa,
and the tribes from the west coast of Malagasy; the second composed of Pygmies and
Bushmen, the tribes living on the east coast
of Malagasy and also African people living
in America (Baltimore).The subgroups differ
from one another by their GclF allele frequencies (Table 2).
The genetic pattern of the African groups
from the United States (Kueppers and Harpel, 1979; Dykes et al., 1983b) show gene
frequencies similar to the ones obtained in
our study. These additional black American
groups are distributed in the two clusters.
Different anthropological investigations have
suggested the presence of approximately 20%
European genes among the American Black
populations (see summary in Bodmer and
Cavalli-Sforza, 1976) but this is not evident
from our data on DBP polymorphism.
Asian and Amerindian groups
A very scattered pattern corresponds to the
distribution of these groups despite common
geographical locations or anthropological
origins. The most original position is occupied by the Karangasem community from
Bali: with their high GclF and low Gc2. allele
frequencies, they look like an African group
in the diagram (Fig. 1).Our observation is
115
confirmed by the data published by Tan et
al. (1981) on Bidayuk and Ibans from Malaya, or on Indonesians.
South Vietnamese, Thais, and Tibetans
present very similar allele frequencies to
those observed among Chinese from Hong
Kong and Taiwan or among Japanese groups
(Matsumoto, 1980; Kwok, 1981; Shibata
1983).This group is characterized by a high
Gc2 frequency (Table 3).
The Jirel tribe from Nepal (Fig. 11, is located in an intermediate position between the
above small Asiatic group and the Tamils
Pondicherry). Newars from Nepal are very
similar to the Jirel Sherpa (Yuasa et al.,
1983). Papiha et al. (1985) present a very
large set of data on different Indian groups.
They confirm the Gc frequencies obtained
among the Tamils and the location of the Indians in a cluster much like the European one.
The other samples belonging to South
Asian regions are widely distributed in the
diagram. Nevertheless, it is possible to delineate three clusters. One is made of the two
Polynesian samples (Cook and Marquesas Islands) and of the Chamorros from Guam
overlaps the cluster of the North Asiatic
groups.
The location of the Anuata sample (Fig. 1)
points to a genetic similarity with the Polynesians. This observation would confirm the
hypothesis proposed by Blake et al. (1983)
concerning the origins of human settlements
in this island. According to Bayard (1976),
linguistic affinities are observed between
Anuata and Tonga, which belongs to the Polynesian cultural influence. The possible presence of genetic Melanesian origins on Anuata should also be considered (Blake et al.,
1983).
In general the DBP polymorphisms of the
Polynesians and North Asians do not differ.
The two Micronesian samples show a higher
GclF allele frequency, which makes them
more similar to the Sunda Islands groups.
The last groups studied belonging to these
South Asian regions comprise the small Aboriginal populations living in Melanesia,
New Hebrides, and in Australia. Kambok
and Kirk (personal communication)obtained
similar DBP allele frequencies for groups belonging to this geographical area. It is interesting to notice that the Melanesians in the
Bank, Torres, and Solomon Islands are located in a cluster clearly distinct from the
others made of Micronesian and Polynesian
116
J. CONSTANS ET AL
TABLE 6. The FST values calculated from the GcfF,Gc", and Gc2 allele frequencies
for eight main geographical areas
FST
Geographical zones
I
I1
I11
Europe
North Asia
South Africa
India
South Asia
North Africa
Australia and New Guinea
South America
1F
1s
2
Nonweighted
mean value
,023
,007
,045
,036
,048
,040
,013
,044
,012
,010
,001
,024
,017
,029
,046
,066
,061
0.015
0.005
0.036
0.024
0.031
0.045
0.045
0.054
samples (Fig.1). From our data it is not possible to delineate a clear difference between
groups speaking Austronesian languages and
the ones belonging to the Papuan linguistic
zone (Tyron, 1979). It seems that the great
heterogeneity of the allele frequencies among
the South Asian populations is, perhaps, due
to different anthropological origins but also
to significant genetic differentiation among
those following ancient migrations and experiencing extreme isolation over long periods of time.
The Amerindian populations can be gathered into two clusters in the diagram (Fig. 1).
One is composed of Bolivian Indians. Palikours from Guyana are not very far from this
cluster. The second cluster is composed of
Gorotire, Kraho, and Caingang from Brazil
and also Lumbees from the United States.
Amerindian groups of this last cluster are
characterized by high Gc2 frequencies, while
the Andeans present the highest GclS frequencies. Iqana Indians are located at the
mean distance between the Brazilian and the
Bolivian groups. It seems that a third group
of Amerindians could be considered, made of
Pima from the United States (Dykes et al.,
1983), Macushi from Brazil, and Ixils from
Guatemala.
Other Indian tribes such as Dogribs and
Athapaskan-speaking groups (Szathmary et
al., 1983) may be related to this third Amerindian cluster.
These data show very different genetic patterns for Asians and Amerindians, a finding
consistent with other genetic systems. (For a
review, refer to Bodmer and Cavalli-Sforza,
1976; Mourant, 197621). One possible explanation for the differences observed among
Amerindian groups is a founder effect among
the first migrants to the New World as a
,008
,038
,017
.015
.049
,056
.058
result of isolation within a vast geographical
region during a relatively short period of time
(MacNeish 1977; Dumond, 1980). Besides, the
Amerindians may have different Asiatic
origins. If we consider the Gc2 frequencies
(0.10 to 0.20 and about 0.30 to 0.40) at least
two separate populations may have participated in the settlements of America. Among
them the Eskimos from Alaska, regarded as
latecomers, are, according to the DBP data
(Matsumoto et al., 19801, very similar to
Andeans.
Genetic Heterogeneity of Gcl< Gc", G 2
Alleles Distributions
The Gc polymorphism among human populations shows that the range of variation of
the gene frequencies differs with the populations. This variability can be estimated by
the FSTvalues determined for each allele in
eight main geographical areas (Table 6). The
lowest nonweighted mean values for FSTare
observed among European (0.015) and North
Asian groups (0.005). The genetic differentiation between the three main alleles of the
DBP appears to be very small among these
populations. This may be due to frequent
interpopulation migrations within the concerned geographical zones over a large period
of their past history giving rise to a process
of homogenization.
A second group consists of populations living in India, South Africa, and in the Soutern part of Asia. In these regions, the FST
values range from 0.024 to 0.036. The third
group (Table 6) is characerized by the highest
values (about 0.050) of the nonweighted FST
parameter. This result may be explained by
genetic drift in groups that share a similar
pattern of social and cultural isolation. A
second reason may be a great variation of
DBP POLYMORPHISM IN HUMANS
TABLE 7. The correlation coe rcients calculated with
the frequencies of the three
Gc", and Gr? alleles
in the different human groups
,ff.
Correlation
coefficient
between
GclF and Gc"
GclF and Gc2
Gc" and Gc2
The data
obtained in
this study
-
+
0.847*
0.577*
0.083 N S
Our data and
including those
summarized by
Papiha et al. (19851
0.905*
0.649*
+ 0.291*
-
*p < 0.01.
population sizes in their past history (bottleneck effect).
Populations from Australia, New Guinea,
and groups living in South Asia show very
different FST values. These differences can
only be the result of factors such as selection
or genetic drift. The present anthropological
and historical knowledge of those populations supports the hypothesis of genetic drift.
But the influence of factors related to selection is the most likely explanation, especially
if we consider the existence of strong geographical associations owing to the presence
of regular clinal variations of the DBP frequencies. From Europe to Africa and from
North to South Asia the G c ' ~ allele frequency decreases. These observations are
corroborated by the values of the correlation
coefficients calculated between the three
DBP alleles (Table 7).
GclF and GclS frequencies are negatively
correlated as well as GclF and Gcz frequencies, but on the contrary, GclS and Gc2 frequencies are positively correlated when
additional data (Papiha et al., 1985) are included in the comparison.
The partial correlation coefficient calculated between GclS and Gc2 when GclF is
maintained constant is -0.915, which is
highly significant (p < 0.01) for a negative
variation between the frequencies of these
two alleles. From these comparisons we can
consider the distribution of the DBP polymorphism as corresponding to the presence
of a balanced equilibrium: a n increased frequency of the GclF allele is followed by a
decrease in the frequency of the GclS and
Gc2 alleles. These data confirm that the gradient of the DBP allele frequencies corresponds to the existence of clinal variations in
relation to geographical parameters. To explain the distribution of the Gc alleles, one
has to consider the influence of selective fac-
117
tors associated with the biological activity of
the proteins produced by the three main alleles. It then remains to show in which way
the three DBP proteins may be involved in
different biological activities.
It has been shown by Constans (1978b) that
the serum DBP level is higher among Gc'
carriers and that the GclS allele is associated
with higher levels than the GclF allele. In
addition, there is, probably, a significant difference of affinity for the vitamin D metabolites between the GclF, Gc", and Gc2
proteins (Constans et al., 1980b). Recently it
was demonstrated by Daiger et al., 1984 that
the serum DBP levels were under the control
of the three main alleles, a polygenic component, and environmental effects.
Different comparisons have been made between the distribution of the Gc allele frequencies and the influence of geographical
factors with respect to skin pigmentation
(Mourant et al., 1976b)and latitudes (Walter,
1969). In this study a n examination of the
two geographical North-South clines corresponding to the GclF and the Gc2 gene frequencies demonstrates a clear convergence
between skin pigmentation (Loomis, 1967)in
the populations concerned and the DBP alleles, with, however, two exceptions: the
Asiatic Indians and the Amerindian groups.
Moreover, a recent investigation of the first
hereditary DBP deficiency failed to reveal
any biological or pathological abnormality in
the family studied (Vavrusa, 1983).
The above observation, therefore, shows
that the most significant biological activity
of the protein is yet to be elucidated in order
to understand in which way selection may
act differently in humans according to the
presence of the GclF, Gc", and Gc2 proteins.
An unexplored pathway for this biological
activity may be found in the DBP binding to
the lymphocyte and in the involvement of
the DBP in the immune defence, since recent
findings show that the most active vitamin
D metabolite (1.25 - (OHIz-DS)plays a part in
the regulating mechanisms of the cell division and differentiation (Shavit et al., 1983;
Frampton et al., 1983).
WORLDWIDE DISTRIBUTION OF RARE MUTANTS
Eighty-four rare mutants of the DBP have
now been detected. In contrast to the three
frequent alleles, the distribution of the rare
mutants is not strictly limited to geographical zones but is more a reflection of the an-
118
J. CONSTANS ET AL.
thropological relationship between groups,
their exchanges, and their migrations.
Anthropological relationship between Asian
groups and Amerindian tribes
As represented in Fig. 2 the following rare
mutants G~1A2,1A3 &1A4,1 A8,1A9 , and
Gc1c2,1c3, are obse&ed in the Northern
Asian groups of Japan, Korea, and Taiwan
(Ishimoto et al., 1979; Omoto and Miyake,
1979; Matsumoto et al., 1980) and also in
some Southeast Asian regions of Borneo,
Java, Indonesia, and Thailand (Matsumoto
et al., 19801, where Chinese communities are
numerous. The same mutants, except for the
Gclc2 and GclC7alleles, were detected among
Eskimos from Alaska and Greenland. The
presence of the GclA4mutant was confirmed
in a recent study of Eskimos from Alaska
(Dykes et al., 1983).Among the South American Indians only the Gc1A3, GclA9, and
GclC7 alleles appear to be present, but no
rare Gc mutant was found in the two samples
from North American Indians. This observation is now confirmed by recent data on South
and North Amerindians (Dykes et al., 1983).
Three significant features emerge from
these results:
The presence of the same mutant, GclC7,
among a Dogpa group living in the Tibetan
mountains and a Gorotire Indian tribe from
Brazil (Constans and Salzano, 1980~)
is probably the first example of a possible anthropological relationship between a Southern
Mongoloi'd group and a n Amerindian tribe.
The G d A 3 , 1 A 8 and GcIA9mutants are found
not only among Aymara and Quechua Indians from Peru and Bolivia but also among
Palikours, (an Arawak group) from French
Guyana. They are the first genetic mutants
found in groups that are culturally different.
It is possible that a t the time of the first
settlements in South America, these rare
mutants and others were present in a population located on the Eastern slopes of the
Andean zone, near the Amazon River. From
this area individuals formed into smaller
groups that moved northward to the Orinoco
swamps. These groups could have included
individuals with rare mutants and interbred
with ancient and already settled Caribbean
tribes.
The GclA2*lA4mutants, detected only
among Eskimos from North America, may
confirm that these groups belonged either to
the last major migrations coming from Asia
before the Bering bridge was submerged, or
to Asian populations (North Mongoloids) of a
genetic origin other than that of the American Indians (Dumond, 1980).
The GclAl0 mutant observed for the first
time among the Chippewa Indians (Cleve et
al., 1963)has not been observed in any other
Amerindian group. This rare mutant might
be called a "private" variant according to the
hypothesis developed by Nee1 (1973).
It can be deduced from the distribution of
these rare mutants that there was probably
considerable differentiation among the Asian
populations when the Americas were occupied. This would also explain why the rare
protein mutants such as those discussed here
are more commonly distributed among North
Asian groups and South American Indians
than they are among the South Asian groups
(Thailand, Indonesia, and Polynesia). One
can also expect to find new DBP mutants
with a very limited geographical distribution
in Melanesian and Micronesian groups which
are anthropologically different from the
North Asian populations.
A very rare example of mutant distribution
is illustrated by GclA12and GclC1', because
they are found in Indonesia (Bali) and India
(Papiha, personal communication). Their
presence in these two groups is in agreement
with the tales and mythologies of the Balinese group, which indicate a n Indian origin
(Breguet et al., 1982b). That these mutants
are also present in Europe constitutes a n interesting genetic evidence of the Indo-European migrations.
Diffusion of the African rare mutants
The second map (Fig. 3) is essentially devoted to the populations that originated from
Africa or are still living there.
The GclC3mutant is detected among North
African groups and in Europe. The same mutant is also present among the Erythreans,
but so far it has not been observed among
black African populations. The G c is ~an- ~
other mutant with a n approximately similar
geographical distribution and is found in
Mali, Senegal, Gambia, and Ethiopia. It is
difficult to ascertain precisely where these
two mutants originated from, but they seem
to be absent from Central and South Africa.
They were probably scattered throughout the
Mediterranean region by population exchanges and in North Africa, from east to
west, by trade and slave caravans.
Anthropological and cultural relationships
between Ethiopians, Somalians, Malagasy
~
DBP POLYMORPHISM IN HUMANS
119
cording to Schanfeld et al. (1980), the
Gml;17,-5,10,11,13,14 when associated with the
Gm23antigen is characteristic of the African
populations. The same haplotype without the
Gm23 antigen was found by the same author among Indian and Aboriginal populations.
With the transferrin system, the TfD1mutant is known to be present in all African
groups but also in Southeast Asia (Bali, Aboriginal groups from Australia a n Melanesia).The partial structure of this protein was
determined (Wang et al., 19671, and no peptide difference was found between the proteins obtained from a n African and from a n
Australian sample.
In red cell enzymes, rare mutants such as
PGM: and PGMZ have been found in India,
Australia, and recently in a Balinese group
(Tenganam) and they are also among Pygmies (Vergnes et al., 1979). Electrophoretic
comparisons have so far failed to show any
difference between the proteins of mutants
from the different ethnic groups (Blake and
Omoto, 1975; Kirk et al., 1977; SantachiaraBenerecetti et al., 1980; Breguet 1982131.
Owing to the simultaneous presence of
these rare mutants in so many different
groups, a multifocus hypothesis seems very
unlikely. According to prehistoric and historic data, the hypothesis of a unique focus
can be supported if we consider a migration
A common ancestor for African and
in the remote past of a common ancestor for
Aboriginal groups
the African and Aboriginal groups. This
Since 1967, several authors have described event had to occur some 1or 1.5 million years
a very high frequency of the GclA1 allele ago during the existence of the first homiamong African and Australian Aboriginal nids. Later, a local and independent evolupopulations (Cleve et al., 1967; Gajdusek and tion in Africa and Asia would give rise to
Alpers, 1972). As samples from such popula- distinct groups such as the Pygmies, Bushtions became available, the mobility of the men, and Hottentots in Africa, and the AboGclA1proteins was compared using three dif- rigines and oceanic populations in Asia.
ferent electrophoretic systems, namely, polyacrylamide gel, isoelectric focusing, and
CONCLUSIONS
isoelectric focusing in presence of 3 M urea
The
DBP
polymorphism
in humans pre(Constans et al., 1983).All the GclA1proteins
obtained from the different geographical sents two patterns, one related to the distriplaces show a n identical electrophoretic mo- bution of the rare mutants and the second to
bility. It can be assumed that the structure the occurence of three main alleles GclF,
of the GclA1protein is the same in the Afri- Gc", and Gc2.
The worldwide distribution of the rare alcan, Malagasy, Australian, New Guinean,
leles is in agreement with the prehistoric and
and Balinese samples.
In addition, other examples of similar rare historic data on the migrations and intermutants in the different geographical groups breeding of human populations. A much better understanding of that distribution can be
can be revised.
In the Gm system, the Gm1,17,23,5,10,11,13,14 expected when the populations of India, the
haplotype was detected in the community of Middle East, and China have been thorTenganam (Bali) (Breguet et al., 1982b). Ac- oughly sampled.
(Lowlands) and Djibouti tribes are supported
by the presence of the GclA6mutant in those
groups.
G c lC lO is another rare mutant restricted to
populations living on the west coast of Africa. It was detected in Bantu and related
groups from Zaire, the Ivory Coast, and Cameroon. Its presence among the Lumbee
sample would correspond to a Negro'id admixture among them as indicated by human
leukocyte antigen (HLA) typing (Grier et al.,
1979).
GclA1 was first described by MacDermid
and Cleve (1972) under a "GcAb" (Aborigine)
denomination. Since then
has been
found with the highest frequency in African
groups living in tropical areas of Central Africa. Its frequency falls rapidly as one moves
north, but it is still frequent in the south,
among the Bushmen. The present authors
have also observed the same GclA1and GcZA3
mutants among tribes living on the east and
west coasts of Malagasy.
In three U S . groups with African ancestry
living in Baltimore, Philadelphia, and Georgia (Kueppers and Harpel, 1979), the GclA1,
GcZA3,GcZA5, were observed.
These data on the Gc mutants are in agreement with the historical and anthropological
knowledge about the various origins of the
Africans brought to America.
120
J. CONS? 'ANS ET AL
donesia. 11. Haemoglobin types and red cell isozymes.
Anthropological microdifferentiations withHum. Hered. 32:308-317.
in the large populations or between villages
H, Kirk, RL, Parker, WC, Bearn, AG, Schacht,
in the same linguistic or cultural area could Cleve,
LE, Kleinman, H, and Horsfall, WR (1963) Two genetic
be investigated by comparing the distribuvariants of the group-specific component of human
tions of these rare mutants. The polymorphserum: Gc Chippewa and Gc aborigine. Am. J. Hum.
Genet.
25:368-379.
ism of the DBP may also contribute to
accurate genetic control of the pedigrees col- Cleve, H, Kirk, RL, Gajdusek, DC, and Guiart, J (1967)
On the distribution of the Gc variant Gc aborigine in
lected in the course of anthropological surMelanesian populations; Determination of Gc-types in
veys.
sera from Tongariki island, New Hebrides. Acta Genet.
Base1 17:511-517.
If the rare mutants show a limited geographical distribution or belong to related Cleve, H, Patutschnick, W, Nevo, S, and Wendt,GG (1978)
Genetic studies of the Gc subtypes. Hum. Genet.
groups, the three main alleles are observed
44: 117-122,
in every human population studied. The Constans, J, and Viau, M (1977) Group-specific compoemerging pattern obtained from the distrinent: Evidence for two subtypes of the Gc' gene. Science 198:1070-107 1.
bution of their gene frequencies shows the
stability of these frequencies over large geo- Constans, J, and Viau, M (1978a) Study by isoelectric
focusing of the serum protein which transports vitagraphical areas. A cline associated with inmin D (DBP) and of the polymorphism of Gc. Imporcreasing GclF and decreasing Gc2 gene
tance in Anthropology. Cr. Acad. Sci. Paris 287,21:809frequencies is, without doubt, present be812.
tween the northern and southern regions. Constans, J , Viau, M, and Ruffie, J (1978b) Study of the
Gc protein in several French population samples: geThe present-day knowledge of the biological
netic polymorphism by isoelectric focusing and quanactivity of DBP is still too limited for the
titative results. Cr. Acad. Sci. (Paris) 287,22:1003-1006.
hypothesis of a selective pressure based on Constans, J, and Cleve, H (1979) Group specific compothis activity to be definitely established.
nent. Report on the first international workshop. Hum.
ACKNOWLE,DGMENTS
We are greatly indebted to Professor A.E.
Mourant for his interest in this work and to
Dr. Kawai (Osaka Medical School) for his
active collaboration. Pr. L.Y.C. Lai is particularly acknowledged for his comments and
fruitful discussions during the preparation of
this paper.
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