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Brief communication Allelic and haplotypic structure at the DRD2 locus among five North Indian caste populations.

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Brief Communication: Allelic and Haplotypic Structure
at the DRD2 Locus Among Five North Indian Caste
Kallur N. Saraswathy,1* S. Yaiphaba Meitei,1 Vipin Gupta,2 Benrithung Murry,1
Mohinder P. Sachdeva,1 and Pradeep K. Ghosh1
Biochemical and Molecular Anthropology Laboratory, Department of Anthropology,
University of Delhi (North Campus), Delhi 110007, India
South Asia Network for Chronic Disease, New Delhi, India
DRD2 gene; haplotype; linkage disequilibrium; caste; India
The dopamine D2 receptor (DRD2)
gene, with its known human-specific derived alleles
that can facilitate haplotype reconstruction, presents
an important locus for anthropological studies. The
three sites (TaqIA, TaqIB, and TaqID) of the DRD2
gene are widely studied in various world populations.
However, no work has been previously published on
DRD2 gene polymorphisms among North Indian populations. Thus, the present study attempts to understand the genetic structure of North Indian upper caste
populations using the allele and haplotype frequencies
and distribution patterns of the three TaqI sites of
the DRD2 gene. Two hundred forty-six blood samples
were collected from five upper caste populations of
Himachal Pradesh (Brahmin, Rajput and Jat) and
Delhi (Aggarwal and Sindhi), and analysis was performed using standard protocols. All three sites were
found to be polymorphic in all five of the studied populations. Uniform allele frequency distribution patterns,
low heterozygosity values, the sharing of five common
haplotypes, and the absence of two of the eight possible
haplotypes observed in this study suggest a genetic
proximity among the selected populations. The results
also indicate a major genetic contribution from Eurasia
to North Indian upper castes, apart from the common
genetic unity of Indian populations. The study also
demonstrates a greater genetic inflow among North Indian caste populations than is observed among South
Indian caste and tribal populations. Am J Phys Anthropol 141:651–657, 2010. V 2010 Wiley-Liss, Inc.
researchers to make conclusions about evolutionary history and human migratory patterns (Kidd et al., 1998;
Vishwanathan et al., 2003; Bhaskar et al., 2008; Prabhakaran et al., 2008; Saraswathy et al., 2009a,b). It is for
this reason that the polymorphisms at the three aforementioned sites in the DRD2 gene have been studied
among various global populations, in addition to the physiological role of the gene in neuropsychiatric and addictive
disorders (Noble, 1998; Spitz et al., 1998; Oliveri et al.,
1999; Li et al., 2004; Dalley et al., 2007). However, even
though the diversity of the DRD2 locus has been reported
in world populations across several continents, almost all
The dopamine D2 receptor (DRD2) is one of the five
common human dopamine receptor genes that are
expressed in the central nervous system and have been
extensively studied in various world populations, including several Indian populations (Kidd et al., 1998; Vishwanathan et al., 2003; Bhaskar et al., 2008; Prabhakaran
et al., 2008; Saraswathy et al., 2009a,b). The three TaqI
restriction sites (SNPs): TaqIA (T?C), rs1800497
(Grandy et al., 1989); TaqIB (G?A), rs1079597 (Hauge et
al., 1991); and TaqID (C?T), rs1800498 (Parsian et al.,
1991) span a distance of 2.5 kb on the coding region of the
gene. The TaqIB site is 913 base pairs (bp) upstream of
the initiation codon in exon 2, the TaqIA site is 10,542 bp
downstream of the termination codon in exon 8 and the
TaqID site is located in intron 2 of the DRD2 gene. With
their known ancestral and human-specific derived alleles
(Kidd et al., 1998), these three sites are located linearly
on chromosome 11 (11q23) (Grandy et al., 1989; Eubanks
et al., 1992; Gelernter et al., 1992), thereby constituting a
haplotype. In various world populations, these three sites
are frequently reported to nonrandomly associate, i.e., are
reported to have linkage disequilibrium. Because a
haplotype is a multisite haploid genotype at two or more
polymorphic sites on the same chromosomal region
(Templeton, 2005), a haplotype’s relative distribution
among different populations can provide more accurate
information on the genetic diversity and similarity among
the populations than an individual allele’s distribution
(Castiglione et al., 1995; Tishkoff et al., 2000; Lonjou
et al., 1999, 2003). This kind of information allows
C 2010
Grant sponsors: University Grants Commission SAP (Special
Assistance Program), Government of India and Delhi University
Research Scheme, University of Delhi.
*Correspondence to: Kallur N. Saraswathy, Department of
Anthropology, University of Delhi, Delhi 110007, India.
Present address of Vipin Gupta: Research Fellow (Genetic
Epidemiology), South Asia Network for Chronic Disease (SANCD),
LSHTM/PHFT Collaboration, C-1/52, First Floor, Safderjung Development
Area, New Delhi 110016, India.
Received 28 May 2009; accepted 3 November 2009
DOI 10.1002/ajpa.21246
Published online 20 January 2010 in Wiley InterScience
among the castes of India, irrespective of their ethnicity
and linguistic affiliations, can be partially explained on
the basis of common minimum genetic substratum that,
according to Kivisild et al. (2003), can be traced to the
Pleistocene. The limited gene flow reported among the
South Indian caste populations (Kivisild et al., 2003;
Sengupta et al., 2006), who are more stringent in their
hierarchy, customs, and beliefs, makes external origins
of the caste system less plausible. However, even if the
caste system came from outside India, North Indian
caste groups, which have not been systematically studied, are expected to have a relatively higher genetic
inflow from Eurasia as compared to South Indian
As such, this study attempts to understand the extent
of external genetic inflow (especially from Eurasia)
among North Indian upper caste populations by analyzing allele and haplotype frequencies at three TaqI sites
of DRD2 gene. Figure 1 shows the presently studied
areas in North India.
Fig. 1. Map of India showing the presently studied areas––
Delhi and Himachal Pradesh.
studies in India come either from South or Northeast
India and focus mostly on tribal populations.
Indian Human Genome diversity studies using mitochondrial (Bamshad et al., 2001; Kivisild et al., 2003;
Quintana-Murci et al., 2004), Y chromosomal (Sengupta
et al., 2006; Sharma et al., 2009), and autosomal DNA
markers (Watkins et al., 2005; Indian Genome Variation
Consortium, 2008; Reich et al., 2009) have tried to
address the human settling of India with special reference to the castes and tribes of India. Linguistic studies
also illustrate the group divisions within India: IndoEuropean languages are spoken by all caste populations
except those of South India. A few tribal populations
also speak Indo-European languages. Austro-Asiatic languages are spoken exclusively by the tribal populations.
Dravidian languages are spoken by all castes and tribes
of South India and some tribes of Central India. TibetoBurman languages are mainly confined to the northeastern region of the country. Except the northeastern
region, tribes in general are thought to be autochthones
of India. Caste groups mainly fall under five––Varna system in South India (Brahmin, Kshatriya, Vashya, Shudra, and Panchama) and four––Varna system in North
India (Brahmin, Kshatriya, Vashya, and Shudra) (Tambiah, 1973; Elder, 1996). The emergence of caste system
in India has been attributed to many different causes.
For example, some suggest it was initiated by the Aryan
invasion (Poliakov, 1974; Renfrew 1989a,b); that it
evolved from a common genetic heritage along with
tribes (Kivisild et al., 2003); that it originated independent of tribes (Cordaux et al., 2004) or that it has existed
since time immemorial (Karve, 1961; Sharma et al.,
2009). Some authors also put forth the theory of tribe
caste continuum (Chaubey et al., 2006; Thanseem et al.,
2006), i.e., the evolution of castes from preexisting tribal
groups. Bamshad et al. (2001) presume a Proto-Asian origin of Indian castes and their hierarchical ranking after
Eurasian admixture, suggesting the presence of ancient
gene pools among the present caste populations. Further,
basic cultural unity in terms of rituals and festivals
American Journal of Physical Anthropology
Genomic DNA was extracted with the salting out procedure (Miller et al., 1988) from 5 ml of intravenous
blood samples collected from upper caste populations of
North India namely Brahmin (51), Rajput (51), and Jat
(48) of Himachal Pradesh and Aggarwal (54) and Sindhi
(42) of Delhi, with informed written consent. Brahmin
fall under the Brahmin Varna. Rajput and Jat, though
both belong to the Kshatriya Varna, are two different
Mendelian groups, the former tracing its origin to Rajasthan and the latter to Punjab and Haryana. Aggarwal
belong to the Vashya Varna system. Sindhi, a migrant
community from the Sindh province (now in Pakistan)
for trade, are usually considered to be an isolated endogamous population and to some extent can be considered
as belonging to the Vashya Varna system. Polymerase
chain reaction (PCR) analyses of the three selected TaqI
sites of DRD2 gene were carried using primers and protocols as described by Castiglione et al. (1995) and Kidd
et al. (1996). After amplification of the specified fragments, the PCR products were digested with TaqI
restriction enzyme according to the manufacturer’s
recommended conditions, followed by 2% agarose gel
electrophoresis with ethidium bromide as a staining
Allele frequencies were calculated by the gene counting method. The ancestral alleles are represented as B2,
D2, and A1, where 2 and 1 represent the presence and
absence of the restriction site, respectively (Castiglione
et al., 1995; Kidd et al., 1998). Heterozygosities (Nei,
1973) at the respective locus were estimated using the
software POPGENE (Yeh and Yang, 1999). Hardy–Weinberg equilibrium was calculated using the v2 goodness of
fit test. The maximum likelihood estimates of haplotype
frequencies were calculated from the multisite marker
typing data using the program HAPLOPOP (Majumdar
and Majumder, 1999). The standardized pair-wise linkage disequilibrium (LD) value (D0 ) was also calculated
for each pair of markers using LD software (Hill, 1974).
To reveal the patterns of genetic relationships among
these populations and other Indian and Eurasian populations, Principal Co-Ordinate (PCO) analysis was performed using the PCO software (http://cse.naro.affrc. This was done from
the DA distances among these populations calculated
TABLE 1. Ancestral allele frequencies and average
heterozygosities of three DRD2 polymorphic sites among studied
population groups
Population (2n)
Brahmin (102)
Rajput (102)
Aggarwal (108)
Jat (96)
Sindhi (84)
TABLE 3. Pairwise linkage disequilibrium values of DRD2 sites
among five studied population groups
LD between
TaqIA and
TABLE 2. Haplotype frequencies of three polymorphic DRD2
sites among five studied population groups
Haplotypes are based on RFLP sites where B1, D1 and A1 alleles denote the site-absent state, while B2, D2 and A2 alleles
denote the site-present state.
using DISPAN software (Ota, 1993), where the allele frequencies were employed for the calculation. The analysis
of molecular variance (AMOVA) among the various tentative categories (Table 4) was done using the software
Arlequin, version 3.1 (Excoffier et al., 2005).
All three DRD2 sites are polymorphic in all studied
populations. The presently studied populations are in
Hardy–Weinberg equilibrium at all three sites, except at
the TaqIA and TaqIB sites among Sindhis. The B2 allele
varies from 0.708 (Jat) to 0.883 (Brahmin), D2 from
0.520 (Jat) to 0.660 (Aggarwal), and A1 from 0.244
(Sindhi) to 0.296 (Aggarwal). Heterozygosities at all
three sites are below 0.4 among all studied groups except
among Jats, who have a heterozygosity value of 0.439
(Table 1). However, the differences in allele frequency
distribution between the populations are not significant
(v2 values ranging from 0.09 to 1.03 at 2 degrees of freedom, P [ 0.05).
Five of the eight possible haplotypes are shared by all
studied populations, with the presence of five haplotypes
in Brahmin and Aggarwal and six haplotypes in Rajput,
Jat, and Sindhi populations (Table 2). The ancestral haplotype B2D2A1 is present in all studied populations with
a frequency ranging from 1.1% among Jats to 10.6%
among Aggarwals. Two haplotypes with derived alleles
at the TaqIB and TaqID sites in combination with
derived and ancestral TaqIA alleles, respectively
(B1D1A2 and B1D1A1), are conspicuously absent in all
studied populations (not included in the table). Moreover, the B2D1A2 and B2D2A2 haplotypes are the most
predominant ones among these populations, ranging
from 31.7% among Aggarwals to 44.6% among Jats, and
from 21.8% among Jats to 38.8% among Rajputs, respectively.
LD between
TaqIA and
LD between
TaqIB and
Significant at 0.05.
The three pairwise, standardized linkage disequilibrium (D0 ) values for the three bi-allelic sites, TaqIB,
TaqID, and TaqIA (Table 3) are low, i.e., below 0.2 with
respect to all populations in each pair. The D0 value is
statistically significant among all studied populations
except Rajput and Sindhi between the TaqIA and TaqID
The high frequency of the B2 allele ([70%) found in
the presently studied populations is in accordance with
the African and European populations, where it is
reported to exceed 74%. Though, in India, the B2 allele
varies from as low as 38.3% among the Toto tribe (Chakrabarti et al., 2002) to as high as 90% among the Toda
tribe (Vishwanathan et al., 2003), with an average frequency of 70% in almost all South Indian tribes, indicating the preponderance of the allele in tribal populations
and also suggesting a long history of ethnically Australoid and linguistically Dravidian populations in India. No
published data is available on the B2 allele frequency
among the Austro-Asiatic speaking tribes and Indo-European speaking caste and tribal populations of India. A2
allele frequencies in the presently studied populations
show a similar trend as that of the B2 allele. This is in
contrast to the distribution of the A2 allele in African
populations, where it ranges from 52 to 73% (Kidd et al.,
1998). This implies that the ancestral forms of the two
sites (A1 and B2) are present at high frequencies in
African populations, whereas in rest of the world, as
supported by the presently studied populations, the
ancestral A1 allele is present at low frequency, pushing
the A2 allele to a higher frequency that is similar to that
of the B2 allele. A1 has a selective disadvantage because
of its clinical association with addictive disorders like
alcoholism and hypertension (Blum et al., 1991; Noble,
2003; Fang et al., 2005) and, as such, its frequency has
been reduced in many populations of world, including
India. As the TaqIA site is in linkage disequilibrium
with the TaqIB site in most populations studied, the variation in B2 frequencies is related to the A2 allele. The
TaqID site, located in between TaqIB and TaqIA sites,
shows a varied frequency distribution in the world, i.e.,
the D2 allele ranges from 60 to 90% in African populations, 38–52% in European populations, and [90%
among Asian, Pacific, and New World populations (Kidd
et al., 1998). Its frequency in India is greater than 60%
in most populations. Little difference in D2 allele distribution is observed between the presently studied populations and other populations of India.
The average heterozygosity values for each population
in this study are lower, i.e., below 0.4 (except for Jat
American Journal of Physical Anthropology
where it is 0.439), than the average heterozygosity values reported for South Indian populations (Vishwanathan et al., 2003; Bhaskar et al., 2008; Prabhakaran
et al., 2008; Saraswathy et al., 2009b) and Northeast Indian populations (Saraswathy et al., 2009a), where they
are generally above 0.4. Most Eurasian populations also
exhibit lower heterozygosity values, ranging from 0.237
to 0.389, except for Samaritans (0.48) and Finns (0.41)
(, and are similar to the presently studied Indo-European language speaking groups.
Heterozygosity values are relatively lower (0.236–0.387)
( in African populations than
in Indian populations as a whole. Population heterozygosity tends to decrease with increasing distance from
Africa, which is a result that is expected for populations
leaving Africa, undergoing bottlenecks and expanding
into Eurasia (Harpending and Rogers, 2000). However,
this trend is not observed with respect to the DRD2
locus in India, as high heterozygosity values are
observed among the tribes of South India (Vishwanathan
et al., 2003; Bhaskar et al., 2008; Prabhakaran et al.,
2008; Saraswathy et al., 2009b) and Northeast Indian
populations (Saraswathy et al., 2009a). European populations that are geographically closer to Africa show
much lower heterozygosities at the three studied sites of
DRD2 gene than the aforementioned Indian populations.
This suggests either that the peopling of India occurred
earlier than that of the Eurasia or that the multiregional
theory of human evolution suggested by Wolpoff and
Caspari (1996) may be correct.
The sharing of a minimum of five haplotypes among
the selected populations demonstrates the genetic proximity of these populations. The ancestral haplotype
B2D2A1, which is common in African populations but
rare or absent elsewhere (Kidd et al., 1998), is found to
be low in the presently studied populations, ranging
from 1.1% (Jat) to 10.6% (Aggarwal). The low frequency
of the ancestral haplotype among these populations is
similar to that of Eurasian populations, where most of
the populations exhibit 0% frequency (; Flegontova et al., 2009). Relatively high frequencies of the ancestral haplotype were reported among
South Indian populations, ranging from 2.1% among
Irula (Vishwanathan et al., 2003) to 35.9% among the
Thoti (Saraswathy et al., 2009b); moderate frequencies
were reported among Northeast Indian populations,
ranging from 1.2% (Paite) to 22.8% (Meitei) (Saraswathy
et al., 2009a). Overall, in India, tribes exhibit higher frequencies of the ancestral haplotype (the highest being
among the Thoti: 35.9%) than caste populations (the
highest being among the Meitei: 22.8%) (Saraswathy
et al., 2009a,b). The cumulative frequency of four haplotypes––B2D2A1, B1D2A1, B2D2A2, and B2D1A2––is
78–100% among African populations, 62–98% among European populations, 41–100% among Asian populations,
and 92–100% among East Asian populations (Bhaskar et
al., 2008). In this study, the cumulative frequency of
these four haplotypes ranges from 91.3% (Jat and
Sindhi) to 98.4% (Brahmin) and is more or less similar
to that of the Eurasian populations. The two haplotypes,
B1D1A1 and B1D1A2, that are absent in the presently
studied populations are also absent in most of the population groups from Europe and Central Asia (Kidd et al.,
1998; Flegontova et al., 2009). In India, these two haplotypes vary from 0% to as high as 41.1% among the Thadou tribe (Saraswathy et al., 2009a), thereby suggesting
that the presently studied populations are similar to
American Journal of Physical Anthropology
Eurasian populations in their haplotype frequency distribution patterns.
Low but significant LD values observed between
TaqIA and TaqIB among all the presently studied populations place them close to other Indian caste and tribal
populations. However, these populations differ from
African and Eurasian populations, where high LD is
observed (Kidd et al., 1998). Similarity with other Indian
populations with respect to LD values between the distantly placed TaqIA and TaqIB sites suggests a common
genetic background of all Indian populations, irrespective of ethnicity, language and geography.
In the PCO analysis plot (Fig. 2), the five caste populations of this study form a close cluster, suggesting a similar genetic structure of these populations. These North
Indian caste populations are placed somewhat in
between Eurasian and South Indian populations, meaning that the chance of genetic influence of Eurasian
populations on North Indian caste populations would
have been greater than on South Indian populations.
However, comparable DRD2 allelic frequency data on
other North Indian populations are not available.
Despite this, Indian populations as a whole, irrespective
of their tribe and caste status (except for a few
Northeastern tribes and the Todas of south India), form
a close cluster, suggesting a commonality in their
genetic makeup. The aforementioned findings are also
supported by AMOVA analysis based on DRD2 haplotypes (Table 4): North Indian populations in general––
both tribes and castes––have highly significant intergroup variance with Eurasian populations (2.29),
whereas it is low and nonsignificant among the presently
studied upper caste populations and Eurasian populations (20.04). This demonstrates the genetic influence of
Eurasian populations on upper North Indian caste populations. The intergroup variance of the presently studied
populations with other North Indian caste populations
(Chamar and Brahmin of Uttar Pradesh) (http://alfred. is higher (0.52) than it is with South
Indian caste populations (0.20). This may be because the
comparable haplotypic data is available on only two
other North Indian caste populations, and one of them
(Chamar) is at the bottom of the social hierarchy. The
high and significant intergroup variance (1.87) observed
between the Eurasian and South Indian caste populations is another indicator of the lesser genetic influence
of Eurasian populations on South Indian populations. As
expected, the variance among individuals and populations within groups is found to be statistically highly significant (P \ 0.001) than the variance between groups.
Very low intergroup variances, though significant in two
categories (Table 4), are observed among castes and
tribes (0.84), Indo-European and Dravidian linguistic
groups (20.29), the four distinct linguistic groups (0.69),
and the five geographical region categories (1.41), suggesting a common genetic unity of Indian population
groups. This is further supported by consistently low LD
values observed between the three sites among all studied Indian populations.
Ancient gene pools of India that supposedly belonged
to the so called ‘‘caste-like system’’ (Karve, 1961) might
have been influenced by the inflow of genes during the
Holocene (Kivisild et al., 2003). The extent of this
genetic admixture must have been geography and group
specific, i.e., more in North India than in South India,
and more in caste groups than in tribal groups, respectively. This is supported by this study, in which upper
Fig. 2. PCO graph showing the presently studied North Indian caste populations with other Indian and Eurasian populations.
TABLE 4. Extent of genetic differentiation estimated by AMOVA among the presently studied caste populations, other Indian and
Eurasian populations
Among population
within groups
Presently studied populations and Eurasian populations
Presently studied populations and other North Indian caste populations
North Indian (tribes and castes) and Eurasian populations
Presently studied populations and South Indian caste populations
South Indian caste populations and Eurasian populations
Castes and tribal groups of India
Indo-European and Dravidian linguistic groups
Among five geographically distinct populations
Among four linguistically distinct populations
Highly significance level at 0.001.
Significance level at 0.05.
caste North Indian populations seem to be genetically
closer to Eurasian populations than South Indian caste
and tribal populations; this conclusion is also supported
by data from Reich et al. (2009), in which populations
with Ancestral North Indians (ANI) ancestry supposedly
belong to caste systems with Indo-European languages
and are genetically closer to Eurasia. We hypothesize
that the reported Ancestral South Indians (ASI) were of
Indian origin but became admixed with later incoming
ANI gene pools (Reich et al., 2009) or Eurasian gene
pools according to this study to various degrees, resulting in separate, distinct genetic ancestors; this gives an
impression of a second ancestral line in Indian populations, apart from the proposed Proto-Australoid genetic
background. This study, though confined to only three
SNPs of one gene, focuses on well-defined endogamous
caste groups of North India with relatively large sample
sizes, allowing for high statistical significance. Moreover,
the available gene frequency and haplotypic data on
other Indian populations at the three sites of DRD2 gene
helps to draw more informative comparisons and inferences. Apart from this, natural selection might not be
acting on these populations, as the TaqIA allele (which
is considered the most likely candidate for selection in
the whole DRD2 gene) frequencies remain almost
uniform in all the presently studied populations. The
chances of genetic drift are also remote in this study
because of higher population sizes (100,000) in the
studied areas, combined with the practice of gotra exogamy without consanguinity, resulting in relatively higher
randomness in mating as compared to that of South Indian populations (both castes and tribes).
American Journal of Physical Anthropology
Even though there is a genetic proximity of the presently studied upper caste populations of North India
with Eurasia, this fact alone is not sufficient to support
the external origin of Indian caste system, which is
deeply rooted in the Indian psyche of both North and
South Indian populations. Moreover, the presence of the
ancestral haplotype (even in small frequencies) in the
presently studied populations, low but significant LD
values between TaqIA and TaqIB, uniform D2 allele frequency distribution and low intergroup variance in
AMOVA analysis with respect to ethnicity (tribe and
caste), language (Austro-Asiatic, Indo-European, Dravidian, Tibeto-Burman) and geography (North, South,
East, West, Central) are indicative of archaic autochthonous genetic substratum among the populations of India.
However, more systematic anthropogenetic studies with
extensive ethnographic accounts, more caste populations
belonging to the different Varna systems and more geographical variety among populations need to be carried
out to have a deeper understanding of this complex
social system.
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