Haplotype and Allelic Variations at Dopamine Receptor Gene (DRD2) among six Austro-Asiatic Speaking Tribal Groups of Central India

 

Moumita Sinha¹*, Pankaj Temunkar², Mitashree Mitra³, I Arjun Rao¹

¹Assistant Professor, Department of Forensic Science, Guru Ghasidas University, Bilaspur (C.G)

²UGC-SRF, School of Studies in Anthropology, Pt. Ravishankar Shukla University,  Raipur (C.G)

 

ABSTRACT:

Central India is mainly constituted by two states, namely; Madhya Pradesh and Chhattisgarh that are homeland of several caste and tribal groups speaking diverse language belongs to Indo-European, Dravidian and Austro-Asiatic thus makes it an important place for testing several language-gene interaction models. Various archaeological evidences indicated that the Narmada region has played a significant role in initial peopling of the Asian subcontinent. There is a necessity to fill the big lacuna by inclusion of this region to reveal a continuous picture of the origin and genetic affinity of the Indian population. It is hypothesized that Austro-Asiatic speaking tribes are autochthonous to India. The present study was conducted to examine the haplotype variations at Dopamine Receptor Gene (DRD2) in the Austro-Asiatic Speaking Tribal Groups of Central India. Haplotypes provide information on evolutionary histories, beyond what can be learned from individual marker. A total of 327 unrelated samples belonging to Birhor, Gadaba, Kol, Hill korwa, Saora and Baiga were analyzed for three selected TaqI sites of DRD2 gene using Polymerase chain reaction (PCR). All the loci were found to be polymorphic among the studied populations. The frequency of ancestral allele B2 is less than 50% in all six populations (41.4-49.2%) while D2 allele exhibit frequency of 15.3-44.8%. A1 allele observed with a frequency ranging from 36.2-48.2%.   The average heterozygosity ranged from 0.417 in Baiga to 0.501 in Kol. The ancestral haplotype (B2D2A1) in all six populations exhibit 0% frequency. LD values calculated for the three bi-allelic sites, TaqIB, TaqID, and TaqIA are low, i.e., below 0.8 with respect to all populations in each pair. Overall, allele frequency distribution patterns and high average heterozygosity values, suggest a genetic proximity among the studied populations. Low recurrence of genealogical alleles and nonattendance of familial haplotype in the examined populace bunches, demonstrating towards indigenous inception of Central Indian Austro-Asiatic talking tribes.

 

 

INTRODUCTION:

Haplotype examinations have turned out to be progressively vital in hereditary investigations of human ailments. At the point when numerous markers, frequently in linkage disequilibrium (LD), in a chromosomal locale are examined to evaluate the relationship between this district and the review attributes of intrigue, a factual examination in view of haplotypes may regularly be more productive than discrete investigations of individual markers. This has been shown both through empirical and simulation considers (Drysdale et al. 2000; Martin ET al.2000; Morris and Kalplan, 2002; Zhang et al. 2002; 2003). Firstly, haplotype examinations assess various firmly connected markers, which are substantially more instructive than individual markers (Stephens et al. 2001; Zhao et al.2003). Secondly, haplotype investigations can distinguish remarkable chromosomal sections prone to harbor illness inclining qualities. The phenotypic impact of a few transformations at various locales inside a quality can rely on upon whether the changes happen on a similar chromosome (in cis, as a haplotype) or on inverse homologous chromosomes (in trans) (Drysdale et al. 2000; Horikawa et al. 2000; Joosten et al. 2000).These discoveries underline a vital part of inspecting applicant qualities by SNP haplotyping. SNP haplotyping at DRD2 gene play important role in evolutionary genetics and studied on a worldwide scale to infer genetic structure of populations (Kidd et al. 1998). DRD2 gene is located on the chromosome 11 and it is one of five different dopamine receptor genes expressed in the central nervous system of humans. DRD2 gene has seven polymorphic sites and some of the polymorphic sites have been used in not only as causative locus for neurological disorders but also in linkage studies (Moises et al. 1991; Su et al. 1993; Gelernter et l. 1990; 1994). Out of seven, 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 and are reported to have linkage disequilibrium as they are non-randomly associated most frequently. This creates a set of haplotype pattern at two or more polymorphic sites at this gene on the same chromosomal region (Templeton, 2005).

 

The set of haplotype’s occur on the same chromosomal region has different distribution pattern among different populations which can avail more accurate and maximum information on the genetic proximity and diversity among the populations (Castiglione et al. 1995; Tishkoff et al. 2000; Lonjou et al.1999; Lonjou et al. 2003). At DRD2, on the basis of presence or absence of TaqI restriction site, allelic variants are observed. TaqI "absent" (B1, D1, A1) and TaqI "present" (B2, D2, A2) alleles are obtained in which alleles B2, D2 and A1 are considered as ancestral alleles because they are the DNA sequences present in chimpanzees, gorillas and orang-utans and their combination frames ancestral haplotype (Kidd et al.1998). The frequency and presence of the ancestral allele in a population will give the information whether population under study have African ancestry. Thus, in the present study, three polymorphic sites TaqIA (rs1800497); TaqIB (rs1079597) and TaqID (rs1800498) of DRD2 locus has been used to determine the frequency and distribution of ancestral alleles and haplotype variations among the six Austro-Asiatic speaking tribal population groups with distinct ethnic and linguistic backgrounds, chosen from Madhya Pradesh and Chhattisgarh state of Central India to infer the indigenous origin of Austro-Asiatic speaking tribes of central region (Fig1.).

 

MATERIAL AND METHODS:

The six populations we have typed for three markers in the DRD2 locus include three Particularly Vulnerable Tribal Groups of Central India namely, Baiga (PVTG) (50), Birhor (PVTG)  (56) and Hill Korwa (PVTG)  (53), Kol (51), Gadaba (59), Saora (58) from various districts of Madhya Pradesh and Chhattisgarh. With prior approval from Institutional Ethics Committee (IEC Ref. no. 015, Letter no. 030/IEC/ PRSU/2013) and written consent of 327 unrelated individuals of both sexes intravenous blood samples of 5 mL each were collected from volunteer donors of respective tribal populations. The DNA extraction was done using the salting-out procedure (Miller ET al.1988). The analysis of three selected TaqI sites of DRD2 gene was carried out through PCR-based amplifications using primers and protocols as described by Castiglione et al. (1995) and Kidd et al. (1996). After amplification, the required fragments were digested with TaqI restriction enzyme as per manufacturer’s specifications following electrophoresis in a 2% agarose gel and EtBr staining. Allele frequencies for each selected site were calculated by a gene counting method. Heterozygosities (Nei, 1973) at the respective locus were obtained using the software DISPAN (Ota, 1993). Hardy–Weinberg equilibrium was tested using chi-square 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 pairwise linkage disequilibrium value (D’) was calculated for each pair of markers using LD software (Hill, 1974). To reveal the patterns of genetic relationships among these populations and other population groups, principal coordinate (PCO) analysis was performed using the R software. We also performed an updated global analysis of B-D-A haplotype frequencies and analysis of molecular variance (AMOVA) with the available data from the ALFRED database (http://alfred.med.yale.edu) using ARLEQUIN.

 

RESULTS:

The observed allele frequencies of presence and absence of restriction site for TaqI restriction enzyme at linked RFLP loci DRD2 among six ethnic groups are given in (Table1). All the loci were observed to be polymorphic in all studied groups. Ancestral alleles (B2, D2 and A1) were found to be lower (< 50%) in all six populations. The frequency of the presence of restriction site at DRD2 TaqIB locus was found to exhibit the highest (49.2 %) in Birhor, while D2 exhibited the highest frequency (44.8 %) in Saora.

Table1. Allele frequencies for three DRD2 gene SNPs among six Austro-Asiatic tribal populations of Central India

 

Table2. Hardy-Weinberg ratios for three DRD2 gene SNPs among six Austro-Asiatic tribal populations of Central India

*Level of Significance represented at for p<0.05

 

Table3. Heterozygosity for three DRD2 polymorphic sites among six Austro-Asiatic tribal populations of Central India

 

Table4. Average observed heterozygosity and Standard Error for three DRD2 polymorphic sites among six Austro-Asiatic tribal populations of Central India

 

Table5. Haplotype distribution three DRD2 polymorphic sites among six Austro-Asiatic tribal populations of Central India

 

Table6. Pairwise Linkage Disequilibrium (Lewontonin ‘D’) values of DRD2 locus

Population	LD betweenTaq1AandTaq1B	LD betweenTaq1A and Taq1D	LD Between Taq1B and Taq1D
	D’	D’	D’
Birhor	-0.108233	-0.06565	-0.04946
Gadaba	-0.14819*	-0.29632*	-0.12137*
Hill Korwa	0.63945*	0.19809*	0.23813*
Kol	0.08119*	0.33352*	-2.58856*
Saora	0.185752*	-2.4078*	0.77143*
Baiga	0.25314*	0.18058*	0.77173*

Level of Significance at d.f.=1 for p<0.05

 

Table7. Extent of Genetic Differentiation Estimated by Analysis of Molecular Variance among Austro-Asiatic Population Groups Studied and Other Indian Populations Based on Three Dopamine Receptor D2 Polymorphic Sites

Groups	Among groups	Among populations within groups	Among individuals
Based on Linguistic family
Presently studied populations and Dravidian	-0.29	3.78	95.93a
Presently studied populations and Tibeto-Burman	0.34	12.80a	86.86a
Presently studied populations and Indo-Europeans	1.64a	5.78a	92.58a
Based on Geography
Presently studied populations and Indo-Europeans  of North Indian –Western Indian region	0.52a	-0.59	100.07
Presently studied populations and South Indian region Dravidians	–0.04	3.60a	96.44a

 a Significant at 0.05.

 

Fig1. Map of Central India

 

 

Fig2. PCO scatter graph showing six Austro-Asiatic populations on three dopamine receptor D2 sites.

 

 

Ancestral allele, A1 was found to exhibit the highest frequency (49.1%) in Kol. Significant deviation from Hardy–Weinberg equilibrium was found in Hill Korwa, Kol, Saora and Baiga at TaqIB. It also exhibits significant deviation in Kol and Saora at TaqID and Birhor, Kol and Saora at TaqIA (Table2) High levels of heterozygosity were observed at all the loci in all the groups (Table3).

 

Average heterozygosity (H) among the studied groups varied from 0.417221 in Baiga to 0.501600 in Kol (Table 4). To determine haplotype distribution among population maximum likelihood was estimated. Haplotype B2--D1--A2 was found to exhibit the highest (>10%) in all population except Kol. Ancestral haplotype B2--D2--A1 was absent in all six populations under study (Table 5). The three pair wise standardized LD (D’) values for the three bi-allelic markers (Table 6) are low, i.e. below 0.2 with respect to all the populations in each pair. The pair wise linkage disequilibrium (D’) is found to be significant among all the studied populations except Birhor between the TaqIB and TaqIA sites TaqID and TaqIA sites and TaqIB and TaqID sites. NJ tree constructed from the genetic distance (DA), which is depicted in (Fig2). It showed that six studied populations grouped in two clusters. All six populations are genetically closest in which Kol, Hill Korwa, Saora, Baiga, and Birhor are genetically closer to each other. Gadaba also shows genetic proximity with other populations by forming a separate outlier.

 

DISCUSSION:

In the present study, the frequency of ancestral allele B2, is lower (<50%) in all six populations which is less than the frequency reported in African and European populations. On the basis of available data, the frequency of ancestral allele B2 in Indo-European speaking tribes varies from 44% to 88% (Saraswathy et al. 2010; Kshatriya et al. 2010) while its frequency in Dravidian speaking tribe is >50% (Vishwanathan et al. 2003; Bhaskar et al. 2008; Prabhakaran et al. 2008; Saraswathy et al. 2009c; Sinha et al. 2015). In Tibeto-Burman speaking tribe’s frequency of this ancestral allele varies from 23% in Kom to 75.6% in Rongmei (Saraswathy ET al.2009c; Pammei et al.2016). This showed that ancestral allele; B2 is present at considerable frequencies in various linguistic groups of India. The ancestral D2 allele ranges from 15.3% in Baiga to 44.8% in Saora in populations under study. In Dravidian- speaking tribes, frequency of D2 allele ranges from 36% in Kota to 50% in Kurumba and falls within the range of Indian values. Indo-European speaking tribes reported frequency of D2 allele from 33.5% in Kolgha to 72.5% in Konkana (Saraswathy et al. 2010; Kshatriya et al. 2010), whereas in Tibeto-Burman its frequency varies from 24% to 65% (Saraswathy ET al.2009c; Pammei et al.2016). The frequency of D2 allele in various linguistic groups of India i.e. Dravidian, Indo-European and Tibeto-Burman is fall within the range of African populations while in present study populations of Austro-Asiatic speaking tribes this frequency is less than the African values.

 

The frequency of ancestral allele A1 varies from 36.2% in Saora to 49% im Kol which is lower that the frequency of A2 allele. Frequency distribution pattern of the A1 allele is in accordance with the distribution pattern of the B2 allele in the present study. An A1 allele is highly frequent in African populations, present study frequencies of A1 allele do not fall within the range of African populations. Dravidian- speaking tribes of India reported A1 allele frequency in the range of 49.8% to 67.4% (Vishwanathan et al. 2003; Bhaskar et al. 2008; Prabhakaran et al. 2008; Saraswathy et al. 2009; Sinha et al. 2015). In Indo-European speaking tribes its frequency varies from 29.5% to 62.7% and in Tibeto-Burman it exhibits the frequency of 37.8% to 82.2%. The frequency of this ancestral allele A1 is higher among Africans and the frequency of this allele in three linguistic groups of India i.e. Indo-European, Tibeto-Burman and Dravidian, are in accordance with the African values.

 

At present, no published database is available for B2, D2 and A1 allele in Austro-Asiatic speaking tribes except Ho and Munda for comparison. Therefore, it can be said that Indo-European, Dravidian and Tibeto-Burman speaking tribes of India has the frequency of ancestral alleles B2, D2 and A1 in significant frequencies and in concordance with the African values. Although, present study frequencies on B2, D2 and A1 allele in six Austro-Asiatic populations do not fall within the range of African values but do show some similarities for Indian  values.

 

The average heterozygosity values for each population in this study are higher i.e. more than 0.4, ranges from 0.41- 0.50. These values are in according to Indian values. Heterozygosity values are relatively higher (>0.4) in all six populations except in Hill Korwa, Kol and Baiga at TaqIA. At DRD2 polymorphic sites, heterozygosity value were lower in African populations (0.236- 0.387) (ALFRED) in comparison to Indian populations where heterozygosity values exhibits higher frequency and do not obey the hypothesis that population heterozygosity tends to decrease with increasing distance from Africa. This indicates towards acceptance of multiregional hypothesis regarding human evolution (Wolpoff and Caspari, 1996). The sharing of seven out of eight haplotypes in present studied populations suggested genetic affinity among the Austro- Asiatic speaking tribes of central India. B2-D2-A1 ancestral haplotype reported higher frequency in Africa and lower in frequency among populations outside Africa (Kidd ET al.1998). Populations under study exhibit 0% frequency for ancestral haplotype B2-D2-A1. Among European populations also, ancestral haplotype B2-D2-A1 reported 0% frequency (ALFRED; Flegentova et al.2009). In Indo-European speaking tribes, ancestral haplotype (B2-D2-A1) reported with frequency of 1.1% in Aggarwal to 15.9% in Mota Chaudhary (Saraswathy et al.2010; Kshatriya et al. 2003). Tibeto-Burman speaking tribe’s exhibits frequency varies from 1.2% in Paite to 22.8% in Meitei (Saraswathy et al.2009; Sinha et al.2015). Dravidian-speaking tribes reported frequency in range of 2.1% in Irula to 35.9% in Thoti while Siddis and Oraon reported 0% frequency of ancestral haplotype (B2-D2-A1) (Vishwanathan et al. 2003; Prabhakaran et al.2008, Sinha et al.2015). On the basis of available data, Munda is the only Austro-Asiatic speaking tribe whose allele frequency and haplotype data is available for DRD2 locus. B2-D2-A1 ancestral haplotype frequency was not reported in Munda (ALFRED) (10). Most recently derived haplotypes B1-D1-A1 and B1-D1-A2 are present in nearly all six Austro-Asiatic populations of central India. Dravidian-speaking tribes also exhibits these two recently derived haplotypes except Irula, Kota, Toda and Kolam (Vishwanathan et al.2003; Prabhakaran et al. 2008) whereas in Indo-European and Tibeto-Burman speaking tribes reported lower frequency or absence of recently derived haplotypes B1-D1-A1 and B1-D1-A2.  This indicates that, these two derived haplotypes are present in all the six Austro-Asiatic speaking tribes of central India implying that these tribal groups of could have been part of the older population substratum of this subcontinent. This further strengthening the observation that Austro-Asiatic tribal group of central India have distant past.  In all the six population samples, the disequilibrium at the DRD2 locus exhibits significant lower LD values i.e. less than 0.8. The SNPs, TaqIB and TaqIA; TaqIB and TaqID; TaqI A and TaqID sites showed significant pairwise disequilibrium. The reason behind low LD values is moderate heterozygosity in populations under study. A population of African and European origin exhibits high LD values (10).  In India, various linguistic and ethnic populations exhibit low significant LD. Therefore, present findings on LD values in six Austro-Asiatic speaking tribes fall within the range of Indian values.

 

AMOVA analysis based on DRD2 haplotypes in populations under study and various linguistic populations of India showed the intergroup variance of the presently studied populations and Dravidian-speaking tribes showed low non-significant values (-0.29). Tibeto-Burman speaking tribes and populations under study also depict low and non-significant intergroup variance (0.34). Presently studied populations and Indo-Europeans exhibit significant intergroup variance (1.64) in linguistic category. This indicates lower genetic influence of Indo-European populations on populations under study.

 

Among individuals variance is found to be statistically significant in all categories at 0.05% significance level. Low intergroup variances were observed in geographical category at DRD2 locus. The intergroup variances are significant in population under study and north western region Indo-European speaking tribe. A very low and non-significant intergroup variance was observed in South Indian Dravidians and studied populations. On the basis of geography, Tibeto-Burman was not compared as they are only observed in north-east regions. These findings suggested genetic propinquity of presently studied populations with Dravidian speaking tribes of south India. This might be due to inflow of genes between Dravidian speaking tribes and Austro-Asiatic speaking tribes.

 

CONCLUSION:

The presently studied populations do not show genetic proximity with Africans in terms of distribution of ancestral alleles and haplotype.  In the Indian context, populations studied showed genetic affinity with Dravidian-speaking tribes. This might be due to inflow of genes between these linguistic groups.  Furthermore, the absence of the ancestral haplotype in the presently studied populations, low but significant LD values between TaqIA -TaqIB, TaqIA - TaqIB and TaqIA- TaqIB and low intergroup variance in AMOVA analysis with respect to language ( Indo-European, Dravidian, Tibeto-Burman) and geography (South and North-West ) are suggesting deep rooted history of Austro-Asiatic speaking tribes of central India. Although, these facts are not solely enough to support the in situ origin of Austro-Asiatic speaking tribes which is considered as autochthonous tribes of India and this language family is chiefly spoken only in tribes. As no published data is available on allele and haplotype distribution of three polymorphic sites at DRD2 locus in Austro-Asiatic speaking tribes of India in this perspective present data will be an important contribution for future research.

 

ACKNOWLEDGMENTS:

We are thankful to the volunteer donors for their cooperation and participation in the study. Special thanks to Dr. Namita Mukherjee and Dr. Sanghamitra Sengupta for their inconstant help in various stages of this study.

 

AUTHORS CONTRIBUTION:

Conceived and designed the experiments: MM, MS, PT. Performed the experiments: MS, PT. Analyzed the data: MS, PT. Contributed reagents/materials/analysis tools: MM. Wrote the paper: MS, MM, IAR.

 

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Received on 01.05.2017         Modified on 24.05.2017

Accepted on 20.06.2017      © RJPT All right reserved