Near Extinction of HbS Among the Tribes in Bengal: An Effect of Epistasis?

Introduction : Tribal communities are genetically isolated populations mostly following endogamy. The large tribal population in India inhabits widely varying ecological and geo-climatic conditions in different concentration throughout the country. It is widely established that the high frequencies of genetic blood disorders (haemoglobinopathies) are the result of evolutionary selection (Haldane 1949; Flint et al. 1998). The sickle gene, which protects against malaria, provides an example of balanced polymorphism (Stuart M.J; 2004). The tribal area in India is mostly associated with high incidence of malaria. Thalassaemia is highly prevalent among the tribal communities in india; and interestingly the occurrence rate of a particular mutation/ type of thalassaemia varies to a great extent from one to another (R.Colah, 2014 ; R.Dastidar, 2007). According to a survey by ICMR the Sickle Cell gene was found amongst different tribal groups of India; which varies from 5 to 34 % (M.Kaur; 2013). The prevalence of alpha thalassaemia, which also gives protection against malaria, varies throughout the country. The frequency and distribution of thalassaemia among the tribes India is less well-documented; especially in the eastern part of the country where there have not been much thorough studies upon hemoglobinopathies among the tribes with a large number sample population. In this study the primary aim was to investigate the prevalence of anemia, Sickle Cell disease and other mutant hemoglobin amongst the tribal community in west Bengal.

Method: Over a duration of 18 months, 17,369 school going children (age= 10 - 18 years), among the tribal community, from almost all the districts of West Bengal were included in this study; and were initially screened by complete haemogram and HPLC analysis. Detection for alpha 3.7 deletion & alpha 4.2 deletion, the most common form of alpha gene defect in India, were carried by GAP-PCR; and HbS mutation analysis by ARMS PCR.

Result: Approximately 6 % among the total study population was found to be carrier for beta thalassaemia; and only 0.4 % of the total population with HbS. 30 % of the population were found to be absolute normal based on the HPLC parameters and RBC indices [Table-1,2 & 3; Figure 1] . Around 62% were found to have 'normal HPLC values with abnormal RBC indices' who were subjected to 'further investigation'.

For 'further investigation' we initially selected six districts; under which total number of individual screened were 5357; among which 65% were found to have 'normal HPLC values with abnormal RBC indices' after initial routine screening [ Table- 4, 5,] who were subjected to further investigation for the detection of alpha 3.7 deletion and alpha 4.2 deletion. Almost 83% of them were found to carry (3.7 or 4.2 or both 3.7 + 4.2) alpha gene deletion [ Table 6, 7, 8]. Though prevalence of alpha thalassaemia carrier was found to be high; HbS carrier was found to be only 0.3% by HPLC. The samples carrying alpha deletion were re-checked for the presence of HbS mutation; none of the which was found carry silent / suppressed form of HbS mutation.

Discussion : Recently few studies have focused on understanding the co-association between alpha gene mutation and HbS in populations under constant pressure of malaria; which have shed light upon few aspects like- Negative Epistasis, Genetic Drift, Positive Selection etc regulating the outcome (S. Penman,2011; MB Rumaney, 2014 ). The high prevalence of alpha gene mutation found in our study may be attributed to the fact that alpha mutation is also known to have protective role against malaria. At the same time there is a genetic drift which has caused lowering the prevalence of HbS. The widely varying prevalence of alpha deletion (high) and exceptionally low prevalence of HbS ( exceptionally low ) may be a consequence of epistasis and positive selection depending upon the risk factors associated with the mutations of two distinct alleles; which can be described by mathematical modeling (S. Penman;2011).

Conclusion: Though asymptomatic, such high prevalence of alpha gene mutation is alarming as it may result in high occurrence of HbH disease among the tribal population where there is high rate consanguine marriage; if not intervened through proper marriage counseling and raising general awareness in the society.

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