Mithun Sikdar Hemoglobin E in Northeast

Anthropological Review • Vol. 79(3), 241–263 (2016)

Hemoglobin E in Northeast India: A review on its origin, distribution, migration and health implication

Mithun Sikdar

DNA Laboratory Unit, Anthropological Survey of India, Government of India, Western Regional Centre

Abstract: A systematic review of the studies on hemoglobin E in Northeast India has been carried out to understand the magnitude of research undertaken on this aspect during the last seven decades. Owing to the high prevalence of hemoglobin E in this part of India different authors have studied this hemoglobin from different perspectives and found conflicting results. However a systematic review of such studies is lacking from a holistic point of view. Most of the epidemiological, in vitro as well as in vivo studies show signatures of selection with this hemoglobin locus. However, how this polymorphism is maintained at dif- ferent rates at different geographical region is still a matter of contention. This review will fill the gap from all perspectives starting from the frequency distribution of hemoglobin E and its spread in different parts of Northeast India, its relationship with malaria hypothesis, the population migration, population affinity and most importantly the health implication arising out of it. A probable origin of hemoglobin E among an Austroasiatic population of Northeast India has been postulated with the help of advance molecular anthropological knowledge like the deep rooted markers of mt DNA and Y-chromosome haplotypes.

Key words: Hemoglobin E, Northeast India, selection, population affinity, health

chromosome 11p15.5 is one of the most Introduction intensely studied genetic polymorphism of all human loci. The DNA polymor- It has been estimated that more than phism present in the hemoglobin cluster 70 lakh babies born each year with ei- is also very interesting and it has also ther a congenital abnormality or with been extensively used to examine human a genetic disease (Christianson et al. evolutionary history (Das and Talukdar 2006). Approximately 25% of these ba- 2001). Mutation of β-globin gene causes bies suffer from only five disorders of β-thallasemia and other hemoglobinopa- which two belong to inherited disorders thies of which HbS, HbE, HbD and HbC of hemoglobin (Weatherall 2010). As are most common genetic abnormalities such human β-globin gene located on in the world including India. Spatial dis-

Review Article Received: January 3, 2016; Accepted for publication: July 22, 2016 DOI: 10.1515/anre- 2016-00 19 © 2016 Polish Anthropological Society 242 Mithun Sikdar tribution of the deleterious β-globin mu- Materials and methods tations in Indian population is extremely diverse and certain mutations are re- A search of PUBMED, MEDLINE and stricted to particular population groups EMBASE (1950 to January 2016) da- only. Various evolutionary forces such tabases was supplemented by manual as natural selection, mutation, recom- searches of bibliographies of key retrieved bination, migration and genetic drift are articles, reviews of abstracts from scien- known to regulate the frequency of these tific meetings, and contact with experts. deleterious mutations in human popula- The search has been carried out taking tion. Of the various structural hemoglo- into consideration few points in mind bin variants, HbS (Codon 6A-T) variant i.e. peopling of Northeast India, hemo- is widespread among various tribal pop- globin research in Northeast India par- ulations of India (frequency 0–40.0%) ticularly in different states of Northeast where a small frequency has also been India, origin and spread of hemoglobin found among the caste populations (Rao, E, hemoglobin E and malaria hypothesis, 1998). HbD Punjab (Codon 121 G-C) hemoglobin E and health. Further the has an incidence of 2–3% among the Sikh frequency distribution of this particular population of Punjab and is also reported hemoglobin variant in different states of among some other population groups of Northeast India has been supplemented India. On the other hand HbE (Codon 26 in different tables. G-A) is confined exclusively (frequency 0.4–64.5%) among the people originat- Peopling of Northeast India ing from Eastern India, especially North- east India. It has been argued that the Many researchers veered their attention different forms of abnormal hemoglobin to Northeast Indian region due to its originated in different parts of the world considerable variation in ethnic and lin- due to its different survival advantages guistic structure. It is bordered by the and one of such advantages being the Himalayas and the Bay of Bengal in the endemic malarial condition. Because of North and South respectively and it con- conduciveness of abnormal hemoglo- stitutes an exclusively slender passage bin in the malaria endemic areas most that connects the Indian subcontinent of the population groups of Northeast to East Asia and Southeast Asia. Earli- India have been studied during the last er the entire Northeastern part of India few decades either singly or in combina- was referred to as but after the tion to have the distributional pattern of Independence of India in 1947 new ter- hemoglobinopathies in different popula- ritories and states were came into being. tion groups. It is very important to have Now the region is composed of seven ad- a sum up of most of the works on he- ministrative units and is the homeland moglobin E in Northeast India to have of different ethnic communities with its trend of research and to gear up new diverse linguistic and sociocultural tra- possibilities of research in this particular ditions. In 2002 the state of was domain. also included as the eight administrative part of Northeast India. It is said that the diverge population came to this main- land India from different directions and Hemoglobin E in Northeast India 243 at different times through various routes represented by the Indid Assamese, the like the Northern passage which opens at major inhabitants of Brahmaputra val- Bhutan and Tibet, the Eastern route of ley. Tibeto-Burmese populations are the Assam-Myanmar and from the Western earliest inhabitants of this land. One of route which constitutes the Ganges and the subdivisions of Tibeto-Burman i.e. Brahmaputra valley. North-Assam group of languages are The extensive linguistic diversity of spoken by most of the tribes of Aruna- Northeast India is represented by three chal Pradesh as well as Assam and Ma- major linguistic families: Austro-Asiat- nipur. Another subdivision known as As- ic, Indo-European and Tibeto-Burman. sam-Burma group is spoken by the Bodo The Austro-Asiatic group has a linguis- group of tribes of Assam, and tic relation with the Mon-Khmer people ; Karbis of Assam; Nagas of Na- of mainland Burma as well as galand; Mizo-kukis of ; Meities and its main representative is the Kha- of etc. Besides, there is anoth- sis of Meghalaya. The Khasis practice er linguistic group i.e. Siamese-Chinese, matriarchy unlike the other tribal popu- which is spoken by a limited number of lation of Northeast India. It is believed population groups. Tai which is one of that the Indo-European group migrated the sub divisions of Siamese Chinese to this particular land from the West and is spoken by Aiton, Turung, Khamti,

Fig. 1. Map of Northeast India showing different regions. 244 Mithun Sikdar

Khamyang and Phakials of Assam and an Assamese caste population of Low- . Once, Tai was also er Assam as a base for comparison. The the original language of the Ahom, a ma- first publication (Das et al. 1971) of this jor population group of Assam. A more study showed a high frequency of HbE recent addition to the population of (0.2 19) among the Khasi, and a higher Northeast India is the tribal people of frequency (0.359) among the Ahom. The Orissa and Chotonagpur most of which second publication of the survey (Flatz are from the Kolarian linguistic group et al. 1972) also validates the earlier and were brought to this mainland as findings. The high frequency of the gene workers in the tea gardens of Assam. among the Khasis was consistent with the hypothesis of a correlation between Hemoglobin E research Austro-Asiatic linguistic affiliations with HbE. in Northeast India At that time the high prevalence of HbE gene among the Ahom led to much Research on hemoglobin E started in speculation. Since Flatz et al. (1965) Northeast India when Chatterjea (1959) did not find HbE genotype among the reported some sporadic cases of HbE in Thai population from South-West Chi- Assamese population. A few years latter na they argued that it was not likely that Chaudhuri et al. (1962) reported a rel- the Ahom descended directly from the atively high percentage of HbE (0.099) Thai population of South-West China. among the Totos, a Tibeto-Burman pop- On the other hand historical records in- ulation of Totopara in the Assam-West dicate a process which they interpreted Bengal border. With these few investi- as ‘Thaization’ of Austro-Asiatic groups gations it became an interesting area of throughout South-East Asia during the research in Northeast India just within early centuries of Thai migration (Wood a decade of its discovery (Chernoff et al. 1961). The process was evident in the 1954; Itano et al. 1954). Shan of Burma, who were Thai speak- Initially a strong relationship be- ers with considerable prevalence of HbE tween HbE and Austro-Asiatic linguistic (Than-Batu and Hla-Pe 1971). It was groups of Southeast Asia was pointed highlighted that the Ahoms were once out by Flatz (1967) and he hypothesized a sub division of the Shan, they specu- that high frequency of HbE could also lated that it was quite possible that their be expected in the population groups of genetic structure was predominantly Northeast India which have ethnic rela- Austro-Asiatic inspite of their prevalent tion with Southeast Asia. In view of this culture and language. This relationship observed association Das et al. (1971) explained the high prevalence of HbE and later Flatz et al. (1972) veered their among the Ahom. A later work (Das et concentration towards three population al. 1975) also confirmed the high - fre groups. The first one was the Khasis of quency of HbE gene among the Ahom Meghalaya (an Austro-Asiatic group); population. the second was that of the Ahom of As- The Assamese population, which in- sam, a Tai group related to Shan of Bur- cludes the Caucasoid caste groups includ- ma (Myanmar), who had migrated from ing the people from indigenous Muslim Myanmar during 13th century A.D., and community, presented a somewhat lower Hemoglobin E in Northeast India 245 but still considerable frequency of HbE it might be not entirely due to their Aus- gene (Ahmed Das 1994). The sample tro-Asiatic background. Their ancestors collected by Flatz et al. (1972) was from in Burma, the Shans have a lower fre- Lower Assam and showed a frequency quency (0.14) of HbE in comparison to of HbE gene of 0.107, whereas the later them. The most likely explanation at the work (Das et al. 1975) was from Upper time of investigation was that it might be Assam with a little higher frequency of related to the considerable flow of genes HbE gene (0.135). They suggested that from the local Tibeto-Burman population these populations had no doubt acquired to this population after their migration the gene from surrounding populations to Assam 700 years ago. Selection and with high frequency of HbE gene. In demographic history were supposed to a later study Flatz et al. (1972) exam- be equally responsible for alterations in ined five individuals from the -Kacha the frequency of a gene like Hb E (Deka ri, a Bodo group of tribes belonging to et al. 1988). the Tibeto-Burman linguistic family and Mukherjee and Das (1990) suggested found that all of them had HbE, either that a possible reason for the rise of HbE in heterozygous or homozygous condi- frequency among the Ahom community tion. This indicated that an appreciable might be related to the gene flow from frequency of HbE gene could be found Chutia population (a Bodo group of peo- in this group. Therefore in 1975 a large ple) as intermixture of Chutias with the number of individuals belonging to this Ahom had been suggested in literature group were examined. The sample was (Chatterjee 1974). Deka et al. (1988) also drawn from rural areas of Upper Assam. conducted a study among the Brahmins It showed frequencies of HbE gene little (a priestly caste) and found that they above 0.50. This observation drew special have a low HbE frequency which was attention at that time in view of the fact significantly different from that of the that so far very little or no HbE had been other Caucasoid groups of Assam. They detected in any Tibeto-Burman groups of suggested that Brahmins being a priestly South-East Asia (Flatz 1967). After that caste occupy the highest position in the the most significant observation was the caste hierarchy and it was possible that finding of high prevalence of HbE in the caste endogamy had been stricter in them other Tibeto-Burman speakers including in comparison to the castes with lower Sonowal Kacharis (0.549), Boro Kacharis position in the hierarchical system. That (0.645), Garos (0.499), Rabhas (0.535), time it was also a matter of query that Lalungs (0.447) and Rajbanshis (0.350), whether the high frequency of abnor- where the percentage of HbAE ranges mal hemoglobin found in Northeast In- from 37.0% to 55% and HbEE ranges dia was really HbE or other variant with from 15.0% to 31.0%. At that time the similar electrophoretic mobility (e.g. Hb presence of HbE among the Bodo Kacha- Agenogi) and the confusion was cleared ris was the highest frequency of any ab- by H. Lehmann in a study of 13 blood normal hemoglobin gene so far reported samples from several ethnic groups in from any population in the world (Deka Assam collected by Prof. Flatz. They went et al. 1988). Thus a rethinking was made for fingerprinting of three samples and about the high frequency of HbE among also electrophoretic studies which proved the Ahom and it was then suggested that that the common abnormal hemoglo- 246 Mithun Sikdar

Table 1. Hb E frequency distribution in several population groups (Mongoloid origin) of Assam, Northeast India Population from HbE Sl. No. N HbAE % HbEE % Source Assam frequency Linguistic group Kam-Tai 1. Ahom 82 45.1 13.4 0.359 Das et al. 1971 2. Ahom 129 46.5 11.6 0.349 Flatz et al. 1972 3. Ahom (Sibsagar) 89 41.6 5.6 0.264 Das et al. 1975 4. Ahom (Dibrugarh) 181 46.4 11.1 0.343 Das et al. 1975 5. Ahom 119 47.1 16.8 0.403 Deka et al. 1988 6. Ahom 125 41.6 10.4 0.304 Balgir 1991a 7. Ahom 238 -- -- 0.414 Das and Sengupta 2013 Linguistic group Tibeto-Burman 8. Boro Kachari 131 47.3 31.3 0.549 Das et al. 1980 9. Boro Kachari 110 38.2 45.4 0.645 Deka et al. 1988 10. Chutiya 62 46.8 6.4 0.298 Deka et al. 1988 11. Garo 135 37 31.1 0.499 Das et al. 1980 12. Mikir 131 27.5 6.1 0.198 Das et al. 1980 13. Mishing 25 32 44 0.600 Deka et al. 1988 14. Mishing 318 49 22.6 0.462 Das and Sengupta 2013 15. Mishing 52 -- -- 0.403 Sharma and Mahanta 2009 16. Karbi 110 29.1 8.2 0.227 Deka et al. 1988 17. Lalung (Tiwa) 114 50.4 19.3 0.447 Das et al. 1980 18. Mech-Kachari 124 44.4 31.5 0.536 Balgir 1992 19. Rabha 128 55.5 25.8 0.535 Das and Deka 1980 20. Rajbanshi (A) 46 43.5 23.9 0.456 Das and Deka 1980 21. Rajbanshi (B) 46 52.1 17.4 0.434 Das and Deka 1980 22. Rajbanshi (C) 72 29.2 8.3 0.229 Das and Deka 1980 23. Rajbanshi (Total) 164 39.6 15.2 0.350 Das and Deka 1980 24. Rajbanshi 102 36.3 4.9 0.230 Deka et al. 1988 25. Sonowal Kachari 555 49.7 26.1 0.509 Das et al. 1975 (Upper Assam) 26. Sonowal Kachari 131 47.3 31.3 0.549 Das and Deka 1980 (Lower Assam) 27. Sonowal Kachari 106 45.3 17 0.396 Deka et al. 1988 28. Sonowal Kachari 158 50 31.6 0.562 Balgir 1993 29. Sonowal Kachari 112 45.5 31.1 0.549 Barua and Kotal 2008 30. Tiwa 27 25.9 18.5 0.315 Balgir 1995 31. Toto (Assam-Bengal 116 19.8 0 0.099 Choudhuri et al. 1962 border) 32. Totos (Assam Bengal 443 49.21 19.19 0.438 Bhattacharyaa et al. 2013 Border) 33. Sut 22 4.6 0 0.023 Balgir 1995 Hemoglobin E in Northeast India 247 bin in Northeast India was actually HbE There were several attempts to re- (Deka et al. 1987). Several small scale view the distribution pattern of HbE in studies in the latter period found that the several population of Northeast India frequency of HbE ranges from 0.000 to (Das and Deka 1980; Mukherjee and Das 0.640 in various populations of Mongol- 1990; Saha 1990; Das 1991; Bhasin et oid origin whereas it is between 0.028 to al. 1994; Balgir 2005) and this is an ad- 0.300 among the populations of Cauca- dition to the earlier studies. Within the soid origin in Assam and its neighbouring Mongoloid populations no HbE has been states (Tables 1–7). reported among the rural Naga tribe of (0.000) and the highest being

Table 2. Hb E frequency distribution in several population groups (Caucasoid origin) of Assam, Northeast India HbE Sl. No. Population from Assam N HbAE % HbEE % Source frequency Linguistic group Indo-European 34. Assamese (Lower Assam) 112 15.9 2.8 0.107 Flatz et al. 1972 35. Assamese (Upper Assam) 133 19.5 3.8 0.135 Das et al. 1975 36. Brahmin 98 10.2 2 0.051 Deka et al. 1988 37. Kalita 104 19.2 1.9 0.115 Deka et al. 1988 38. Kaibarta 101 24.8 1 0.133 Deka et al. 1988 39. Kaibarta 124 20.2 18.5 0.286 Balgir 1991b 40. Muslim 104 19.2 1 0.101 Deka et al. 1988 41. Muslim (Garia) 205 13.2 0.5 0.070 Ahmed Das 1994 42. Muslim (Maria) 155 23.8 3.8 0.158 Ahmed Das 1994 43. Mixed Indid group 324 17.9 3.4 0.123 Deka et al. 1988 44. Sikh (Assamese) 15 20.0 20.0 0.300 Balgir 1995 45. Sikh (Assamese) 107 32.71 5.6 0.209 Sharma and Mahanta 2013

Table 3. Hb E frequency distribution in several population groups (Mongoloid origin) of Arunachal Pradesh, Northeast India HbE Sl. No. Population N HbAE % HbEE % Source frequency Linguistic group Tibeto-Burman 46. Adi 35 11.4 0 0.057 Balgir and Dutta 1990 47. Adi (Gallong) 113 25.7 5.3 0.181 Saha 1990 48. Adi (Gallong) 108 35.2 3.7 0.210 Urade 2014 49. Adi (Minyong) 42 16.7 0 0.083 Saha1990 50. Adi (others) 60 16.7 1.6 0.099 Saha1990 51. Apatani 29 10.3 0 0.052 Balgir and Dutta 1990 52. Apatani 79 11.4 0 0.057 Saha 1990 53. Nishi 117 12.0 0 0.060 Balgir and Dutta 1990 54. Nishi 216 13.0 0.9 0.074 Saha 1990 55. Other mixed tribes 22 9.1 4.5 0.090 Balgir and Dutta 1990 56. Other mixed tribes 58 10.3 1.7 0.068 Saha 1990 248 Mithun Sikdar

Table 4. Hb E frequency distribution in several population groups (Caucasoid origin and Mongoloid Origin) of Manipur, Northeast India HbE Sl. No. Population N HbAE % HbEE % Source frequency Caucasoid origin Linguistic group Indo European 57. Brahmin 108 5.6 0 0.028 Singh et al. 1986 Mongoloid origin Linguistic group Tibeto-Burman 58. Ghagte 117 5.9 0 0.030 Singh and Singh 2008 59. Kabui 162 7.4 0 0.037 Singh 2008 60. Hill Kabui 270 6.3 0.3 0.035 Singh et al. 2010 61. Khurkhul (Section of Meitei) 123 15.4 0.8 0.085 Singh and Singh 2008 62. Meitei 203 11.3 1.4 0.071 Chakravarti and Roy 1979 63. Meitei 104 18.3 1.0 0.101 Singh et al. 1986 64. Meitei 626 15.81 1.92 0.101 Singh et al. 2010 65. Muslim 136 11.7 0 0.059 Singh and Singh 2009 66. Ningthoukhong 122 9.02 0 0.045 Singh and Singh 2009 67. Phayengs (Section of Meitei) 104 31.7 6.7 0.226 Singh and Singh 2008 68. Thadou 115 6.9 0 0.035 Singh and Singh 2009 69. Koireng 174 5.75 0 0.029 Singh et al. 2010 70. Simte 164 2.44 0 0.012 Singh et al. 2010 found among the Bodo Kacharis (0.640) In Southeast Asia HbE polymorphism of Assam. Within the Caucasoid group is maintained by heterozygote advan- the highest frequency of HbE gene being tage through protection against malaria detected among the Assamese Sikhs of (Flatz, 1967) and there was evidence for Assam (0.300) and lowest being detected a reduced fertility in HbE homozygote fe- among the Brahmins (0.028) of Manipur. males (Flatz et al. 1965; Hofliger 1971). It was suggested that population ge- A study among the Kachari population netics of HbE in Assam differs from that of Assam (Deka 1981), where falcipar- of Southeast Asia (Deka et al. 1988). um malaria was highly prevalent till the

Table 5. Hb E frequency distribution in several population groups (Mongoloid origin) of Meghalaya, North- east India HbE Sl. No. Population N HbAE % HbEE % Source frequency Linguistic group Austro-Asiatic 71. Khasi (from Shillong) 80 38.8 2.5 0.219 Das et al. 1971 72. Khasi (Shillong) 302 – – 0.008 Das and Sengupta 2011 73. Khasi (from Shillong) 120 36.4 4.29 0.225 Flatz et al. 1972 74. Khasi (from Cherrapunji) 157 4.5 0 0.022 Saha 1990 Linguistic group Tibeto-Burman 75. Mixed Bodo 24 16.8 29.1 0.375 Saha 1990 Hemoglobin E in Northeast India 249

Table 6. Hb E frequency distribution in several population groups (Mongoloid origin) of Nagaland, North- east India HbE Sl. No. Population group N HbAE % HbEE % Source frequency Linguistic group Tibeto-Burman 76. Rangma Naga 148 1.4 0 0.007 Saha 1990 77. Urban Naga 65 3.1 0 0.015 Saha and Tay 1990 78. Rural Naga 83 0 0 0.000 Saha and Tay 1990 79. Hmar 81 2.4 0 0.012 Saha and Tay 1990 80. Naga 44 6.8 0 0.035 Balgir 1991a

Table 7. Hb E frequency distribution in several population groups (Mongoloid origin) of Tripura, Northeast India HbE Sl. No. Population group N HbAE % HbEE % Source frequency Linguistic group Tibeto-Burman 81. Chakma 162 51.8 9.9 0.358 Das et al. 2002 82. Darlong 57 49.1 26.3 0.509 Das et al. 2002 83. Deb barman 104 49 16.3 0.409 Das et al. 2002 84. Halam 60 50 18.3 0.433 Das et al. 2002 85. 65 38.5 13.8 0.331 Das et al. 2002 86. Marek 64 50 31.2 0.562 Das et al. 2002 87. Mog 74 41.9 5.4 0.263 Das et al. 2002 88. Morasingh 20 0 15 0.150 Das et al. 2002 89. 27 11.1 14.8 0.204 Das et al. 2002 90. Riang 48 50 20.8 0.458 Das et al. 2002 91. Tripuri 89 53.9 12.3 0.416 Das et al. 2002 92. Uchai 70 60 21.4 0.514 Das et al. 2002 93. Mixed tribes 204 41.5 15.6 0.365 De et al.1997 beginning of control measures in 1950s, ulations of Assam. Therefore Das et al. demonstrated no decrease in reproduc- (1980) suggested that the HbE polymor- tive fitness of HbE homozygotes. Deka et phism in Assam is of transient nature al. (1988) suggested that this might be as HbE allele tends to replace both HbT because of the fact that high frequency and HbA. But deviation of the trend has of HbE in the Tibeto-Burman of Assam been observed when Das and Sengupta was connected with homozygote advan- (2013) found that HbE induced anaemia tage. On the other hand Balgir (1992) is the determining factor of increased also did not find any significant variation spontaneous abortion and infant mortal- in the reproductive performance of nor- ity among the Ahom population there- mal and abnormal hemoglobin bearers by controlling much of the selection among the Ahom population of Assam pressure on this community upto infant who were suggested to be related to the stage. Till date the research outcomes Austro-Asiatic population. Deka (1981) suggest various selection opportunities once suggested that ‘E gene is a neutral at this particular locus within the broad allele’ among the Tibeto-Burman pop- sphere of population variation. Therefore 250 Mithun Sikdar further study in this direction may give (Thailand) and the presence of the same more insight and opportunity to explore haplotype among the Kachari population other dimensions. of Northeast India suggests single origin of HbE in Thailand and Assam (Hun- Origin and spread drieser et al. 1988). Deka et al. (1988) once suggested that in case of multi- of Hemoglobin E ple mutational events, a second mutant might have its origin in the Tibeto-Bur- It is very difficult to assert the place of man population of Assam. A study (Das origin of hemoglobin E mutation with et al. 2000) among the tribal population possible explanation because of the as- from Tripura of Tibeto-Burman linguistic sociation of its multiple haplotypes with affiliation suggested that all the - muta different β-globin frameworks. And it is tions observed were linked to framework also difficult to assess the possible expla- 2 and also found that type-2 haplotype nation of such a high frequency of HbE in (5′+++βE-3′) was most common among Northeast India than the other Southeast them (19 out of 26 chromosomes). In an- Asian countries. Once it was suggested other study in Tripura similar result was that the mutation on HbE occurred in- also reported by Sil (2008) strengthening dependently in each haplotype, thus as- the proposition of common origin of HbE sociating it with multiple origin of HbE gene in populations of Southeast Asia, genotypes. It was proposed that the mu- Assam and Tripura. Thus a separate mu- tation occurred twice in Southeast Asia tational event among the Tibeto Burman (Antonarakis et al. 1982; Fucharoen et al. population cannot be asserted with the 1990). As per Antonarakis et al. (1982), present state of knowledge. Exploration the Southeast Asian population possess of HbE mutation in other Tibeto-Burman βE mutation in two β-gene frameworks, populations of Northeast India may give i.e. 2 and 3, with three different haplo- further insight to come to a firm conclu- types namely haplotype a (-+-+++-), sion. haplotype b (+----+-) and haplotype c In another study (Kazazian et al. (-+-++-+). They suggested that the 1984) a separate hemoglobin E mutation less common haplotype b (framework in two German families (one of Czech 2) might have been generated from extraction and the other of Northern Eu- common haplotype a (framework 2) by ropean ancestry) was observed to be as- meiotic crossing over between δ and β sociated with 41-1 and 33-2 haplotypes globin gene, but haplotype c (framework not observed in Southeast Asia. This 3) represented an independent origin finding further supported the hypoth- of βE gene. Since these two frameworks esis that framework-1 associated HbE differ at positions, 70 nucleotides to the gene was a separate mutation and there 5′ side of the βE mutation and 382 nu- is nothing to do with this mutation in cleotides to the 3′ side of it, their data Northeast India. suggested the existence of atleast two A clarification related to the high independent origins of the βE mutation frequency of HbE in different frame- in Southeast Asia. As per their findings works in Northeast India might be ex- hemoglobin associated haplotype 27-2 plained in terms of the occurrence of is the most common in Southeast Asia single mutation as well as single origin Hemoglobin E in Northeast India 251 of HbE mutation in Southeast Asia. In a deleterious β-globin mutation followed due course of time the single mutational by recombination and interallelic gene genotype might have extended to mul- conversion through time is the reasona- tiple haplotypes through the recombi- ble as well as quite acceptable hypothe- nation ‘hot spot’ region by crossing over sis at this time to explain the association (Chakraborty et al. 1984; Das and Talu- of the available mutations with multi- kdar 2001). If normal alleles of β-globin ple haplotype backgrounds and frame- are found on multiple haplotype back- works (Das and Talukdar 2001). With grounds then existence of mutant allele the help of forward-in-time simulation it in the haplotypes of same framework can has been shown that 95% credibility in- only be comprehended through crossing terval estimated age of the HbE variant over (Fukumaki and Fuchareon 1991; was between 1240 and 4440 years which Fullerton 1996). However explanation coincides with the estimated period in of this conjuncture cannot be perceived which P.falciparum spread from its Afri- while we see the simultaneous occur- can tropical origins to other tropical and rence of mutation at multiple β-globin subtropical regions in the world (Ohashi frameworks. At this point the third most et al. 2004). Therefore their data sup- reasonable suggestion proposed by Das ports a recent origin of HbE along with and Talukdar (2001) is about inter-allel- the spread of P.falciparum and a rapid in- ic gene conversion. This particular event crease in allele frequency. suggests non-reciprocal transfer of DNA However with the present knowledge sequences from one chromosome to an- the origin and spread of HbE mutation other by which a mutant allele induces from Southeast Asia cannot be explained a normal allele to convert into a mutant with the help of simple gene diffusion allele (Shiokawa et al. 1989; Starck et model. HbE is very much prevalent in al. 1990). The existence of a mutation South-east Asia but its highest frequency on different β-globin frameworks can be is found in the periphery of its distribu- explained by an event of interallelic gene tion i.e. in Assam as well as in the other conversion also (Fukumaki and Fuchar- Northeast Indian states. With the pres- oen 1991; Papadakis and Patrinos 1999). ent knowledge it may be assumed that In a study among the Thai population the single mutation on HbE took place (Ohashi et al. 2004) four major haplo- in one of the Northeastern states and it types (H1-H4) were found and H1 hap- diffused to Southeast Asia because of the lotype was appeared to have arisen from interethnic relations that were present in the H2 haplotype by a single mutation. the near past at least 3000 to 4000 years On the basis of the pattern of extended ago. In the absence of concrete data the linkage disequilibrium they found that earlier proposed hypothesis of Prof. Flatz β-globin gene cluster contain a recom- and supported by Prof B. M. Das regard- bination hotspot region from position ing the ‘Austro-Asiatic’ linkage with HbE 1663110 to 1665044 of the NT_028310.8 cannot be completely ruled out as op- and there is an effect of natural selection posed to independent mutation of HbE on the pattern of linkage disequilibrium. among the Tibeto-Burman population Their study also contributes to the single of Northeast India (Deka et al. 1988) or origin theory of HbE mutation in Thai among a Proto-Tibeto-Burman of South- population. Therefore, single origin of east Asia (Das 2015). Forward-in-time 252 Mithun Sikdar simulation of different mutational events of migration as suggested by Kumar et al. can be a better option to draw the atten- (2006) and Thangaraj et al. (2005). The tion of various researchers in this respect. foundation of M31 and M32 macrohap- It might be possible that HbE mu- logroup of mt DNA in India along with tation once occurred among one of the its migration shows some new insight Austro-Asiatic population group of like recent gene flow from Northeast In- Northeast India like that of the Kha- dia to Southeast Asia (Barik et al. 2009, sis (a Austra-Asiatic group) residing in Wang et al. 2011). The distribution of the foothill region of Meghalaya. The O-M95 haplotype is almost parallel to mutation on the hemoglobin loci oc- HbE where a high frequency is found in curred after they separated from the Indian Austro-Asiatic population (54%) Mundari population. It might be possi- than the Southeast Asian Austro-Asiatic ble that they separated quite early form population (38%). It is unlikely that the the Mundari population and underwent haplotype O-M95 may also have selec- a major demographic event such as com- tion relaxation in malarial environment mon founder effect followed by a bot- in Northeast India as already suggested tleneck. The mutation on β globin locus for HbE. Highest frequency and highest occurred much before agriculture as well diversity is the best way to speculate the as falciparum malaria started spreading. origin of any particular gene or haplotype A branched Austro-Asiatic group then in a particular geographical location. In migrated to Southeast Asia through such hypothetical situation the origin of Northeastern corridor taking with them HbE can be established in Northeast In- the hemoglobin E. dian population. Based on Y-Chromosome O-M95 The age estimation of fossils of ana- haplotype­ data it has been suggested tomically modern man excavated from that Mundari population appear to be East Asia is not older than 40,000 YBP one of the earliest source of populations (Wu and Poirier 1995; Jin and Su 2000) from which the Khasi-Khmuic and Mon- which again may imply that earliest pos- Khmer populations have separated and sible migration of Austro-Asiatic pop- migrated to and settled in Southeast ulation to Southeast Asia is very recent Asia, while another wave of migration phenomena (Kumar et al. 2007). The occurred much latter from Southeast age estimation of haplogroup O-M95 in Asia to Andaman and Nicobar island Southeast Asia is also suggested to be through Thailand and coastal southern ~8000 YBP (Kayser et al. 2003) which Burma (Kumar et al. 2007). If Indian is almost akin to the period of agricul- Austro-Asiatic population would have tural expansion. All these data may pos- migrated from Southeast Asia then they sibly suggest that during migration the should have shown the presence of hap- Austro-Asiatic population might have logroup O-M122 in Indian populations took away HbE mutation to Southeast as suggested by Kumar et al. (2007). But Asia. While another wave of migration as this is not the case in reality and thus suggested by Kumar et al. (2007) much goes against the view point of Kayser et later by the Mon-Khmer people from al. (2003) on Austro-Asiatic migration Southeast Asia to Andaman and Nico- from Southeast Asia to India. However bar may brought HbE to the this Island. mtDNA markers show a different picture A high frequency of Hb E in Northeast Hemoglobin E in Northeast India 253

India, its presence in the migratory route group), the earliest inhabitants of Assam as well as its presence among the popu- and the next neighbour to the Garo pop- lation groups of Andaman and Nicobar ulation. Due to the selection relaxation Islands (Murhekar et al. 2001, Barik and in the absence of malaria at high altitude, Sarkar 2012–13) may bear the testimony the frequency of HbE got reduced among of this proposed hypothesis. If this hy- the Khasis residing in the hill region in pothesis holds true more genetic analy- due course of time (0.0 20) as opposed sis along the migratory routes of possible to their plain counterpart (0.222). The Austro-asiatic migration and among the Garos and the Kacharis who received the other Mongoloid tribes of Andaman and HbE gene from the Khasis got it multi- Nicobar Island can throw light in this plied and reached a very high frequency particular issue. in due course of time (Garo, 0.50; Kacha- Now it may be speculated that HbE ri, 0.64). The presence of high frequency originated among the Khasis of Megha- of Y-chromosomal haplotype OM95 in laya. It might also be possible that from the Khasis as well as the Garos (Kumar the Khasis HbE first diffused to the near- et al. 2007) suggests that earlier both the by Garo population (a Tibeto-Burman) two matrilineal tribes had close genetic population. Then the gene flow occurred relationship. among the Kacharis (a Tibeto-Burman

Fig. 2. Hemoglobin E distribution in Southeast Asia (based on average frequency). 254 Mithun Sikdar

Here special mention may be made man linguistic family. If hemoglobin E is regarding a study made on the Phayengs acting as a neutral allele among the Ti- of Manipur (Singh et al. 2010) which beto-Burman population then all the Ti- shows a considerable frequency of HbE beto-Burman groups of Northeast India gene (0.226). In the absence of clear including Southeast Asia should indicate historical background of Phayengs the high frequency of HbE and researches authors also speculated that Phayengs going on in the present situation shows have an Austro-Asiatic origin and also the same trend. Studies made on Y chro- pointed out the possibility of matriarchal mosome haplogroup OM122 and also its society among them in near past. There- derivatives like M-134 (Das and Sengup- fore with the present state of knowledge ta 2010) among the Tibeto-Burman pop- the origin and diffusion of HbE can be ulation of Northeast India and Southeast associated with Austro-Asiatic popula- Asia show striking similarity of these tion groups. With time the hemoglobin population groups. In other way the neu- E possibly then diffused to Tibeto-Bur- trality of the hemoglobin E among all man population groups and multiplied the Tibeto-Burman population and their to a higher extent probably due to its linkages through molecular analysis can neutrality in Tibeto-Burman populations also be established. In this backdrop in malaria endemic zones. As Deka et al. a high frequency of hemoglobin E among (1988) once suggested hemoglobin E to other Tibeto-Burman groups of North- be a ‘neutral allele’ among the Tibeto-Bur- east India can also be expected.

Fig. 3. Routes of migration of different Austro-Asiatic sub-groups (Taken from Kumar et al. 2007). Hemoglobin E in Northeast India 255

Hemoglobin E and Malaria βT is near 3×10-3 in all the studied groups in Assam. The same type of relation is There is no reason to reject the associ- also found among the rural population ation of hemoglobin E with malaria. It groups of Cambodia (Sanguansermsri et is already established by in vitro anal- al. 1987).It was found that a rough meas- yses that p. falciparum grows slowly in ure of the selection pressure required to homozygous HbE containing RBCs but maintain the triallelic Hb polymorphism, not in the heterozygous one (Nagel et is 3.94×10-3 and it is comparable with al. 1981; Vemes et al. 1986). It is shown that of the earlier study already made in to be due to the membrane abnormality Northeast India. which includes the differences in mem- It might be possible that this type brane rigidity particularly in glycophor- of reciprocal relationship exist between in and sialic acid content (Chotivanish other genetic polymorphisms of blood. 2002). Thus the same relationship of Recent studies also have found a recip- HbE with malaria can be expected in rocal relationship between the presence Northeastern population groups also. of HbE and G6PD deficiency in differ- It has been found that populations ent population groups of Assam (Sikdar with different ethnic origin show corre- et al. 2008). In the same context it can lation of HbE frequency with mean an- be highlighted that the blood group ‘O’ nual rainfall and mean annual humidity may provide a protection against ma- (Bhasin et al. 1994). The reason was an- laria. Researchers have found that in O ticipated as the factors responsible for blood group the rosetting is reduced to breeding of malarial vector. But question a significant level and because of that it rises why there is differences in the fre- may give protection against falciparum quency of HbE in similar environment malaria (Rowe et al. 2007). In Northeast with endemic malaria and sometimes India the frequency of O blood group is there is absence of HbE in the same envi- also found to be quite high among sever- ronment. Notwithstanding the fact that al population groups (Singh 2011) which there are other genetic abnormalities like may have a protective role in malarial β-thalassemia and G6Pd deficiency that environment. Apart from these, there act as protective force in malaria ende- may be other factors which may have micity and are prevalent in various popu- impact on gene frequencies of several lation groups of Northeast India. There- allelomorphs. One of such factors might fore we may assume the existence of be the practice of inbreeding. Denic and dynamic interaction within these alleles Nicholls (2007) postulated a hypothesis in such a malarial environment. There that human inbreeding is the route cause may be a reciprocal relationship existing for emergence of some of the most com- within these genes which may alter the mon genetic polymorphisms in humans frequency of each other. Therefore while that are known to protect against malar- conducting research on any genetic ab- ia. There is also evidence of consanguin- normality that can have relationship with ity among different population groups of malaria hypothesis we can observe the Northeast India. Therefore emergence interaction of such alleles with each oth- of various genetic polymorphisms and er. Infact Flatz et al. (1972) once found fixation of the same with the increase that the gene frequency product of βE and of inbreeding cannot be ruled out com- 256 Mithun Sikdar

increase of inbreeding and increase in the selective polymorphism. Similarly in the aftermath of potato famine in Ireland and cholera epidemic in Costa Rica in the mid 19th century, an abrupt increase in the rate of consanguineous marriage was also reported (Denic and Nicholls 2007). In the same context Singh et al. (2010) also reported high rate of village endog- amy among the Pheyeng population of Manipur together with a high frequency of HbE. An increase in HbE among the Totos of Assam-West Bengal (from 0.099 Fig. 4. The world distribution of the origins of He- in 1962 to 0.438 in 2013) with the high moglobin S and Hemoglobin E (From Weather- all and Clegg 2001). incidence of consanguineous marriages may also supports the present conjecture. pletely in Northeast India. It may be possible that once the population groups of Northeast India went through the ca- tastrophes of malaria with a concomitant

Fig. 5. World distribution of various genetic variants and malaria hypothesis Source: https://en.wikipedia.org/wiki/Human_genetic_resistance_to_malaria. Hemoglobin E in Northeast India 257

Hemoglobin E and Health though the rate of progression of the ep- idemiologic and demographic transitions Northeast India is undergoing the phase may be slower in countries with a rapidly of demographic transition with the im- increasing population, there is no doubt provements in public health measures that, given the world distribution of the and hygienic conditions (Hemam and hemoglobin disorders, these transitions Reddy 1998; Das and Sikdar 2010; Sik- combined with increased population dar 2008a; Sikdar 2012a, 2012b). This growth will lead to a major increase in in turn may increase the genetic load in the numbers of babies born with one or terms of hemoglobin disorders through other hemoglobin disorder over the next reduced level in infant and childhood half-century (Weatherall 2010). There- mortality who will survive until their fore an increasing concern is also going reproductive period for diagnosis and on about the ill effect of hemoglobin E treatment. Once I hypothesized that to- on the health condition of the individ- gether with demographic transition the uals around the world and particularly frequency of the recessive genes like that among the population groups in North- of hemoglobin E may increase leading east India. to genetic load in a population (Sikdar With respect to hemoglobin E, it is 2008a) and it became very much implicit still not clear that whether it has any with the studies among the Sonowal pop- lethal effect on human health or not. In ulation of Assam (Barua and Kotal 2008) Northeast India many researchers (Sin- and Totos of West Bengal (Bhattacharyaa gh et al. 2010) have found that HbE ho- et al. 2013). This type of conjuncture can mozygotes live normal life like that of the further be established with the help of other polymorphisms of blood groups. In restudy of different population groups on another study in Assam (Das et al. 1979) different abnormal hemoglobin variants no significant difference has been found over a particular period of time. in the hemoglobin percent between the In terms of the frequency of thalla- three genotypic variation of hemoglobin semia same type of demographic chang- (HbAE, HbAA and HbEE) in both the es was graphically illustrated in Cyprus sexes which further demonstrates that many years before. In this connection it HbE homozygotes do not produce any can be relevantly noted that Cyprus un- physical abnormality among the people derwent this kind of demographic transi- of Northeast India. De et al. (1997) also tion shortly after World War II. Although found that homozygous E individuals thalassemia was not identified in Cyprus of Tripura are not anaemic compared to until 1944, by the early 1970’s it was es- genotypically normal individuals of the timated that, if no steps were taken to same population. control the disease, in approximately 40 However deflection of this general years’ time, the blood required to treat trend has been found when the present thalassaemic children would amount to researcher during one of his fieldwork 78,000 units per annum, 40% of the pop- found that a tribal child of twelve years ulation would need to be donors, and the old with hemoglobin E homozygous total cost to the health services would condition was undergoing regular blood equal or exceed the island’s health budget transfusion from a hospital of nearby (Weatherall and Clegg 2001). Hence, al- town in Assam. Chaliha et al. (2013) 258 Mithun Sikdar found that there is a significant differ- groups over consecutive generation as ence of anemic status among the college envisaged in different studies. going girls of Dibrugarh, Assam with re- There is another condition known as spect to the presence of abnormal HbE compound heterozygosity of HbE with either in homozygous or heterozygous thallasemia which is very much frequent condition. The trend was further corrob- in Southeast Asia including Northeast orated in other population groups of As- India. Hb E/β-thalassaemia results from sam (Sikdar et al. 2008). A recent study co-inheritance of a β-thalassaemia al- (Pathak et al. 2014) among the pediatric lele from one parent and the structural group showed that there is high frequen- variant hemoglobin E from the other. cy of anemia among the children having Hemoglobin E produces structurally ab- HbE either in homozogote, heterozygote normal hemoglobin as well as activates or compound heterozygote condition. a cryptic splice site that result in abnor- Weakness, aches and pain, splenomeg- mal messenger RNA (mRNA) process- ally, hepatosplenomegally, joint pain and ing. In this action the level of normally stomach pain are also the other morbid spliced mRNA, βE, is reduced. A new conditions among these children. stop codon is generated and as a result In this regard attention can be drawn the abnormally spliced mRNA become to a study done on the population groups non functional. Hence, hemoglobin E is of South Bengal and Tripura (Das et al. synthesized at a reduced rate (Orkin et 2000) where four types of HbE hap- al. 1982) and behaves like a mild form of logroup have been found and all of which β-thalassaemia. The pathophysiology of were linked to framework 2. A compar- Hb E/β-thalassaemia is related to many ative account between this haplotype factors including reduced β chain synthe- based genotypes and their respective he- sis. It may ultimately result into globin matological and clinical profiles showed chain imbalance, ineffective erythro- that type 1 homozygotes are more anae- poiesis, apoptosis, oxidative damage and mic compared to the homozygotes for shortened red cell survival (Dutta et al. type 2 haplotypes. At this stage it is very 2006, Pootrakul et al. 2000). In general, much prudent to identify the different it appears that the recognized instability haplotype variation of HbE while con- of hemoglobin E is a minor factor in the ducting further research on hemoglobin overall pathophysiology of Hb E/β-thal- in this part of India to see the role of dif- assaemia, except during inter-current ferent haplotypes on the health profile of febrile illnesses during which such insta- the various population groups of North- bility may result in accelerated hemol- east India. In Austro-Asiatic populations ysis (Jetsrisuparb et al. 2006). There is the HbE is associated with framework 3 much more to be done in this particular (Hundreiseret et al. 1988, Yongvanitet domain of research and Northeast Indian et al. 1989; Fucharoen et al. 1997, 2002) region offers us prospective issues to be which may have yielded differential sur- uncovered in due course of time. vival among the Austro-Asiatic popula- tion lowering the HbE frequency among Conclusion the Austro-Asiatic population in compar- ison to the Tibeto-Burman population The present review on hemoglobin E in Northeast India has been divided into Hemoglobin E in Northeast India 259 five headings i.e. peopling of Northeast moglobin E in Northeast India will not India, hemoglobin E research in North- only enrich the existing dataset on hemo- east India, origin and spread of hemoglo- globin research but will also try to fill the bin E, hemoglobin E and malaria hypoth- gap of new perspectives to be undertaken esis, hemoglobin E and health. The first in due course of time. part describes the ethnic composition of Northeast India along with its linguistic Conflict of interest diversity. It offers us the scope to carry out population based screening of hemo- The author declares that there is no con- globin E to understand the dynamics of flict of interests regarding this work. the genetics of hemoglobin E in different population groups of Northeast India Corresponding author which is yet to be conducted in real sense of the term. The second part takes into Mithun Sikdar, DNA Laboratory Unit, account the history of research on hemo- Anthropological Survey of India, Gov- globin E in Northeast India and also the ernment of India, Western Regional Cen- studies showing differential frequency tre, Udaipur, Rajasthan-313001, India, distribution of hemoglobin E in differ- e-mail address: [email protected] ent population groups of Northeast In- dia. We can have a look that most of the References works on hemoglobin E have been con- fined to Assam and Manipur thus offer- Ahmed Das F. 1994. A biological profile of the ing us a scope to extend our dimension Assamese Muslim of Dibrugarh, Upper of research to other parts of Northeast Assam. In: A K Ghosh, editor. People of India. The third part describes the proba- India: Biocultural dimensions. Inter India publication, New Delhi 84–91. ble origin of HbE among an Austro-asiat- Antonarakis SF, Orkin SH, Kazazian HH, Goff ic population group with the help of mo- SC, Boehm CD, Waber PG, et al. 1982. lecular anthropological knowledge and Evidence for multiple origins of the B glo- new insight on population migration. bin gene in South Asia. Proc Nat Acad Sci The probable correlation of hemoglo- USA 79:6608–11. bin E with malaria has been dealt in the Balgir RS. 1992. Reproductive profile of forth section. 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