How Do Sickle Cell Genes Protect Tribal People from Deadly Malaria? Is This a Type of Natural Selection?

Special Article - Anaemia

Ann Hematol Onco. 2023; 10(5): 1437.

How Do Sickle Cell Genes Protect Tribal People from Deadly Malaria? Is This a Type of Natural Selection?

Shanti Lal Choubisa*

Department of Advanced Science and Technology, National Institute of Medical Science and Research, NIMS University Rajasthan, Jaipur, Rajasthan 303121, India; Former Department of Zoology, Government Meera Girls College, Udaipur, Rajasthan 313002, India

*Corresponding author: Shanti Lal Choubisa Department of Advanced Science and Technology, National Institute of Medical Science and Research, NIMS University Rajasthan, Jaipur, Rajasthan 303121, Indial; Department of Zoology, Government Meera Girls College, Udaipur, Rajasthan 313002, India. Email: [email protected]

Received: July 28, 2023 Accepted: August 30, 2023 Published: September 14, 2023

Abstract

In humans, genetic mutations have led to the formation of several haemoglobin (Hb) variants during human evolution. These mutations usually occur in the genes for a and Β- polypeptide or globin chains of haemoglobin located on chromosomes 11 and 16, respectively. Among these haemoglobin variants, sickle cell haemoglobin (Hb-S) is highly significant in the humans. In fact, this abnormal or mutant haemoglobin is the resultant of a point mutation in the gene for Β-globin, located on chromosome 11. No doubt, this sickle cell gene is relatively more prevalent among tribal people and widely distributed in those geographic regions where the dreaded Plasmodium falciparum-malaria is hyperendemic. In the human population, this mutant gene exists in two forms, the heterozygous (Hb-AS) and homozygous (Hb-SS) states. But this sickle cell gene is also found in association with other mutant genes of erythrocyte or red cell genetic disorders, such as abnormal Hb-C, Β-thalassemia, G-6-PD enzyme deficiency, etc.

It is well known that tribal people generally live in forest ecosystem where dreaded malaria is also found to be endemic. How have these tribal people been able to protect themselves from this dreaded malaria for thousands of years in such a hostile environment, when they were most likely to be infected with the malaria parasite? Actually, its secret is hidden in these sickle cell genes only. Tribal individuals who have these genes in the heterozygous state (Hb-AS) do not get malaria or are protected from malaria and lead a healthy life. Several studies have confirmed that AS heterozygote people are protected against malaria. In contrast, those who have these genes in the homozygous (Hb-SS) state (homozygotes) develop sickle cell anaemia, which is fatal. Such patients die early due to severe malaria i.e AS heterozygotee individuals have a double advantages. In fact, it is a type of natural selection and also shows a balanced polymorphism in tribal people which is based on Darwin’s theory. This current communication provides factual and scientific information about the origin of sickle cell genes in the context of natural selection and how these genes protect tribal individuals from malaria. This communication is useful and important for zoologists, scientists working on human evolution, and medical scientists.

Keywords: Alleles; Erythrocytes; Haemoglobin; Homozygotes; Heterozygotes; Malaria; Natural selection; Sickle cell gene; Sickle cell haemoglobin; Sickle cell anaemia; Sickle cell trait; Tribals

Introduction

Except perhaps Africa, India has the largest population of tribal people in the world. In a way, these people are also called the children of nature and their lifestyle is determined and molded by the ecosystem. There are over 533 tribes in India that live in diverse forest ecosystems. As per 2011 census, 10.42 Cr. Indians notified as 'Scheduled Tribes' (ST) constitute 8.6% of the total population in the country. In 2001, the tribal population of India increased to 10.43 million from 8.43 Cr. In the world, among diverse ethnic groups or tribes, many tribes are still primitive types that still survive in hostile environments where malaria is more prevalent and highly endemic. It is well known that malaria is fatal, which is caused by infection with Plasmodium falciparum-malaria parasite. According to the recent World Malaria Report, 2022, by World Health Organization [1], thousands of people die due to malaria worldwide every year in malaria endemic countries. Interestingly, the malaria parasite and its vectors and the tribal people have been living together for thousands of years or centuries and are still living together, yet the tribal people are still alive and protected from malaria infection. After all, how do these tribal people escape from malaria and stay safe? In fact in these tribal people it has been possible by natural selection. Probably this is a wonderful, unique and rare example in human biological development or evolution.

In fact, malaria itself is an important biological factor responsible for this natural selection [2,3]. During biological evolution, this malarial strain or pressure caused a mutation in the Β-polypeptide or globin gene on chromosome 11 associated with human red blood cells (erythrocytes), leading to the formation of sickle cell haemoglobin (Hb-S) in these cells [4]. Because of this, the shape of the blood cells becomes sickle (Figure 1). These mutated Β- globin genes are also known as sickle genes, which inherited from one generation of tribals to another, which are still present in them. These sickle genes are responsible and capable of protecting these tribals from deadly malaria [5-21]. In addition to the sickle cell gene, some other genes for red cell genetic disorders, such as Hb-C, Β-thalassaemia, glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, and blood groups are also found for genetic resistance to malaria in human populations [22-36]. This current communication provides factual and scientific information about the origin of sickle cell genes in the context of natural selection and how these genes protect tribal individuals from malaria. This communication is useful and important to zoologists, scientists working on human evolution, and medical scientists.

Figure 1: Red blood cells or erythrocytes are usually round and flexible. But in sickle cell anaemia, some red blood cells appear in sickle forms.

    

    
    

    

    Figure 1: Red blood cells or erythrocytes are usually round and flexible. But in sickle cell anaemia, some red blood cells appear in sickle forms.

Sickle Cell Haemoglobin (Hb-S)

Human or mammalian haemoglobin (Hb) is a tetrameric conjugated protein composed of two subunits, each of the a (alpha) and Β (beta)- polypeptide or globin chains. Each polypeptide chain is attached to a heme prosthetic group. These chains are made up of amino acid residues. The a-chain consists of 141 residues while the Β-chain consists of 146. Thus normal adult Hb (Hb-A) consists of two a and two Β-chains and is composed of 574 amino acid residues [37,38]. Globin chains are produced in the cytosol of erythrocytes and occur by genetic transcription and translation. The presence of heme in the erythrocyte induces globin gene transcription. The alpha and beta- chain genes are located on chromosomes 16 and 11, respectively. The heme prosthetic group is synthesized both in the cytosol and mitochondria of erythrocytes [37,38].

The synthesis of sickle cell haemoglobin (Hb-S) is the result of a single base-pair point mutation (GAG to GTG) in the Β-polypeptide or globin gene located on chromosome 11. This genetic mutation is responsible for the substitution of the amino acid glutamic acid (hydrophilic) for valine (hydrophobic) at the 6th position of the Β-chain of haemoglobin (Β6Glu) → Val), the resulting Hb is called sickle cell haemoglobin (Hb-S). In fact, this amino acid substitution leads to the formation of linear polymers of deoxygenated Hb-S. The gene responsible for Hb-S synthesis is known as the sickle cell gene. Heterozygous individuals (heterozygotes) have a mutation in only one of the two Β-globin chains, resulting in sickle cell trait (Hb-AS). Resistance to falciparum-malaria infection and complications are benefits of the sickle cell trait. Homozygotes have mutations in both Β-globin chains, resulting in sickle cell disease. When deoxygenated, Hb-S causes deformation of erythrocytes from a bulging disc into a crescent or "sickle" shape. This change in shape damages erythrocyte membranes, causing premature destruction of erythrocytes and chronic hemolytic anaemia. Sickled erythrocytes can obstruct blood flow and cause tissue hypoxia, which can lead to severe ischemic pain or even stroke. These patients also have functional asplenia and are at risk of infection with encapsulated organisms [39,40]. This abnormal Hemoglobin (Hb-S) was discovered by Herrick in 1910 in a black student in the West Indies [4]. His blood film revealed the presence of sickle shaped RBCs or sickle cells (Figure 1).

Sickle Cell Genes among Tribal People

The prevalence of sickle cell trait varies markedly between different regions, but reaches as high as 40% in some regions of sub-Saharan Africa, eastern Saudi Arabia, and central India, where fatal malaria is also endemic [40,41]. In the Scheduled Tribe (ST) population of India, the prevalence of sickle cell gene ranges from 0 to 35% in different ethnic groups of the tribes. Tribal groups with high prevalence of Hb-S (20–35%) include Bhils, Madiyas, Pawaras, Pardhans, and Otkars [42,43]. In India, apart from tribal individuals [44-54], red cell genetic disorders, such as abnormal Hbs, thalassaemia syndrome, and Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, have also been reported in various ethnic groups belonging to Scheduled Castes (SCs), Other Backward Castes (OBCs) and minorities including Muslim, Bohra-Muslim and Jain communities have also been reported in Rajasthan state [55-67]. In fact, this state has two distinct ecosystems arid or desert and humid where malaria is found to be hypo and hyperendemic, respectively.

Interestingly, these sickle cell genes appear to follow Mendel's laws of inheritance and are distributed accordingly in human or tribal population. Sickle cell gene alleles are commonly found in two forms, the heterozygous (AS) and homozygous (SS) states. In the population, those who are AS heterozygotes have genes for both normal Hb (Hb-A) and sickle cell Hb (Hb-S) and these people live as normal individuals and are protected from malaria but SS homozygotes have the SS alleles and these people have an inherited hemolytic disease, Sickle Cell Anaemia (SCA). This hemolytic disease is usually fatal. There's no cure for most people with sickle cell anaemia. Treatments can relieve pain and help prevent complications associated with the disease.

How do Sickle Cell Genes Protect Tribal People from Malaria?

Based on seminal work confirmed by numerous experimental works, clinical and epidemiological field studies from different parts of Africa covering large population or having large sample size [5], it has been concluded that in AS heterozygotes P. falciparum-infected erythrocytes sickle preferen tially and are then removed by macrophages by following the phagocytosis mechanism [19]. Furthermore, these studies have also been validated by rigorous statistical analysis [15]. These studies have revealed that AS heterozygotes are more prone to malaria and have a lower number of parasitized erythroctes in their blood. In addition, AS heterozygotes have a lower incidence of two forms of life-threatening severe malaria, cerebral malaria and severe anemia, and very rarely AS heterozygotes die from malaria, even in rare cases when they develop cerebral malaria [12]. These studies also indicate that malarial environments increase the fitness of AS heterozygotes [20].

Interestingly, in protection against malaria, the sickling event has a potential and important role that occurs in AS erythrocytes that had been parasitized (6,68). This indicates that once the malaria parasite has triggered sickling (probably due to deoxygenation and lowering pH caused by the malaria parasite), the sickle cells will be removed by macrophages by a phagocytosis mechanism [10,69]. This sickling-phagocytosis model or mechanism has also been confirmed [27]. No doubt, through this process the parasitemia density or load is relatively reduced in AS heterozygotes [7,8,13,20,27,31]. For easier understanding the sickling-phagocytosis model is also shown in Figure 2. A recent study conducted in Uganda observed that AS heterozygous children (age 1–10) were found to be protected from (i) establishment of blood-stage malaria parasite infection, (ii) development of higher densities of parasites, and (iii) progression of infection to symptomatic malaria [18]. In addition, another reason for protection against malaria is that sickle-shaped erythrocytes create a very unfavorable environment for the development of the malaria parasite, partly due to the low oxygen level. Reduced parasite growth may allow more time for the immune system to respond and destroy infected erythrocytes. In addition, it was confirmed that the malaria parasite, Plasmodium, is unable to penetrate or infect the plasma membrane of erythrocytes containing sickle cell haemoglobin (Hb-S) [32]. However, scientists are still working to piece together the exact mechanisms involved in such malaria genetic resistance in humans or tribal people.

Figure 2: Schematic diagram showing how AS heterozygotes relatively protected from severe Plasmodium falciparum-malaria. The upper part of the diagram shows the red cell (erythrocyte) of a normal (Hb-AA) individual suffering from malaria. After the invasion of the erythrocyte by the merozoite, it becomes a ring shape, and then undergoes the schizogonic cycle and release of new merozoites from erythrocytes. The lower part of the diagram shows what happens to the red cell in an AS heterozygote with malaria. The red cell, which appears normal at the time of invasion, undergoes sickling once infected and thus becomes an easy prey for macrophages. Phagocytosis of the parasitized red cells apparently interrupts the schizogonic cycle and thus parasitism can be controlled naturally. Source [19].

    

    
    

    

    Figure 2: Schematic diagram showing how AS heterozygotes relatively protected from severe Plasmodium falciparum-malaria. The upper part of the diagram shows the red cell (erythrocyte) of a normal (Hb-AA) individual suffering from malaria. After the invasion of the erythrocyte by the merozoite, it becomes a ring shape, and then undergoes the schizogonic cycle and release of new merozoites from erythrocytes. The lower part of the diagram shows what happens to the red cell in an AS heterozygote with malaria. The red cell, which appears normal at the time of invasion, undergoes sickling once infected and thus becomes an easy prey for macrophages. Phagocytosis of the parasitized red cells apparently interrupts the schizogonic cycle and thus parasitism can be controlled naturally. Source [19].

Is it Natural Selection Against Malaria in Tribals?

No doubt, in human evolution, it is a complex or unique type of natural selection in tribal people who are living in geographical areas where malarial parasitic disease is more prevalent and hyperendemic. That is, the origin of the sickle cell gene is thought to have resulted from genetic mutation under the pressure of the biological agent malaria. It is well documented that ‘natural selection’ is the major driving force for the evolution of living organisms [70] and “evolutionary theory” is largely based on an understanding of “selection” and its consequences for the origin of species. The concept of ‘fitness’ is a central theme of the theory of evolution. The Darwinian concept of selection is now understood in population genetics as the operational force that determines the relative fitness of a genotype in the population, thus affecting the gene concerned [71]. It is also recognized that selection has playing an important role the one hand, in the evolution of living organisms in achieving change in gene frequency by differential survival and reproduction of genotype, and on the other hand, playing a conservative role by producing equilibrium between mutation and selection [72]. One of the best examples for balance polymorphism or natural selection is sickle cell gene (Hb-S) which is more prevalent in tribes inhabiting malaria endemic regions. The AS heterozygote or individual has sickle cell trait (Hb-AS) is protected against falciparum malaria and does not suffer from lethal sickle cell anaemia or disease (Hb-SS), whereas the normal homozygote (Hb-AA) is vulnerable to malaria parasite infection [73]. Further it was also confirmed that malaria parasite, Plasomodium is unable to penetrate or infect the plasma membrane of red blood cells containing sickle cell Haemoglobin (Hb-S) [68].

Apart from sickle cell gene, G-6-PD enzyme deficiency and beta- thalassaemia genes are also examples of natural selection and are protective factors against the malaria in tribals [74]. The relationship between malaria and these mutant genes has also been investigated and it is now generally accepted that malaria exerts a selective pressure for the maintenance of higher frequencies of sickle cell, Β-thalassaemia, and G-6-PD enzyme deficiency genes. In southern Rajasthan (India) where malaria is also hyperendemic, abnormal haemoglobin, such as Hb-C and Hb-SC have also been detected and reported. Though, these genes are less prevalent but their presence in the tribal population has great significance in relation to malaria. The relationship between other abnormal Hb variants and malaria is still unclear or controversial. However, these are, perhaps, due to effect of physical and biological factors of particular geographical region or environment. However, for its justification, more in-vitro and scientific studies are highly suggested.

Sickle Cell Anaemia (Hb-SS) and Fluoride Poisoning in Tribals

In India, especially in rural areas with a high tribal population, almost all drinking groundwater sources are contaminated with fluoride [75-78]. In these areas, thousands of tribal people suffer from chronic fluoride poisoning or hydrofluorosis disease due to the consumption of fluoridated water for both drinking and cooking [79-82]. Neighborhood fluorosis due to long-term industrial fluoride exposure has also been reported in tribals in India [83,84]. It is well established that fluoride damages not only hard tissues (teeth and bones) but also various soft tissues including blood cells. In recent studies, it has been concluded that excess fluoride exposure accelerates various hematological degenerations leading to erythrocyte death and anaemia [85-87]. In tribals, sickle cell disease and Β-thalassaemia major are also fatal and cause varying degrees of anemia in tribal adults and children, respectively [25]. Therefore, premature death due to chronic fluoride intoxication is possible in tribal people with these inherited red blood cell genetic diseases. But the attention of the people of the concerned department about this danger has not gone yet, while there is a need for more attention and research.

Conclusion

There is no doubt that malaria is a deadly disease in humans, which is still prevalent and endemic in many countries where tribal populations are also found prominently. Thousands of tribal people live in rural and forest areas where even primary health facilities are not available. Yet these people have been found to be protected from malaria. How can this be possible? Actually, its secret is hidden in the special type of genes present in them. These are called sickle cell genes, which originated during biological evolution due to mutations in genes under malaria pressure. These genes are relatively more prevalent in tribal people and are responsible for the synthesis of sickle cell haemoglobin (Hb-S) and formation of sickle-shaped erythrocytes. In tribal people, these genes are distributed and exist in two forms, the heterozygous (AS) and homozygous (SS) states. Several studies have proved and confirmed that AS heterozygote individuals lead normal lives and are protected from malaria, whereas SS homozygote subjects suffer from the hemolytic fatal disease, sickle cell anemia. This is a kind of “natural selection” in humans. In this only that individual survives (AS heterozygote) who is compatible with nature and is capable of living, otherwise nature automatically eliminates or destroys it (SS heterozygote). In humans, this type of phenomenon also reflects “survival of the fittest” as well as balanced polymorphism in human populations. However, more scientific studies are needed to uncover the exact mechanisms involved in malaria genetic resistance in humans.

Author Statements

Conflict of Interest

There is no conflict of interest of the author.

Acknowledgements

The author thanks to Dr. Darshana Choubisa, Associate Professor, Department Prosthodontics and Crown & Bridge, Geetanjali Dental and Research Institute, Udaipur, Rajasthan 313002, India for cooperation.

References

  1. WHO. World malaria report. Geneva: World Health Organization. 2022; 1-133.
  2. Haldane JBS. The causes of evolution. London: Longmans Green & Co; 1932.
  3. Haldane JBS. Disease and evolution. Ric Sci. 1949; 19: 68-76.
  4. Herrick JB. Peculiar elongated and sickle-shaped red blood corpuscles in a case of severe anemia. Arch Intern Med (Chic). 1910; 6: 517-21.
  5. Allison AC. Protection afforded by the sickle cell trait against subtertian malarial infection. Br Med J. 1954; i: 290-4.
  6. Luzzatto L, Nwachuku-Jarrett ES, Reddy S. Increased sickling of parasitised erythrocytes as mechanism of resistance against malaria in the sickle-cell trait. Lancet. 1970; 1: 319-21.
  7. Friedman MJ. Erythrocytic mechanism of sickle cell resistance to malaria. Proc Natl Acad Sci U S A. 1978; 75: 1994-7.
  8. Guggenmoos-Holzmann I, Bienzle U, Luzzatto L. Plasmodium falciparum malaria and human red cells. II. Red cell genetic traits and resistance against malaria. Int J Epidemiol. 1981; 10: 16-22.
  9. Choubisa SL. Sickle cell haemoglobin, glucose-6-phosphate dehydrogenase deficiency and thalassaemic genes in relation to malaria endemicity. Indian J Parasitol. 1985; 9: 131-3.
  10. Luzzatto L, Pinching AJ. Commentary to R Nagel -innate resistance to malaria: the intra erythrocytic cycle. Blood Cells. 1990; 16: 340-7.
  11. Choubisa SL. Abnormal haemoglobins, thalassaemia and G-6-PD enzyme deficiency in Rajasthan (Western-India). Haematologia. 1991; 24: 153-65.
  12. Olumese PE, Adeyemo AA, Ademowo OG, Gbadegesin RA, Sodeinde O, Walker O. The clinical manifestations of cerebral malaria among Nigerian children with the sickle cell trait. Ann Trop Paediatr. 1997; 17: 141-5.
  13. Aidoo M, Terlouw DJ, Kolczak MS, McElroy PD, Ter Kuile FO, Kariuki S, et al. Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet. 2002; 359: 1311–1312.
  14. Williams TN, Mwangi TW, Roberts DJ, Alexander ND, Weatherall DJ, Wambua S, et al. An immune basis for malaria protection by the sickle cell trait. PLOS Med. 2005; 2: e128.
  15. Williams TN. Human red blood cell polymorphisms and malaria. Curr Opin Microbiol. 2006; 9: 388-94.
  16. Cholera R, Brittain NJ, Gillrie MR, Lopera-Mesa TM, Diakité SA, Arie T, et al. Impaired cytoadherence of Plasmodium falciparum-infected erythrocytes containing sickle hemoglobin. Proc Natl Acad Sci USA. 2008; 105: 991-6.
  17. Ferreira A, Marguti I, Bechmann I, Jeney V, Chora A, Palha NR, et al. Sickle hemoglobin confers tolerance to Plasmodium infection. Cell. 2011; 145: 398-409.
  18. Gong L, Maiteki-Sebuguzi C, Rosenthal PJ, Hubbard AE, Drakeley CJ, Dorsey G, et al. Evidence for both innate and acquired mechanisms of protection from Plasmodium falciparum in children with sickle cell trait. Blood. 2012; 119: 3808-14.
  19. Luzzatto L. Sickle cell anaemia and malaria. Mediterr J Hematol Infect Dis. 2012; 4: e2012065.
  20. Taylor SM, Parobek CM, Fairhurst RM. Haemoglobinopathies and the clinical epidemiology of malaria: a systematic review and meta-analysis. Lancet Infect Dis. 2012; 12: 457-68.
  21. Choubisa SL, Choubisa A. Status of erythrocyte genetic disorders in people of desert and humid environments, Rajasthan, India: focus on natural selection in tribals against malaria. Proc Indian Natl Sci Acad. 2021; 87: 433-45.
  22. Luzzatto L, Usanga FA, Reddy S. Glucose 6-phosphate dehydrogenase deficient red cells: resistance to infection by malarial parasites. Science. 1969; 164: 839-42.
  23. Choubisa SL, Sharma PN, Parmar L. Haemoglobin-A2 and glucose-6-phosphate dehydrogenase deficiency in relation to malaria. Indian J Parasitol. 1984; 8: 247-9.
  24. Miller LH, Mason SJ, Dvorak JA, McGinniss MH, Rothman IK. Erythrocyte receptors for (Plasmodium knowlesi) malaria: Duffy blood group determinants. Science. 1975; 189: 561-3.
  25. Choubisa SL. Study of certain haematological genetic polymorphic systems in relation to malaria endemicity in tribes residing in arid and humid ecosystems of Rajasthan. A technical report. New Delhi, India: Indian Council of Medical Research. 1997; 1-24.
  26. Modiano D, Luoni G, Sirima BS, Simporé J, Verra F, Konaté A, et al. Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature. 2001; 414: 305-8.
  27. Ayi K, Turrini F, Piga A, Arese P. Enhanced phagocytosis of ring-parasitized mutant erythrocytes: a common mechanism that may explain protection against falciparum malaria in sickle trait and beta-thalassemia trait. Blood. 2004; 104: 3364-71.
  28. Choubisa SL, Choubisa DK, Choubisa L. The ABO blood groups and malaria. J Parasit Dis. 2005; 29: 109-11.
  29. Fairhurst RM, Baruch DI, Brittain NJ, Ostera GR, Wallach JS, Hoang HL, et al. Abnormal display of PfEMP-1 on erythrocytes carrying haemoglobin C may protect against malaria. Nature. 2005; 435: 1117-21.
  30. Verra F, Simpore J, Warimwe GM, Tetteh KK, Howard T, Osier FH, et al. Haemoglobin C and S role in acquired immunity against Plasmodium falciparum malaria. PLOS ONE. 2007; 2: e978.
  31. Danquah I, Ziniel P, Eggelte TA, Ehrhardt S, Mockenhaupt FP. Influence of haemoglobins S and C on predominantly asymptomatic Plasmodium infections in northern Ghana. Trans R Soc Trop Med Hyg. 2010; 104: 713-9.
  32. Kreuels B, Kreuzberg C, Kobbe R, Ayim-Akonor M, Apiah-Thompson P, Thompson B, et al. Differing effects of HbS and HbC traits on uncomplicated falciparum malaria, anemia, and child growth. Blood. 2010; 115: 4551-8.
  33. Achoubi N, Asghar M, Meitei SY, Sachdeva MP, Sarawathy KN, Murry B. Haemoglobinopathies and glucose-6-phosphate dehydrogenase deficiency in a malaria endemic region of Manipur, northeast India. Anthropol Sci. 2010; 118: 201-4.
  34. Hedrick PW. Population genetics of malaria resistance in humans. Heredity. 2011; 107: 283-304.
  35. Cyrklaff M, Sanchez CP, Kilian N, Bisseye C, Simpore J, Frischknecht F, et al. Hemoglobins S and C interfere with actin remodeling in Plasmodium falciparum-infected erythrocytes. Science. 2011; 334: 1283-6.
  36. Tan X, Traore B, Kayentao K, Ongoiba A, Doumbo S, Waisberg M, et al. Hemoglobin S and C heterozygosity enhances neither the magnitude nor breadth of antibody responses to a diverse array of Plasmodium falciparum antigens. J Infect Dis. 2011; 204: 1750-61.
  37. Perutz MF, Rossmann MG, Cullis AF, Muirhead H, Will G, North ACT. Structure of haemoglobin. A three-dimensional Fourier synthesis at 5.5Å resolution, obtained by X-ray analysis. Nature. 1960; 185: 416-22.
  38. Perutz MF, Lehmann H. Molecular pathology of human haemoglobin. Nature. 1968; 219: 902-9.
  39. Forget BG, Bunn HF. Classification of the disorders of hemoglobin. Cold Spring Harb Perspect Med. 2013; 3: a011684.
  40. Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L, et al. Sickle cell disease. Nat Rev Dis Primers. 2018; 4: 18010.
  41. Serjeant GR. The natural history of sickle cell disease. Cold Spring Harb Perspect Med. 2013; 3: a011783.
  42. Bhatia HM, Rao VR. Genetic atlas of India. Bombay, India: Institute of Immunohaematology, Indian Council of Medical Research, Seth GS Medical College; 1987.
  43. Colah RB, Mukherjee MB, Martin S, Ghosh K. Sickle cell disease in tribal populations in India. Indian J Med Res. 2015; 141: 509-15.
  44. Jain RC, Andrew AMR, Choubisa SL, Acharya A, Joshi KC. Sickle cell gene in the Mina tribal population of Kherwara tehsil of Udaipur district in Rajasthan. Indian J Med Res. 1983; 78: 552-5.
  45. Jain RC, Andrew AMR, Choubisa SL. Sickle cell and thalassaemic genes in tribal population of Rajasthan. Indian J Med Res. 1983; 78: 836-40.
  46. Jain RC, Choubisa SL, Acharya A, Andrew AMR, Chhaparwal JK, Joshi KC. Incidence of G-6-PD deficiency in the tribal population of southern Rajasthan. J Assoc Phys India. 1983; 32: 266-7.
  47. Choubisa SL. Abnormal haemoglobins, thalassaemia and G-6-PD deficiency in school children belonging to scheduled castes and tribes of Rajasthan, India. Indian J Phys Anthropol Hum Genet. 1988; 14: 31-40.
  48. Choubisa SL. Sickle cell traits in Damor tribe of Dungarpur district, southern Rajasthan. Man India. 1990; 70: 454-8.
  49. Choubisa SL, Choubisa DK, Choubisa L. Erythrocyte genetic disorders in inhabitants of Aravali hilly environment. Indian J Phys Anthropol Hum Genet. 2004; 23: 145-59.
  50. Mandot S, Khurana VL, Sonesh JK. Sickle cell anemia in Garasia tribals of Rajasthan. Indian Pediatr. 2009; 46: 239-40.
  51. Choubisa SL. Sickle cell haemoglobin, thelassaemia and G-6-PD enzyme deficiency genes in Garasiya tribe inhabited malaria endemic areas of Sirohi district, Rajasthan (India). J Commun Dis. 2009; 41: 13-8.
  52. Choubisa SL, Choubisa A. A brief review of sickle-cell haemoglobin, Β-thalassaemia and G-6-PD deficiency genes among tribals of scheduled area of Rajasthan, India: focus on tribal health. J Biomed Res Environ Sci. 2021; 2: 1187-96.
  53. Mohanty SS, Parihar S, Huda RK, Toteja GS, Sharma AK. Prevalence of sickle cell anemia, Β-thalassemia and glucose-6-phosphate dehydrogenase deficiency among the tribal population residing in the Aravali hills of Sirohi region of Rajasthan state. Clin Epidemiol Glob Health. 2022; 13: 100916.
  54. Choubisa SL. How to prevent and control sickle-cell anaemia and Β-thalassaemia major in the tribal people of the scheduled area of Rajasthan (India)?. Ann Hematol Oncol. 2022; 9: 1-5.
  55. Choubisa SL, Parmar L, Purohit VK. Abnormal haemoglobins in subjects belonging to scheduled castes of Udaipur district (Rajasthan). Indian J Med Res. 1984; 80: 463-8.
  56. Choubisa SL. Erythrocyte glucose-6-phosphate dehydrogenase deficiency and thalassaemic genes in schedule castes of Rajasthan. Indian J Med Res. 1985; 82: 554-8.
  57. Choubisa SL, Parmar L, Chouhan MB, Sharma SL. Sickle cell trait in scheduled castes of Rajasthan. Indian J Pathol Microbiol. 1986; 29: 386-90.
  58. Choubisa SL, Choubisa L, Pande S, Srivastava YK. Incidence of abnormal haemoglobins and G-6-PD deficiency in school children of Udaipur (Rajasthan), India. J Trop Med Hyg. 1987; 90: 215-6.
  59. Choubisa SL, Choubisa L, Pande S, Bhatt DK. Abnormal haemoglobins, thalassaemia and G-6-PD deficiency in Suthar community of southern Rajasthan. Indian J Phys Anthropol Hum Genet. 1987; 14: 9-16.
  60. Choubisa SL. Distribution of Hb-Bart’s (a-thalassaemia) in various population of Dungarpur district of Rajasthan (India). Indian J Phys Anthropol Hum Genet. 1990; 6: 43-8.
  61. Choubisa SL. Study of G-6-PD deficiency, abnormal haemoglobins and thalassaemic genes in the tribal students of Dungarpur district, Rajasthan. A technical report. New Delhi, India: University Grants Commission. 1990; 1-36.
  62. Choubisa SL, Choubisa DK. Erythrocyte glucose-6-phosphate dehydrogenase deficiency in senile cataracts. Man India. 1994; 74: 267-70.
  63. Choubisa SL, Choubisa DK. Mutant Hbs. Β-thalassaemia and G-6PD enzyme deficiency in tribal population of southern Rajasthan (India). In: Proceedings of the 9th international congress of human genetics. Brazil: Rio de Jaeiro. 1996; 98.
  64. Choubisa SL, Choubisa DK, Khare S. a-thelassaemia (Hb-Bart’s) in Rajasthan (India). Haematologia. 2000; 30: 209-13.
  65. Choubisa SL. Erythrocyte genetic disorders in subject belonging to general castes and other backward castes of Aravali hilly region of Rajasthan (India). Indian J Phys Anthropol Hum Genet. 2003; 22: 33-43.
  66. Choubisa SL, Choubisa L. Erythrocyte mutant genes in inhabitants of arid environment of Western-Rajasthan (India). Indian J Phys Anthropol Hum Genet. 2006; 25: 45-50.
  67. Choubisa SL. Haemoglobin-C gene in India? Curr Sci. 2010; 99: 860.
  68. Beet EA. Sickle cell disease in the Balovale District of Northern Rhodesia. East Afr Med J. 1946; 23: 75-86.
  69. Vernes A. Phagocytosis of P. falciparum parasitised erythrocytes by peripheral monocytes. Lancet. 1980; 2: 1297-8.
  70. Darwin C. On the origin of species. London: Murray. 1956.
  71. Thomson JS, Thomson MW. Genetics in medicine. W B Saunders Company. 1986.
  72. Stem C. Principal of human genetics. Delhi: Euresia Publishing House. 1968.
  73. Allison AC. Sickle cell and evolution. Sci Am. 1956; 195: 87-94.
  74. Swarup M. Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. In: Ahuja SMS, editor. Progress in Clinical medicine. New Delhi: Arnold Heine Mann. 1978; 570.
  75. Choubisa SL, Sompura K, Choubisa DK, Pandya H, Bhatt SK, Sharma OP, et al. Fluoride content in domestic water sources of Dungarpur district of Rajasthan. Indian J Environ Health. 1995; 37: 154-60.
  76. Choubisa SL, Sompura K, Choubisa DK, Sharma OP. Fluoride in drinking water sources of Udaipur district of Rajasthan. Indian J Environ Health. 1996; 38: 286-91.
  77. Choubisa SL. Fluoride distribution and fluorosis in some villages of Banswara district of Rajasthan. Indian J Environ Health. 1997; 39: 281-8.
  78. Choubisa SL. Fluoride distribution in drinking groundwater in Rajasthan, India. Curr Sci. 2018; 114: 1851-7.
  79. Choubisa SL. Endemic fluorosis in southern Rajasthan (India). Fluoride. 2001; 34: 61-70.
  80. Choubisa SL, Choubisa L, Choubisa DK. Endemic fluorosis in Rajasthan. Indian J Environ Health. 2001; 43: 177-89.
  81. Choubisa SL. A brief and critical review of endemic hydrofluorosis in Rajasthan, India. Fluoride. 2018; 51: 13-33.
  82. Choubisa SL. Fluoride in drinking water and its toxicosis in tribals, Rajasthan, India. Proc Natl Acad Sci India B. 2012; 82: 325-30.
  83. Choubisa SL, Choubisa D. Status of industrial fluoride pollution and its diverse adverse health effects in man and domestic animals in India. Environ Sci Pollut Res Int. 2016; 23: 7244-54.
  84. Choubisa SL, Choubisa D. Neighbourhood fluorosis in people residing in the vicinity of superphosphate fertilizer plants near Udaipur city of Rajasthan (India). Environ Monit Assess. 2015; 187: 497.
  85. Agalakova NI, Gusev GP. Excessive fluoride consumption leads to accelerated death of erythrocytes and anaemia in rats. Biol Trace Elem Res. 2013; 153: 340-9.
  86. Yasmin S, Ranjan S, D’Souza D. Haematological changes in fluorotic adults and children in fluoride endemic regions of Gaya district, Bihar, India. Environ Geochem Health. 2014; 36: 421-5.
  87. Pornprasert S, Wanachantararak P, Kantawong F, Chamnanprai S, Kongpan C, Pienthai N, et al. Excessive fluoride consumption increases haematological alteration in subjects with iron deficiency, thalassaemia, and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. Environ Geochem Health. 2017; 39: 751-8.

Citation: Choubisa SL. How Do Sickle Cell Genes Protect Tribal People from Deadly Malaria? Is This a Type of Natural Selection?. Ann Hematol Onco. 2023; 10(5): 1437.