User talk:Muntuwandi/ African admixture in Europe

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African admixture in Europe refers to the European presence of human genetic polymorphisms, which are considered to be evidence for movements of people from Africa to Europe in both the prehistoric and historic past.[1]


Geographical influences[edit]

The Mediterranean Sea and the Sahara Desert were formidable barriers to gene flow between Sub-Saharan Africa and Europe. But Europe was periodically accessible to Africans due to fluctuations in the size and climate of the Sahara. At the Strait of Gibraltar, Africa and Europe are separated by only 15 km of water. At the Suez, Eurasia is connected to Africa forming a single land mass. The Nile river valley, which runs from East Africa to the Mediterranean Sea served as a bidirectional corridor in the Sahara desert, that frequently connected people from Sub-Saharan Africa with the peoples of Eurasia.[2]

Migratory times and vectors[edit]

First Settlers[edit]

Suggested routes of the initial settlement of Europe based on mtDNA haplogroups, Metspalu et al. 2004

According to the leading theory of human origins, known as the Out of Africa theory, anatomically modern humans first emerged in Africa 150,000-200,000 years ago. All non-Africans, including Europeans, are descended from at least one group of humans who migrated out of Africa into western Asia 50,000-70,000 years ago. The first modern humans in Europe, the Cro-Magnon arrived from Western Asia and are believed to have completely replaced the previous inhabitants, the Neanderthals. Cro-Magnons were in the Middle East(Lebanon) by 45,000 years ago and in Eastern Europe by 40,000 years ago. By 30,000 years ago, the Cro-Magnon people had populated much of Europe. The "Out of Africa" migration resulted in the genetic isolation of Africans from non-Africans

Duration within refuges[edit]

During the Last Glacial Maximum, a period between 25,000 and 19,000 years ago, large ice sheets over a kilometer thick covered much of Northern Europe making the region uninhabitable to humans. It is believed that human populations retreated south to warmer regions near the Mediterranean. Refuges during this period are believed to have been in Iberia, Southern France and Italy.

DNA evidence suggests that during the Last Glacial Maximum, there was some gene flow from Africa into Iberia. After the Last Glacial Maximum, when the European climate warmed up, the refuges are thought to have the been source from which Europe was repopulated. African lineages that had previously been introduced into the Iberian refuge would have have then dispersed all over Europe with the Northward expansion of humans. This could explain the presence of genetic lineages in Eastern Europe, and as far North as Russia, that appear to have prehistoric links to Northwest and West Africa(see MtDNA).[3] In addition, the expansion of human populations from Iberian refuges is also believed to have spilled over back in to Northwest Africa.[4]

Neolithic to the end of the prehistoric[edit]

The transition from hunting and gathering to agriculture during the Neolithic Revolution was a major event in world history. The societies that first made the transition to agriculture are believed to have lived in the Middle East around 10,000 BCE. Agriculture was then introduced into Europe by migrating farmers from the Middle East. [5] According to the demic diffusion model, these Middle Eastern farmers either replaced or interbred with the local hunter-gather populations that had been living in Europe since the "out of Africa" migration.[6] It has also been established that the first Middle Eastern farmers had African influences. Genetic lineages of African origin would have then been carried into Europe with the diffusion of farming from the Middle East. The first Agricultural societies in the Middle East emerged out of the Natufian Culture, which existed in Israel from 12,000 BCE-10,000 BCE. An important migration from Africa across the Sinai appears to have occurred leading up to the formation of the Natufian.

Historic period[edit]

In historical times, there has been a well-documented period of North African influence in Southern Europe, especially southern Iberia and Southern Italy, during the time of the Islamic Golden Age. The genetic effect of this period on modern European populations is the subject of on-going discussion (see below). In more recent history, the peoples of Europe and Africa came into contact during the, the exploration and colonisation of Africa and as a consequence of the Atlantic slave trade.[7] As a result of these recent contacts, lineages of African descent have also been detected in Europe. In general, African admixture is distributed along a South-to-North cline, with peaks in the Mediterranean region and Iberia.

Assessing African genetic contributions in non-Africans[edit]

The evolutionary forces that contribute to the current patterns of human genetic variation include new mutations, natural selection, sexual selection, genetic drift, population bottlenecks, founder effects, isolation by distance, genetic admixture and barriers to gene flow. The most influential factors affecting human genetic variation are founder effects and isolation by distance. [8].[9]

Founder effect occurs when a population is established by only a small number of individuals who have departed from a much larger population. Several generations after the population has expanded, individuals will still possess the limited gene pool of the original founders. Therefore, founder effects result in a loss of genetic diversity. Genetic evidence suggests that the out of Africa migration involved only small number of individuals. The out of Africa migrants carried only a small subset of the prehistoric African genetic diversity, resulting in a founder effect of the Non-African population. As humans spread across the globe populating Eurasia, Australia and the Americas, there were several subsequent founder effects. As a result of these serial founder effects, genetic diversity tends to decrease with geographic distance from Africa. [8][9]

The other major factor contributing to patterns of human genetic variation is "Isolation by distance". According to this model populations that live near each other are more likely to exchange mates than populations that live further apart. As a result populations that live near each other are genetically more similar than populations that live far apart.

Percentage genetic distances among major continents based on 120 classical polymorphisms
Africa Oceania East Asia Europe
Oceania 24.7
East Asia 20.6 10
Europe 16.6 13.5 9.7
America 22.6 14.6 8.9 9.5

Genetic distance is one measure used to compare the genetic relationship between different populations. It is based on the principal that populations that share similar frequencies of a trait are more closely related than populations that have different frequencies of a trait. The genetic distance between two populations increases linearly with the geographic distance between the two populations due to isolation by distance and serial founder effects. [8][9]

Cavalli-Sforza (1997) applied genetic distance measures to various populations around the world to infer phylogenetic relationships( see Table on the right). All non-African populations are more closely related to each other(ie short genetic distance) than they are to African populations. This is consistent with a founder effect of the non-African population in that only a few individuals participated in the initial out of Africa migration. The largest genetic distances observed are between Africa and Oceania and Africa and the Americas. This is consistent with the isolation by distance and serial founder effects.

Cavalli-Sforza (1997) suggests that the genetic distance between Sub-Saharan Africa and Europe is anomalously lower than it should be if the two populations have been evolving independently. The study suggests that the lower genetic distance between Europe and Africa can be explained by genetic admixture.

Defining African admixture[edit]

Generally lineages used to characterize African admixture are those that are specific only to Africa. However, some DNA polymorphisms are shared by Europeans, West Asians, North Africans and Sub-Saharan Africans. Examples of such variants include the y-chromosomal haplogroup E1b1b and mitochondrial haplogroup M1.[7]

This sharing of polymorphisms is the result of long distance movements of peoples between Sub-Saharan Africa and Eurasia that involved traversing North Africa and sometimes the Middle East. Consequently, the definitions African, Sub-Saharan African, North African will depend on the time frame of reference or the semantic preferences of any particular scientist. Due to prehistoric migrations in and out of Africa, North African populations tend to exhibit allele frequencies that are intermediate between Sub-Saharan Africa and Eurasia[10][11]. Due to this complex genetic profile of Africa, African admixture in Europe could be the result of direct contact with Sub-Saharan Africans, or indirectly through contact with North Africans with Sub-Saharan affiliations.

In some cases, lineages found in Africa and Europe may have a common origin in Asia (for example Y haplogroups R1, T) and Haplogroup U. One clade of haplogroup U, U6a1 is known to have expanded from East Africa back into Europe, and has been described as a diagnostic Sub-Saharan marker[12].[13] Other lineages are known to have moved from Europe directly into Africa (for example mitochondrial haplogroups H1, H3.[4][14] Such back migrations between Africa and Eurasia also complicate defining admixture.

Y-DNA[edit]

distribution of Haplogroup E (Y-DNA)

Post LGM Y chromosome flow from Africa to Europe is primarily represented by haplogroup E. Haplogroup E entered Europe, predominantly through its subclade E1b1b1, which is thought to have emerged about 22,000 years ago in East Africa and branches of it are thought to have migrated to the Middle East by 11,000 years ago during the late Pleistocene or early Neolithic periods.

Entering the late mesolithic Natufian culture, the E1b1b1a2 (E-V13) sub-clade has been associated with the spread of farming from the Middle East into Europe either during or just before the Neolithic transition. E1b1b1 lineages are found throughout Europe but are distributed along a South-to-North cline, with a E1b1b1a mode in the Balkans.[1][15][16][note 1][note 2]

In separate migrations, E lineages in the form of the E1b1b1b subclade appear to have entered Europe from Northwest Africa into Iberia. In a sample of European males, Cruciani et al observed Haplogroup E at a frequencies of 7.2%. The timing of this movement is one given widely variant estimates at this time.[17]

A major expansion of peoples throughout Sub-Saharan Africa occurred after the introduction of agriculture 5,000 years ago. During the Bantu expansion people carrying Haplogroup E(not including E1b1b) lineages dispersed across much of Sub-Saharan Africa from their original homeland near the border between Nigeria and Cameroon. The haplogroup most often associated with this expansion is E1b1a, which constitutes up to 48% of the African male gene pool. The presence of E1b1a lineages outside Africa can typically be associated with events that occurred after the Bantu Expansion, such as the trade in African slaves or the Moorish occupation of Iberia. In much of Europe frequencies of E lineages which are not E1b1b are very low, usually less than 1%. For example Cruciani et al. 2004, report such lineages at 2% in Southern Portugal, 4% in Northern Portugal, 2.9% in Istanbul, and 4.3% among Turkish Cypriots. E1b1a is closely related to E1b1b, the most frequent clade in Europe. E lineages that are not E1b1a or E1b1b could therefore reflect either a recent expansion associated with E1b1a or ancient population movements associated with E1b1b. For example haplogroup E1a lineages have been detected in Portugal (5/553 = 1%) [18], among Italians in Calabria (1/80=1.3%) and among Albanians in Calabria (2/68=2.9%) [15]. According to a study by Goncalves et al. (2005), The distribution of Haplogroup E1a lineages in Portugal was independent of the distribution of the younger and more ubiquitous E1b1a. The authors suggest that this distribution is consistent with a prehistoric migration from Africa into Iberia, possibly alongside mtDNA haplogroup U6.

Haplogroups A and B, are thought to have been the predominant haplogroups in Central and Southern Africa prior to the Bantu Expansion. Currently these haplogroups are less common than E lineages. In a sample of 5,000 African men, haplogroup A had a frequency of 5%. Haplogroup A has rare occurrences in Europe, but recently the haplogroup was detected in seven males with the same surname who were in Britain.[19]

MtDNA[edit]

Haplogroup L lineages are relatively infrequent (1% or less) throughout Europe with the exception of Iberia, where frequencies as high as 11.7% percent have been reported. Current debates are concerned with whether these lineages are associated with prehistoric migrations, the Islamic occupation of Iberia, or the slave trade. Pereira et al. (2000) suggested that African lineages in Iberia were predominantly the result of Atlantic Slave Trade. Gonzalez et al. (2003) revealed that most of the L lineages in Iberia matched Northwest African L lineages rather than contemporary Sub-Saharan L lineages. The authors suggest this pattern indicates that most of the Sub-Saharan L lineages entered Iberia in prehistoric times rather than during the slave trade. However, according to Pereira et al. (2005), the sub-Saharan lineages found in Iberia matched lineages from diverse regions in Africa. They suggest this pattern is more compatible with recent arrival of these lineages after slave trade was initiated in the 15th century. According to the study, alternative scenarios, that invoke much older and demographically more significant introductions (Gonzalez et al. (2003)) or that claim a substantial role of the Roman and/or Islamic periods on the introduction of sub-Saharan lineages, seem unlikely. The study detected L lineages at an average frequency of 3.83%(40 out of 1,045) in Iberia with frequencies reaching 11.38% in south Portugal. Casas et al. (2006) extracted DNA from human remains that were exhumed from historic burial sites in Al-Andalus, Spain. The remains date to between 12th-13th century. The frequency of Sub-Saharan lineages detected in the samples was 14.6%. The authors suggest both the Muslim occupation, and prehistoric migrations before the Muslim occupation would have been the source of these lineages.

Haplogroup L lineages are present at low frequencies in Eastern Europe. Though a high diversity of African mtDNA lineages have been detected, few lineages have accumulated enough mutations in Europe to form monophyletic clusters. Malyarchuk et al. (2005) detected only two monophyletic clusters, L1b and L3b, in Russians, with an estimated age no greater than 6,500 years. Malyarchuk et al. (2008) identified African L1b, L2a, L3b, L3d and M1 clades in Slavic populations at low frequencies. L1b, L3b and L3d had matches with West African populations, indicating that these lineages probably entered Europe through Iberia. One lineage L2a1a, appeared to be much older, indicating that it may have entered Europe in prehistoric times. This clade was possibly related to L2a1 clades identified in ten individuals of Ashkenazi heritage from France, Germany, Poland, Romania and Russia. L2a lineages are widespread throughout Africa, as a result, the exact origins of this lineage are uncertain. [3][20]

Haplogroup M1 is also found in Europe at low frequencies, but it is not uncommon in Southern Europe. In a study by Gonzalez et al 2007, haplogroup M1 had an overall frequency of 0.3% in the samples that were analyzed. The highest frequencies were found in Sicily where 3.8% of the population were members of haplogroup M1. The origins of haplogroup M1 have yet to be conclusively established. However, one clade of haplgroup M1, M1a is widely accepted to be of East African origin. About 40% of all clades of M1 found in Europe are M1a and consequently of recent East African origin.

Autosomal[edit]

  • Measures of genetic distance between Europe and Sub-Saharan are generally smaller than Genetic distances between Africa and other continental populations. Cavalli-Sforza states that the relatively short genetic distance is likely due to prehistoric admixture.[21]
  • A 2009 autosomal study by Moorjani et al that used about 500K-1M SNPs estimated that the proportion of sub-Saharan African ancestry is 2.4% in Spain, 1.9 % in Greece and 1.5% in Tuscany.[22]
  • A 2009 study by Auton et al found a North-South Cline of Hapmap Yoruba haplotypes (YRI) in Europe. The study determined that South and Southwest subpopulations had the highest proportion of YRI This distribution is indicative of recurrent gene flow into Europe from both the Southwest and the Middle East. The authors suggest that the haplotype sharing between Europe and the YRI are suggestive of gene flow from Africa, albeit from West Africa and not necessarily North Africa. [23]
  • A 2007 study conducted at Penn State University found low levels of African admixture(2.8-10%) that were distributed along a North South cline. The authors suggest that the distribution of this African admixture mirrors the distribution of haplogroup E3b-M35(E1b1b).[note 3][24]
  • A principal component analysis of data from Human Genome Diversity Project by Reich et al detected a West-to-East gradient of Bantu related ancestry across Eurasia. The authors suggest that after the Out of Africa migration, there was most likely a later Bantu-related gene flow into Europe.[25]

HLA[edit]

Distribution of the B18-DR3 component of the A30-Cw5-B18-DR3-DQ2 haplotype in the Old World

One of the most convincing evidences of gene flow from Africa is the A30-B18-DR3 haplotype, this or component haplotypes reaches a peak frequency in Sardinia with components of ~20%. Three independent studies conclude this haplotype is paleo North African in origin.[26][27] Several HLA haplotypes and alleles that appear to be of recent Africa origin are found in Europe with frequencies declining from SW to north east similar to A30-B18-DR3.[28] A number of other alleles including, Cw*0501, Cw*0701 and Cw*1601 appear restricted to European and African populations. This pattern has been described as being suggestive of a close historical relationship between Europeans and Africans. [29]

Sickle cell trait[edit]

Sickle cell genes of African origin have been detected in Europe, mostly in the Mediterranean region. The sickle cell trait is associated with resistance to Malaria. Individuals with one copy of the sickle cell gene, heterozygotes, have higher resistance to Malaria than individuals with no sickle cell genes. In regions affected by Malaria, the fertility of sickle cell heterozygotes will be higher than average. However, individuals with two copies of the sickle cell gene, homozygotes, will be affected by sickle cell disease and historically have had lower than average fertility. The sickle cell trait is thus an example of heterozygote advantage which is subject to balancing selection. When the sickle cell trait is introduced into a region affected by malaria, balancing selection will on one hand act to increase the frequency of the trait to counter malaria. On the other hand if the frequency of the trait in the population becomes high enough so that homozygotes with sickle cell disease become common, balancing selection will act to limit the spread of the trait. Therefore in regions affected by malaria, the sickle cell trait is maintained at intermediate frequencies relative to the incidence of Malaria.

In Africa, Malaria is believed to be one of the most important factors that contributed to restricting population growth in prehistoric times. Sickle cell mutations are believed to have occurred independently at least 5 times. Four variants are of African origin and one of Indian/Arabian origin. The African variants are referred to as Cameroon, Senegal, Benin and Bantu. The emergence of the sickle cell trait would have contributed to the successful population expansion, with the emergence of farming, into tropical regions where Malaria was endemic.

Archeological and historical evidence suggest that the Malaria had been endemic in the Mediterranean regions of Europe in historical times.[30] In the Eastern Mediterranean regions, such as Italy, Greece, Albania, and Turkey the Benin haplotype is the most frequent sickle cell variant. The Benin haplotype is also the most frequent variant in the Middle East and has been observed in Syrians, Palestinians, Israeli Arabs, Israeli Jews[31] and Western Saudi Arabians. This suggests that the Benin haplotype may have expanded from West Africa into North Africa and then into the Middle East and Europe. The spread of the Benin haplotype to the Mediterranean region has been associated with various events including Late Stone Age expansions from West Africa into North Africa, the trans-Saharan trade and the Arab Slave Trade[32]. The occurrence of sickle cell trait is particularly high in Sicily where frequencies of 13% have been reported.[33][34] In New York City, Sicilian Americans are second to African Americans in occurrence of the Sickle cell disease. The high frequencies of the trait have been associated with the Arab invasion of Sicily in the 7th Century during which Sudanese soldiers were recruited by the Caliphate[32]. Portugal is the only region in Europe where the Senegal and Bantu haplotypes are frequent. These may be associated with the Portuguese Naval exploits, including the Atlantic Slave Trade and the colonization of various African countries.[35]

Paleoanthropology[edit]

The migration of farmers from the Middle East into Europe is believed to have significantly influenced the genetic profile of contemporary Europeans. Some recent studies have focused on corroborating current genetic data with the archeological evidence from Europe, the Middle East and Africa[17]. The Natufian culture which existed about 12,000 years ago in Israel, has been the subject of various archeological investigations as the Natufian culture is generally believed to be the source of the European and North African Neolithic.

According to a hypothesis stated by Bar-Yosef (1987), Natufian culture emerged from the mixing of two distinct stone age cultures: "The Kebaran" , a culture indigenous to the Levant, and "The Mushabian" a culture introduced into the Levant from North Africa. This Mushabian culture is suggested to have originated in Africa as archeological sites with Mushabian industries in the Nile Valley predate those in the Levant. The Mushabians would have then moved into the Sinai from the Nile Delta bringing with them their distinct technologies. Bar-Yosef (1987) states: "the population overflow from Northeast Africa played a definite role in the establishment of the Natufian adaptation, which in turn led to the emergence of agriculture as a new subsistence system".

A study by Brace et al. (2005) analysed human remains from the Natufian culture. According to the study, there is clear evidence of Sub-Saharan influences in the Natufian samples. They further argue that over time, these influences would have been diluted by the interbreeding of the Neolithic farmers from the Near East with the indigenous foragers in Europe. Ricaut et al. (2008) associate the Sub-Saharan influences detected in the Natufian samples with the migration of E1b1b lineages from East Africa to the Levant and then into Europe.

Notes[edit]

  1. ^ Cruciani et al specifically state: "Recently, it has been proposed that E3b originated in sub-Saharan Africa and expanded into the Near East and northern Africa at the end of the Pleistocene. E3b lineages would have then been introduced from the Near East into southern Europe by immigrant farmers, during the Neolithic expansion."
  2. ^ Underhill et al, 2001 state" A Mesolithic population carrying Group III lineages with the M35/M215 mutation expanded northwards from sub-Saharan to north Africa and the Levant. The Levantine population of farmers that dispersed into Europe during and after the Neolithic carried these African Group III M35/M215 lineages, together with a cluster of Group VI lineages characterized by M172 and M201 mutations."
  3. ^ <Halder et al state. "We observed patterns of apportionment similar to those described previously using sex and autosomal markers, such as European admixture for African Americans (14.3%) and Mexicans (43.2%), European (65.5%) and East Asian affiliation (27%) for South Asians, and low levels of African admixture (2.8–10.8%) mirroring the distribution of Y E3b haplogroups among various Eurasian populations.

See also[edit]

Footnotes[edit]

  1. ^ a b Cruciani et al. (2004)
  2. ^ mtDNA Analysis of Nile River Valley Populations: A Genetic Corridor or a Barrier to Migration?
  3. ^ a b Malyarchuk et al. (2008)
  4. ^ a b Cherni et al. (2008)
  5. ^ Brace et al. (2005)
  6. ^ Cavalli-Sforza (1993)
  7. ^ a b Malyarchuk et al. (2005)
  8. ^ a b c Ramachandran et al. (2005). "Support from the relationship of genetic and geographic distance in human populations for a serial founder effect originating in Africa". Proc. Natl. Acad. Sci. U. S. 
  9. ^ a b c Handley, L.J.L. et al (2007). "Going the distance: human population genetics in a clinal world". Trends in Genetics. doi:10.1016/j.tig.2007.07.002. 
  10. ^ Piancatelli et al. (2004). Human leukocyte antigen-A, -B, and -Cw polymorphism in a Berber population from North Morocco using sequence-based typing. 
  11. ^ Coudray et al (2009). The Complex and Diversified Mitochondrial Gene Pool of Berber Populations. 
  12. ^ Rando et al. (1999). Phylogeographic patterns of mtDNA reflecting the colonization of the Canary Islands. 
  13. ^ Ana M González, "Mitochondrial lineage M1 traces an early human backflow to Africa"
  14. ^ Ennaffaa et al. (2009)
  15. ^ a b Semino et al. (2004)
  16. ^ Underhill et al. (2001). The phylogeography of Y chromosome binary haplotypes and the origins of modern human populations. 
  17. ^ a b Lancaster (2009)
  18. ^ Goncalves et al. (2005)
  19. ^ King (2007). Africans in Yorkshire? - the deepest-rooting clade of the Y phylogeny within an English genealogy. 
  20. ^ Behar et al. (2006). The Matrilineal Ancestry of Ashkenazi Jewry: Portrait of a Recent Founder Event. 
  21. ^ Bowcock et al. (1991). Drift, admixture, and selection in human evolution: A study with DNA polymorphisms. 
  22. ^ Characterizing the history of sub-Saharan African gene flow into southern Europe, Moorjani et al. 2009
  23. ^ Auton et al (2009). Global distribution of genomic diversity underscores rich complex history of continental human populations. 
  24. ^ Frudakis, Tony (2007). "West African ancestry in Southeastern Europe and the Middle East". Molecular photofitting: predicting ancestry and phenotype using DNA. pp. page 326. ISBN 0120884925. 
  25. ^ Reich (2008). Principal component analysis of genetic data. 
  26. ^ Sanchez-Velasco P, Gomez-Casado E, Martinez-Laso J, et al. (May 2003). "HLA alleles in isolated populations from North Spain: origin of the Basques and the ancient Iberians". Tissue Antigens 61 (5): 384–92. PMID 12753657. 
  27. ^ Choukri F, Chakib A, Himmich H, Raissi H, Caillat-Zucman S (June 2002). "HLA class I polymorphism in a Moroccan population from Casablanca". Eur. J. Immunogenet. 29 (3): 205–11. PMID 12047355. 
  28. ^ Gómez-Casado et al. (March 2000), "HLA genes in Arabic-speaking Moroccans: close relatedness to Berbers and Iberians", Tissue Antigens 55 (3): 239–49, PMID 10777099 
  29. ^ Sanchez-Mazas et al (2001). The molecular determination of HLA-Cw alleles in the Mandenka (West Africa) reveals a close genetic relationship between Africans and Europeans. doi:10.1034/j.1399-0039.2000.560402.x. 
  30. ^ Salares et al. (2004). The Spread of Malaria to Southern Europe in Antiquity: New Approaches to Old Problems. 
  31. ^ Rund et al. (1989). The origin of sickle cell alleles in Israel. doi:10.1007/BF00194229. 
  32. ^ a b Bloom (1995). Understanding Sickle Cell Disease. ISBN 0878057455. 
  33. ^ Ragusa et al. (2006). "Presence of an African -globin gene cluster haplotype in normal chromosomes in Sicily". American Journal of Hematology. doi:10.1002/ajh.2830400413. 
  34. ^ Ragusa et al. (2006). "S gene in Sicily is in linkage disequilibrium with the Benin haplotype: Implications for gene flow". American Journal of Hematology. doi:10.1002/ajh.2830270214. 
  35. ^ Monteiro et al. (1988). "The frequency and origin of the sickle cell mutation in the district of Coruche/Portugal". Human Genetics. ISSN 1432-1203. 

References[edit]