The Genetics of the Samaritans and Other Middle Eastern Peoples

Transcription

1 The Genetics of the Samaritans and Other Middle Eastern Peoples Marc Feldman Department of Biology, Stanford University For class: From Generation to Generation: Scientific and Cultural Approach to Jewish Genetics September 27, 2012

2 Tools to detect human variation 1) Morphology/phenotypes/diseases 2) Blood groups 3) Proteins/allozymes DNA 4) Restriction fragment length polymorphisms (RFLPs) 5) Microsatellites (short tandem repeats, STRs) 6) Single nucleotide polymorphisms (SNPs)

3 HUMAN DNA: ABOUT 3 BILLION NUCLEOTIDES (A, T, C, G) Microsatellites: Short Tandem Repeats (about 100,000 of these.) 2 6 base repeats, e.g., (CA CA CA)n. Single Nucleotide Polymorphisms Me A T A A C C G T A You A T A T C C G T A More than 10 million of these.

4 DNA in nucleus of cells organized as 23 pairs of chromosomes. 22 pairs are autosomes; one of each pair from mother, one from father, with breakage and reunion (recombination). One pair are the sex chromosomes: female XX, male XY Y is passed from father to son with no recombination like surnames. Within cells are DNA containing organelles called mitochondria, which are passed from mother to child without recombination 16,000 nucleotides. Y is paternally transmitted male lineage. mt DNA is maternally transmitted female lineage.

5 Mutations: changes in nucleotides, e.g., A T, accumulate over time, so a measure of the differences between lineages can be a proxy for time since divergence. Mutations in microsatellites are more difficult to use for dating because the changes are frequent and reversible, e.g., repeats. STRs With enough variation due to accumulation of mutations, we can compare families, populations, nations, continents.

6 Explanations of the patterns of observed variation (ultimately traced to mutation) 1. Migration 2. Natural selection (reproduction/survival) 3. Marriage patterns 4. Population size

7 Polymorphisms reveal different Y- chromosomal and autosomal histories in Samaritans

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11 Facts: (i) Assyrians conquer Israel BCE, (ii) Assyrians replace [some?] locals with foreigners. (iii) Hezekiah, king of Judah BCE. The inhabitants of Samaria/Samerina, who agreed [and plotted] with a king [hostile to] me not to do service and not to bring tribute [to Ashshur] and who did battle, I fought against them with the power of the great gods, my lords. I counted as spoil 27,280 people, together with their chariots, and gods, in which they trusted. I formed a unit with 200 of [their] chariots for my royal force. I settled the rest of them in the midst of Assyria. I repopulated Samaria/Samerina more than before. I brought into it people from countries conquered by my hands. I appointed my eunuch as governor over them. And I counted them as Assyrians. (Nimrud Prisms, COS 2.118D, pp )

12 Politics and history in the ancestry of the Samaritans Returnees from Babylonian exile ( BCE) start to rebuild the temple destroyed by Babylonians. Samaritans want to participate, but they want the temple at Mount Gerizim (near Shechem, Nablus). Spurned by Zerubavel and colleagues. The Jews claim (1) Samaritans are not Hebrews ; (2) They have adopted non-hebrew customs. Result: Jewish documents from 6 th century BCE and later regard Samaritans as bad, at best 2 nd class citizens. Except for the famous story in the New Testament.

13 Books of Kings (originally one book): post-solomon era BCE. Division into: Israel (north), Judah (south). Books of Chronicles (written much later, perhaps 4 th century BCE) retells a lot of Kings. II Chronicles 30:1 And Hezekiah sent to all Israel and Judah and wrote letters also to Ephraim and Manasseh that they should come to the home of the Lord at Jerusalem to keep the Passover. II Kings 17: 24 And the king of Assyria brought men from Babylon and from Cuthah and from Ara and from Hamath and from Sepharaim and placed them in the cities of Samaria instead of the children of Israel and they possessed Samaria

14 The Samaritans claim to be descendants of the remnants of Israel not transplanted by the Assyrians but descended from Joseph s sons, Ephraim and Manasseh. Samaritans numbered more than a million in early Roman times. Decimated by later Romans, Christians, Muslims Location: Less than 150 in About 750 in about half in Holon (Tel Aviv) about half in Nablus (Shechem). Extreme endogamy and marriage within the four remaining lineages. Samaritan belonging is passed via male lineage: Cohen, Joshua-Marhiv, Danfi, Tsedaka

15 Classical Genetics of the Samaritans Blood group O: 67%. One of the highest frequencies in the world (indigenous Americans excepted). Rh : 19%. (Basques ~ 21% Europeans ~ 16% Africans < 1% Asians < 1%) G6PD (favism): Absent (> 4% in most Middle East Arab populations). Red-green color blindness: More than 28% of males, 24% of mothers or sisters of color blind men were color blind. (Bonné, B. (1966) Am. J. Phys. Anthrop. 24: 1 20) 84% of marriages are first or second cousins. Mean inbreeding coefficient 0.062, highest of any human population.

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17 Sample from Holon 27 males 20 females 12 males separated by > 2 paternal generations 9 males, 7 females separated by > 2 maternal generations Study sample 12 Y chromosomes 16 Mt DNA

18 Table 8. Y chromosome haplotype distances among Samaritan families. Tribe Levi Ephraim Manasseh Lineage Family C1 C2 JM JM JM JM D1 D2 TS1 TS1 TS1 TS2 Cohen C C JM Joshua-Marhiv JM JM JM Danfi D D TS Tsedaka TS1 0 1 TS1 1 TS2 Entries in the table are the total number of single-step repeats mutations between two corresponding chromosomes. Tribes may include more than one lineage as defined by family name. Family names annotated as in Table 1.

19 Table 2. Polymorphism of STR markers Gene diversity Number of alleles Marker Samaritans* Average for non-samaritan populations* Samaritans Average for non-samaritan populations Y chromosome Autosomes DYS19 a DYS385A DYS385B DYS DYS DYS DYS DYS GGAAT1B Average exp. (obs.) exp. (obs.) D1S (0.50) 0.79 (0.72) D2S (0.60) 0.70 (0.82) D2S (0.70) 0.65 (0.57) D3S (0.50) 0.79 (0.69) D3S (0.78) 0.86 (0.73) D4S (0.50) 0.76 (0.62) D5S (0.89) 0.79 (0.72) D7S (0.56) 0.74 (0.73) D8S (0.80) 0.80 (0.71) D9S (1.00) 0.79 (0.76) D10S (0.50) 0.73 (0.71) D11S (0.50) 0.75 (0.71) D17S (0.60) 0.69 (0.59) D20S (0.90) 0.86 (0.71) Average 0.73 (0.67) 0.70 (0.76) (a) All Samaritans have allele 190 at DYS19. * All Y-chromosome values calibrated as in equation (1). The average calibrated diversity is the average of the transformed values; the transformed value of the averages are 0.77 and 0.86, respectively.

20 Table 4. Y-chromosome haplotypic distances between sets of populations from AMOVA. Comparison Jews- Samaritans Jews- Palestinians Samaritans- Palestinians No. of different alleles Sum of squared size differences 0.04 (0.293) 0.05 (0.281) 0.15*** (<0.001) 0.04 (0.246) 0.11 (0.213) 0.35*** (<0.001) Calibrated Y-chromosome genetic distances (between-population F values reported by Arlequin). Genetic distance is based on the number of different alleles (top row) or the sum of squared size differences (bottom row). *** P < Ethiopians are excluded from Jews. Numbers in parentheses are the exact P values for the differentiation test as reported by Arlequin.

21 Table 7. Estimated time of divergence between Samaritans and Jews, and between Samaritans and Palestinians (Y and autosomes) Divergence of Y Autosomes* Samaritans- Jews (0.411) Samaritans-Palestinians (2.115) 12,046 15, (0.07) (0.118) Top line gives estimated delta-mu-squared for Samaritans from Jews and for Samaritans from Palestinians for Y chromosome and autosomes. Figures in parentheses represent standard errors. Divergence times in years (Goldstein et al. 1995) are given in the second and fourth rows with the first number corresponding to a generation time of 20 years and the second to a generation time of 25 years. * The effective mutation rate for autosomes is the weighted average of those for di- ( ), tri- ( ), and tetranucleotides ( ) as calculated by Zhivotovsky et al. (2000).

22 Y-chromosome tree of individuals from 9 Israeli populations

23 mtdna (maternal lineages): 16 Samaritans, 158 other Israelis

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25 Cohanim. Modal Y chromosome (CMH). 50% of Cohanim have CMH (males). 5% of other Jews have CMH (males). 50% of Buba clan of Lemba (South Africa). >50% of Bene Israel (Marathi speakers from Mumbai). All Samaritans have CMH except the Samaritan Cohens Levites. A Y chromosome with probable origin in the Volga-Khazar region. Khazar converts to Judaism in 8th or 9th century % of Levites share this Y. Generally: Jewish Y chromosomes tend to be more Middle Eastern and mitochondria relatively local.

26 Finer subdivision of CMH Y chromosomes Using 12 STRs:one SNP haplotype: 46% of Askenazi and non-ashkenazi Cohanim but no non Jews. Dated about 3,000 years ago A second SNP Haplotype: 14% of all Cohanim, Dated about 4,000 years ago All Cohanim descend from a very small group of ancestors

27 Jews and the World s populations

28 Human Genome Diversity Cell Line Panel Publicly available DNA collection administered by Centre d Etude du Polymorphisme Humain (CEPH) individuals from 52 predefined populations. 938 unrelated Individual genotypes at about 650,000 SNPs

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32 STRUCTURE results for Jewish populations combined with Middle Eastern, European, East Asian, and African populations from HGDP. K values of 3 7 are shown; each represents an alignment of 10 independent runs. Campbell C L et al. PNAS 2012;109: by National Academy of Sciences

33 Jews and Inherited Diseases

34 For it was taught: If she circumcised her first and he died, and she had the second one circumcised and died, she must not circumcise her third child so stated Rabbi Judah Ha-Nasi. Rabbi Shimon ben Gamliel however said, She may circumcise the third child but most not circumcise the fourth if the third child dies. It once happened with four sisters from Tzippori, where the first had her son circumcised and he died, when the second sister had her son circumcised he died, when the third sister had her son circumcised, he also died and the fourth sister came before Rabbi Shimon ben Gamliel and he told her you must not circumcise your son. Talmud, order Nashim, tractate Yevamot 64b If a woman had her first son circumcised and he died as a result of the circumcision, which enfeebled his strength, and she similarly had her second circumcised and he died as a result of the circumcision whether [the latter was] from her first husband or from her second husband the third son may not be circumcised at the proper time [on the eighth day of life]. Rather one postpones the operation for him until he grows up and his strength is established. One may circumcise only a child that is totally free of disease, because danger to life overrides every other consideration. It is possible to circumcise later than the proper time, but it is impossible to restore a single [departed] soul of Israel forever. Maimonedes, from Mishneh Torah

35 Small Ashkenazi founding populations Breast cancer: 5-10% of BC patients have BRCA mutations. Ashkenazi BC patients or women with family history of early onset BC have much higher BRCA mutation rate (also Moroccan Jews). Fact or X1 deficiency Gaucher disease Bloom s disease Chron s disease Familial Mediterranean fever Nieman-Pick Up to 25 Ashkenazi genetic diseases. (Ashkenazi and Iraqi) (Ashkenazi and Europeans) (1% carrier frequency in Ash) (highest frequency in Ash) (in non-ashkenazi Jews, 14 20% carriers) (one in 71 Ashkenazi are carriers)

36 Tay-Sachs 1. Traced to 15th CE Europe. ~3 4% Ashkenazi are carriers. 2. Another mutation in French Canadians. Almost all births with Tay-Sachs are French Canadian. Traced to a mutation in a 17th CE migrant. 3. Irish carriers ~2%. 4. General population 0.3%. Classical founder effect

37 Some characteristic genetic disorders among Oriental Jewry Community Kurdistan India Iran Iraq Yemen Disorder G6PD deficiency a Thalassemia (alpha and beta) Ichthyosis vulgaris (autosomal dominant) Thalassemia (alpha and beta) Dubin-Johnson syndrome G6PD deficiency Pituitary dwarfism, type II Pseudocholinesterase deficiency Selective hypoaldosteronism Benign familial hematuria Bronchial asthma Dubin-Johnson syndrome FMF G6PD deficiency Glanzmann thrombasthenia Icthyosis vulgaris (X-linked) Meckel syndrome Pituitary dwarfism, type II Pseudocholinesterase deficiency Celiac disease Cystic disease of lung Metachromatic leucodystrophy in Habbanites PKU Thalassemia (alpha) a Italics indicate that the condition is found in more than one Jewish community

38 Genome-wide IBD sharing for the average pair of individuals within (A) and across (B and C) populations. Campbell C L et al. PNAS 2012;109: by National Academy of Sciences

39 Inferred IBD Statistics for Diverse Human Populations Henn et al. (2012) PLoS One

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41 Men are not born good or evil It is impossible for man to be endowed by nature from his very birth with either virtue or vice, just as it is impossible that he should be born skilled by nature in any particular art. It is possible, however, that through natural causes he may from birth be so constituted as to have a predilection for a particular virtue or vice, so that he will more readily practice it than any other. For instance, a man whose natural constitution inclines toward dryness, whose brain-matter is clear and not overloaded with fluids, finds it much easier to learn, remember, and understand things than the phlegmatic man whose brain is encumbered with a great deal of humidity. But if one who inclines constitutionally toward a certain excellence is left entirely without instruction, and if his faculties are not stimulated, he will undoubtedly remain ignorant. On the other hand, if one by nature is dull and phlegmatic, possessing an abundance of humidity, is instructed and enlightened, he will, though of course with difficulty, gradually succeed in acquiring knowledge and understanding. In exactly the same way, he whose blood is especially warm has the requisite quality to become a brave man. But another whose heart is colder than it should be, is naturally inclined toward cowardice and fear, so that if he should be encouraged to be a coward, he would easily become one. If, however, it be desired to make a brave man of him, he can without doubt become one, providing he receive the proper training which would require, of course, great exertion. I have entered into this subject so that thou mayest not believe the absurd ideas of astrologers, who falsely assert that the constellation at the time of one s birth determines whether one is to be virtuous or vicious, the individual being thus necessarily compelled to follow out a certain line of conduct. Moses Maimonedes Commentaries on the Mishna, Eight Chapters VIII

42 References Samaritans B. Bonne-Tamir (1966) Am. J. Phys. Anthr 24: 1-19 P. Shen et al. (2004) Human Mutation 24: M. Hammer et al (2009) Human Genetics 126: World J. Z. Li et al. (2008) Science 319: M. Jakobsson et al. (2008) Nature 457: Jewish Genetics N. Rosenberg et al. (2001) Proc. Natl Acad. Sci. USA 98: N. M. Kopelman et al. (2009) BMC Genetics 10: D. B. Behar et al. (2010) Nature 466: L. C. Campbell et al. (2012) Proc Natl Acad Sci USA 109(39): General David Goldstein (2008) JACOB S LEGACY: A GENETIC VIEW OF JEWISH HISTORY Yale University Press