- Email: [email protected]
The origin of the p.E180 growth hormone receptor gene mutation
YGHIR-01093; No of Pages 2 Growth Hormone & IGF Research xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Growth Hormone & IGF Research journal homepage: www.elsevier.com/locate/ghir
The origin of the p.E180 growth hormone receptor gene mutation Harry Ostrer ⁎ Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, United States Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, United States
a r t i c l e
i n f o
Article history: Received 4 June 2015 Received in revised form 22 July 2015 Accepted 3 August 2015 Available online xxxx Keywords: Laron syndrome GHR gene GHR deficiency Founder mutation Population genetics
a b s t r a c t Laron syndrome, an autosomal recessive condition of extreme short stature, is caused by the absence or dysfunction of the growth hormone receptor. A recurrent mutation in the GHR gene, p.E180, did not alter the encoded amino acid, but activated a cryptic splice acceptor resulting in a receptor protein with an 8-amino acid deletion in the extracellular domain. This mutation has been observed among Sephardic Jews and among individuals in Ecuador, Brazil and Chile, most notably in a large genetic isolate in Loja, Ecuador. A common origin has been postulated based on a shared genetic background of markers flanking this mutation, suggesting that the Lojanos (and others) may have Sephardic (Converso) Jewish ancestry. Analysis of the population structure of Lojanos based on genome-wide analysis demonstrated European, Sephardic Jewish and Native American ancestry in this group. X-autosomal comparison and monoallelic Y chromosomal and mitochondrial genetic analysis demonstrated gender-biased admixture between Native American women and European and Sephardic Jewish men. These findings are compatible with the co-occurrence of the Inquisition and the colonization of the Americas, including Converso Jews escaping the Inquisition in the Iberian Peninsula. Although not found among Lojanos, Converso Jews also brought founder mutations to contemporary Hispanic and Latino populations in the BRCA1 (c.68_69delAG) and BLM (c.2207_2212delATCTGAinsTAGATTC) genes. © 2015 Elsevier Ltd. All rights reserved.
For many years, there have been attempts to use genetics to characterize the communities of the Jewish Diaspora, including the use of genome-wide analysis [1,5], and the identification of several mutations for Mendelian diseases that are over-represented in Jewish Diaspora communities. These include the breast and ovarian cancer susceptibility mutation, BRCA1 c.185delAG [6,10,19,26], the Laron syndrome growth hormone receptor mutation, GHR c.E180 [15], and Bloom syndrome mutation, blmash [11] (for review, see [21]). Despite the overwhelming prevalence of these mutations and/or diseases in Diaspora communities, they have also been observed in non-Jewish Hispanic/Latino groups [3,7,9,14,16,17,24]. When considering the history of Jews in the Iberian Peninsula during the European colonization of Latin America, the Jewish origin of these mutations can be explained. The Sephardic Jews of Iberia had a millennial history that originated in Classical Antiquity. Their time in that peninsula had alternating periods of relative tolerance and total discrimination that culminated in the forced conversions and expulsions from the late 15th century and into the 17th century [23] — just at the time that the New World was being colonized by Spain and Portugal. Following a traquil period in the 13th century, known as La Conviviencia, the Reconquista of the 15th century led to the Inquisition. The descendants of the Sephardim of this era became to be known as Conversos (or converted) Jews. In ⁎ Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Ullman 817, Bronx, NY 10461, United States. E-mail address: [email protected].
the presence of Inquisitorial and government pressure, Jewish orthodoxy was lost with integration into Catholic colonial society and inheritance of disjointed relics or total abandonment of Jewish ritual [25]. Facing conversion or death, many Jews fled Iberia. Some settled in the territories of the Ottoman Empire, whereas 100,000 chose to remain for the meantime in the peninsula by fleeing into Portugal, increasing the population to 3–5% of the total population [23,25]. When the Inquisition came to Portugal, following the union of these kingdoms under Felipe II, many fled to New World territories, especially the fringes of northern New Spain in modern day Colorado and in the mountainous regions of colonial Peru in what is now Ecuador [4]. Conversos sailed with Columbus, helped topple the indigenous Aztec and Incan Empires, and were integral members of the political and religious hierarchies of the Viceroyalties of New Spain and Peru [4,20,25,28]. It has been difficult to determine the degree of intermarriage in the New World between newly converted Christians and Christians from older communities. Here, we review our earlier studies that linked the rich history and mutation data of people in Latin America with Converso heritage. One community resided in the Loja province of Ecuador and will be referenced as Lojanos [20]. Another community resided in the San Luis Valley of Colorado and will be referenced as Hispanos [13,20]. Although the Jewishness of such communities has been strenuously refuted by some [27], there is evidence of Converso ancestry in these communities. Furthermore, population genetic studies can distinguish Sephardim reliably from other Jewry and the basis for this difference can be detected in modern Iberian and Latin American populations [2,5,8,12,22].
http://dx.doi.org/10.1016/j.ghir.2015.08.003 1096-6374/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article as: H. Ostrer, The origin of the p.E180 growth hormone receptor gene mutation, Growth Horm. IGF Res. (2015), http:// dx.doi.org/10.1016/j.ghir.2015.08.003
2
H. Ostrer / Growth Hormone & IGF Research xxx (2015) xxx–xxx
Both communities differ from other Latin American communities in their relative isolation from the colonial and religious authorities, making them natural destinations for Converso migration [13,20]. This hypothesis was tested by comparing Hispanos and Lojanos to a Latin American population derived from urban Guadalajara, Mexico [18], an important colonial center less remote than these other two locales during the Spanish Imperial Era. The Hispanos and Lojanos thus experienced a Converso Frontier Phenomenon. There was a remarkable similarity about the nature of admixture between Hispanos and Lojanos and other communities with origins in Latin America. There were hallmarks of Jewish ancestry, with particular enrichment in the Lojano community. Both Hispanos and Lojanos appear to be descendants of Native American and European groups with marginal sub-Saharan ancestry. This is not surprising given the large geographical distances between the principal slave trading routes of the Caribbean Basin and the Southwestern US and Southern Ecuador. There was a strong gender bias in the foundation of the Hispano and Lojano groups. Mitochondrial DNA was representative of Native American haplogroups, and Y-chromosomes non-Native American with representation from Old World populations. The majority of Y-chromosomes analyzed from both groups were predictably of European origin with a minority that appeared to be derived from Middle Eastern origin, thus a strong likelihood of cryptic Jewish or other Middle Eastern origin. Similar cryptic Jewish or Middle Eastern ancestry has been demonstrated by analysis of paternal lineages in historically Christian, Spanish-speaking populations throughout the Iberian Peninsula [2] and in genome-wide surveys of various Caribbean and continental Latin American populations [8]. The Hispanos and Lojanos are known to harbor mutations that are prevalent within Jewish Diaspora communities, providing further evidence for possible Jewish origins [17,24]. The Bloom syndrome, blmAsh mutation, originally identified in Ashkenazi Jews, was found in the Hispano cohort and in Hispanic/Latino individuals living in he Southwestern US, Mexico, and El Salvador [9]. The observable Sephardic ancestry in both Hispanos and Lojanos, provides genomic evidence to the historical narrative of the Frontier Phenomenon of Converso migration to the New World with Lojanos demonstrating a greater degree of Converso ancestry than Hispanos. The maintenance of mutations previously characterized in the Jewish Diaspora communities in populations with non-Jewish ancestry resulted from the endogamy within these populations. The observation of the GHR p.180E in other Latin American populations suggests that they and perhaps all Latin American populations have a certain degree of cryptic Jewish ancestry. Conflict of interest
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13] [14]
[15]
[16]
[17]
[18]
[19]
[20] [21] [22]
[23] [24]
There are no conflicts of interest to disclose. References [1] The International HapMap Project, Nature 426 (2003) 789–796. [2] S.M. Adams, E. Bosch, P.L. Balaresque, S.J. Ballereau, A.C. Lee, E. Arroyo, A.M. LopezParra, M. Aler, M.S. Grifo, M. Brion, A. Carracedo, J. Lavinha, B. Martinez-Jarreta, L. Quintana-Murci, A. Picornell, M. Ramon, K. Skorecki, D.M. Behar, F. Calafell, M.A. Jobling, The genetic legacy of religious diversity and intolerance: paternal lineages of Christians, Jews, and Muslims in the Iberian Peninsula, Am. J. Hum. Genet. 83 (2008) 725–736. [3] N.Ah. Mew, N. Hamel, M. Galvez, M. Al-Saffar, W.D. Foulkes, Haplotype analysis of a BRCA1: 185delAG mutation in a Chilean family supports its Ashkenazi origins, Clin. Genet. 62 (2002) 151–156. [4] S. Alberro, Crypto-Jews and the Mexican Holy Office in the Seventeenth Century, in: P. Bernardini, N. Fiering (Eds.), The Jews and the Expansion of Europe to the West 1450–1800, Berghahn, New York, 2001. [5] G. Atzmon, L. Hao, I. Pe'er, C. Velez, A. Pearlman, P.F. Palamara, B. Morrow, E. Friedman, C. Oddoux, E. Burns, H. Ostrer, Abraham's children in the genome era:
[25]
[26]
[27]
[28]
major Jewish diaspora populations comprise distinct genetic clusters with shared Middle Eastern Ancestry, Am. J. Hum. Genet. 86 (2010) 850–859. R.B. Bar-Sade, A. Kruglikova, B. Modan, E. Gak, G. Hirsh-Yechezkel, L. Theodor, I. Novikov, R. Gershoni-Baruch, S. Risel, M.Z. Papa, G. Ben-Baruch, E. Friedman, The 185delAG BRCA1 mutation originated before the dispersion of Jews in the diaspora and is not limited to Ashkenazim, Hum. Mol. Genet. 7 (1998) 801–805. K. Bordenave, J. Griffith, S.M. Hordes, T.M. Williams, R.S. Padilla, The historical and geomedical immunogenetics of pemphigus among the descendants of Sephardic Jews in New Mexico, Arch. Dermatol. 137 (2001) 825–826. K. Bryc, C. Velez, T. Karafet, A. Moreno-Estrada, A. Reynolds, A. Auton, M. Hammer, C.D. Bustamante, H. Ostrer, Colloquium paper: genome-wide patterns of population structure and admixture among Hispanic/Latino populations, Proc. Natl. Acad. Sci. U. S. A. 107 (Suppl. 2) (2010) 8954–8961. N.A. Ellis, S. Ciocci, M. Proytcheva, D. Lennon, J. Groden, J. German, The Ashkenazic Jewish Bloom syndrome mutation blmAsh is present in non-Jewish Americans of Spanish ancestry, Am. J. Hum. Genet. 63 (1998) 1685–1693. L.S. Friedman, C.I. Szabo, E.A. Ostermeyer, P. Dowd, L. Butler, T. Park, M.K. Lee, E.L. Goode, S.E. Rowell, M.C. King, Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families, Am. J. Hum. Genet. 57 (1995) 1284–1297. J. German, D. Bloom, E. Passarge, K. Fried, R.M. Goodman, I. Katzenellenbogen, Z. Laron, C. Legum, S. Levin, Wahrman, Bloom's syndrome. VI. The disorder in Israel and an estimation of the gene frequency in the Ashkenazim, Am. J. Hum. Genet. 29 (1977) 553–562. R. Goncalves, A. Freitas, M. Branco, A. Rosa, A.T. Fernandes, L.A. Zhivotovsky, P.A. Underhill, T. Kivisild, A. Brehm, Y-chromosome lineages from Portugal, Madeira and Acores record elements of Sephardim and Berber ancestry, Ann. Hum. Genet. 69 (2005) 443–454. S.M. Hordes, To the End of the Earth, a History of the Crypto-Jews of New Mexico, Columbia University Press, New York, 2005. E.M. John, A. Miron, G. Gong, A.I. Phipps, A. Felberg, F.P. Li, D.W. West, A.S. Whittemore, Prevalence of pathogenic BRCA1 mutation carriers in 5 US racial/ethnic groups, JAMA 298 (2007) 2869–2876. Z. Laron, A. Pertzelan, S. Mannheimer, Genetic pituitary dwarfism with high serum concentation of growth hormone—a new inborn error of metabolism? Isr. J. Med. Sci. 2 (1966) 152–155. I. Makriyianni, N. Hamel, S. Ward, W.D. Foulkes, S. Graw, BRCA1:185delAG found in the San Luis Valley probably originated in a Jewish founder, J. Med. Genet. 42 (2005) e27. L.G. Mullineaux, T.M. Castellano, J. Shaw, L. Axell, M.E. Wood, S. Diab, C. Klein, M. Sitarik, A.M. Deffenbaugh, S.L. Graw, Identification of germline 185delAG BRCA1 mutations in non-Jewish Americans of Spanish ancestry from the San Luis Valley, Colorado, Cancer 98 (2003) 597–602. M.R. Nelson, K. Bryc, K.S. King, A. Indap, A.R. Boyko, J. Novembre, L.P. Briley, Y. Maruyama, D.M. Waterworth, G. Waeber, P. Vollenweider, J.R. Oksenberg, S.L. Hauser, H.A. Stirnadel, J.S. Kooner, J.C. Chambers, B. Jones, V. Mooser, C.D. Bustamante, A.D. Roses, D.K. Burns, M.G. Ehm, E.H. Lai, The Population Reference Sample, POPRES: a resource for population, disease, and pharmacological genetics research, Am. J. Hum. Genet. 83 (2008) 347–358. C. Oddoux, J.P. Struewing, C.M. Clayton, S. Neuhausen, L.C. Brody, M. Kaback, B. Haas, L. Norton, P. Borgen, S. Jhanwar, D. Goldgar, H. Ostrer, K. Offit, The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%, Nat. Genet. 14 (1996) 188–190. R. Ordóñez-Chiriboga, La Herencia Serfardita en la Provincia de Loja, Casa de la Cultura Ecuatoriana “Benjamín Carrión”, Quito2005. H. Ostrer, A genetic profile of contemporary Jewish populations, Nat. Rev. Genet. 2 (2001) 891–898. P.R. Pacheco, C.C. Branco, R. Cabral, S. Costa, A.L. Araujo, B.R. Peixoto, P. Mendonca, L. Mota-Vieira, The Y-chromosomal heritage of the Azores Islands population, Ann. Hum. Genet. 69 (2005) 145–156. J. Prinz, The Secret Jews, Random House, New York, 1973. A.L. Rosenbloom, J. Guevara-Aguirre, Growth hormone receptor deficiency in South America: colonial history, molecular biology, and growth and metabolic insights, J. Pediatr. Endocrinol. Metab. 21 (2008) 1107–1109. R. Rowland, New Christian, Marrano, Jew, in: P. Bernardini, N. Fiering (Eds.), The Jews and the Expansion of Europe to the West 1450–1800, Berghahn Books, New York, 2001. J.P. Struewing, D. Abeliovich, T. Peretz, N. Avishai, M.M. Kaback, F.S. Collins, L.C. Brody, The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals, Nat. Genet. 11 (1995) 198–200. W.K. Sutton, A. Knight, P.A. Underhill, J.S. Neulander, T.R. Disotell, J.L. Mountain, Toward resolution of the debate regarding purported crypto-Jews in a SpanishAmerican population: evidence from the Y chromosome, Ann. Hum. Biol. 33 (2006) 100–111. E.A. Uchmany, The Participation of New Christians and Crypto-Jews in the Conquest, Colonization, and Trade in Spanish America, 1521–1660, in: P. Bernardini, N. Fiering (Eds.), The Jews and the Expansion of Europe to the West 1450–1800, Berghahn, New York, 2001.
Please cite this article as: H. Ostrer, The origin of the p.E180 growth hormone receptor gene mutation, Growth Horm. IGF Res. (2015), http:// dx.doi.org/10.1016/j.ghir.2015.08.003
Contents lists available at ScienceDirect
Growth Hormone & IGF Research journal homepage: www.elsevier.com/locate/ghir
The origin of the p.E180 growth hormone receptor gene mutation Harry Ostrer ⁎ Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, United States Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, United States
a r t i c l e
i n f o
Article history: Received 4 June 2015 Received in revised form 22 July 2015 Accepted 3 August 2015 Available online xxxx Keywords: Laron syndrome GHR gene GHR deficiency Founder mutation Population genetics
a b s t r a c t Laron syndrome, an autosomal recessive condition of extreme short stature, is caused by the absence or dysfunction of the growth hormone receptor. A recurrent mutation in the GHR gene, p.E180, did not alter the encoded amino acid, but activated a cryptic splice acceptor resulting in a receptor protein with an 8-amino acid deletion in the extracellular domain. This mutation has been observed among Sephardic Jews and among individuals in Ecuador, Brazil and Chile, most notably in a large genetic isolate in Loja, Ecuador. A common origin has been postulated based on a shared genetic background of markers flanking this mutation, suggesting that the Lojanos (and others) may have Sephardic (Converso) Jewish ancestry. Analysis of the population structure of Lojanos based on genome-wide analysis demonstrated European, Sephardic Jewish and Native American ancestry in this group. X-autosomal comparison and monoallelic Y chromosomal and mitochondrial genetic analysis demonstrated gender-biased admixture between Native American women and European and Sephardic Jewish men. These findings are compatible with the co-occurrence of the Inquisition and the colonization of the Americas, including Converso Jews escaping the Inquisition in the Iberian Peninsula. Although not found among Lojanos, Converso Jews also brought founder mutations to contemporary Hispanic and Latino populations in the BRCA1 (c.68_69delAG) and BLM (c.2207_2212delATCTGAinsTAGATTC) genes. © 2015 Elsevier Ltd. All rights reserved.
For many years, there have been attempts to use genetics to characterize the communities of the Jewish Diaspora, including the use of genome-wide analysis [1,5], and the identification of several mutations for Mendelian diseases that are over-represented in Jewish Diaspora communities. These include the breast and ovarian cancer susceptibility mutation, BRCA1 c.185delAG [6,10,19,26], the Laron syndrome growth hormone receptor mutation, GHR c.E180 [15], and Bloom syndrome mutation, blmash [11] (for review, see [21]). Despite the overwhelming prevalence of these mutations and/or diseases in Diaspora communities, they have also been observed in non-Jewish Hispanic/Latino groups [3,7,9,14,16,17,24]. When considering the history of Jews in the Iberian Peninsula during the European colonization of Latin America, the Jewish origin of these mutations can be explained. The Sephardic Jews of Iberia had a millennial history that originated in Classical Antiquity. Their time in that peninsula had alternating periods of relative tolerance and total discrimination that culminated in the forced conversions and expulsions from the late 15th century and into the 17th century [23] — just at the time that the New World was being colonized by Spain and Portugal. Following a traquil period in the 13th century, known as La Conviviencia, the Reconquista of the 15th century led to the Inquisition. The descendants of the Sephardim of this era became to be known as Conversos (or converted) Jews. In ⁎ Department of Pathology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Ullman 817, Bronx, NY 10461, United States. E-mail address: [email protected].
the presence of Inquisitorial and government pressure, Jewish orthodoxy was lost with integration into Catholic colonial society and inheritance of disjointed relics or total abandonment of Jewish ritual [25]. Facing conversion or death, many Jews fled Iberia. Some settled in the territories of the Ottoman Empire, whereas 100,000 chose to remain for the meantime in the peninsula by fleeing into Portugal, increasing the population to 3–5% of the total population [23,25]. When the Inquisition came to Portugal, following the union of these kingdoms under Felipe II, many fled to New World territories, especially the fringes of northern New Spain in modern day Colorado and in the mountainous regions of colonial Peru in what is now Ecuador [4]. Conversos sailed with Columbus, helped topple the indigenous Aztec and Incan Empires, and were integral members of the political and religious hierarchies of the Viceroyalties of New Spain and Peru [4,20,25,28]. It has been difficult to determine the degree of intermarriage in the New World between newly converted Christians and Christians from older communities. Here, we review our earlier studies that linked the rich history and mutation data of people in Latin America with Converso heritage. One community resided in the Loja province of Ecuador and will be referenced as Lojanos [20]. Another community resided in the San Luis Valley of Colorado and will be referenced as Hispanos [13,20]. Although the Jewishness of such communities has been strenuously refuted by some [27], there is evidence of Converso ancestry in these communities. Furthermore, population genetic studies can distinguish Sephardim reliably from other Jewry and the basis for this difference can be detected in modern Iberian and Latin American populations [2,5,8,12,22].
http://dx.doi.org/10.1016/j.ghir.2015.08.003 1096-6374/© 2015 Elsevier Ltd. All rights reserved.
Please cite this article as: H. Ostrer, The origin of the p.E180 growth hormone receptor gene mutation, Growth Horm. IGF Res. (2015), http:// dx.doi.org/10.1016/j.ghir.2015.08.003
2
H. Ostrer / Growth Hormone & IGF Research xxx (2015) xxx–xxx
Both communities differ from other Latin American communities in their relative isolation from the colonial and religious authorities, making them natural destinations for Converso migration [13,20]. This hypothesis was tested by comparing Hispanos and Lojanos to a Latin American population derived from urban Guadalajara, Mexico [18], an important colonial center less remote than these other two locales during the Spanish Imperial Era. The Hispanos and Lojanos thus experienced a Converso Frontier Phenomenon. There was a remarkable similarity about the nature of admixture between Hispanos and Lojanos and other communities with origins in Latin America. There were hallmarks of Jewish ancestry, with particular enrichment in the Lojano community. Both Hispanos and Lojanos appear to be descendants of Native American and European groups with marginal sub-Saharan ancestry. This is not surprising given the large geographical distances between the principal slave trading routes of the Caribbean Basin and the Southwestern US and Southern Ecuador. There was a strong gender bias in the foundation of the Hispano and Lojano groups. Mitochondrial DNA was representative of Native American haplogroups, and Y-chromosomes non-Native American with representation from Old World populations. The majority of Y-chromosomes analyzed from both groups were predictably of European origin with a minority that appeared to be derived from Middle Eastern origin, thus a strong likelihood of cryptic Jewish or other Middle Eastern origin. Similar cryptic Jewish or Middle Eastern ancestry has been demonstrated by analysis of paternal lineages in historically Christian, Spanish-speaking populations throughout the Iberian Peninsula [2] and in genome-wide surveys of various Caribbean and continental Latin American populations [8]. The Hispanos and Lojanos are known to harbor mutations that are prevalent within Jewish Diaspora communities, providing further evidence for possible Jewish origins [17,24]. The Bloom syndrome, blmAsh mutation, originally identified in Ashkenazi Jews, was found in the Hispano cohort and in Hispanic/Latino individuals living in he Southwestern US, Mexico, and El Salvador [9]. The observable Sephardic ancestry in both Hispanos and Lojanos, provides genomic evidence to the historical narrative of the Frontier Phenomenon of Converso migration to the New World with Lojanos demonstrating a greater degree of Converso ancestry than Hispanos. The maintenance of mutations previously characterized in the Jewish Diaspora communities in populations with non-Jewish ancestry resulted from the endogamy within these populations. The observation of the GHR p.180E in other Latin American populations suggests that they and perhaps all Latin American populations have a certain degree of cryptic Jewish ancestry. Conflict of interest
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13] [14]
[15]
[16]
[17]
[18]
[19]
[20] [21] [22]
[23] [24]
There are no conflicts of interest to disclose. References [1] The International HapMap Project, Nature 426 (2003) 789–796. [2] S.M. Adams, E. Bosch, P.L. Balaresque, S.J. Ballereau, A.C. Lee, E. Arroyo, A.M. LopezParra, M. Aler, M.S. Grifo, M. Brion, A. Carracedo, J. Lavinha, B. Martinez-Jarreta, L. Quintana-Murci, A. Picornell, M. Ramon, K. Skorecki, D.M. Behar, F. Calafell, M.A. Jobling, The genetic legacy of religious diversity and intolerance: paternal lineages of Christians, Jews, and Muslims in the Iberian Peninsula, Am. J. Hum. Genet. 83 (2008) 725–736. [3] N.Ah. Mew, N. Hamel, M. Galvez, M. Al-Saffar, W.D. Foulkes, Haplotype analysis of a BRCA1: 185delAG mutation in a Chilean family supports its Ashkenazi origins, Clin. Genet. 62 (2002) 151–156. [4] S. Alberro, Crypto-Jews and the Mexican Holy Office in the Seventeenth Century, in: P. Bernardini, N. Fiering (Eds.), The Jews and the Expansion of Europe to the West 1450–1800, Berghahn, New York, 2001. [5] G. Atzmon, L. Hao, I. Pe'er, C. Velez, A. Pearlman, P.F. Palamara, B. Morrow, E. Friedman, C. Oddoux, E. Burns, H. Ostrer, Abraham's children in the genome era:
[25]
[26]
[27]
[28]
major Jewish diaspora populations comprise distinct genetic clusters with shared Middle Eastern Ancestry, Am. J. Hum. Genet. 86 (2010) 850–859. R.B. Bar-Sade, A. Kruglikova, B. Modan, E. Gak, G. Hirsh-Yechezkel, L. Theodor, I. Novikov, R. Gershoni-Baruch, S. Risel, M.Z. Papa, G. Ben-Baruch, E. Friedman, The 185delAG BRCA1 mutation originated before the dispersion of Jews in the diaspora and is not limited to Ashkenazim, Hum. Mol. Genet. 7 (1998) 801–805. K. Bordenave, J. Griffith, S.M. Hordes, T.M. Williams, R.S. Padilla, The historical and geomedical immunogenetics of pemphigus among the descendants of Sephardic Jews in New Mexico, Arch. Dermatol. 137 (2001) 825–826. K. Bryc, C. Velez, T. Karafet, A. Moreno-Estrada, A. Reynolds, A. Auton, M. Hammer, C.D. Bustamante, H. Ostrer, Colloquium paper: genome-wide patterns of population structure and admixture among Hispanic/Latino populations, Proc. Natl. Acad. Sci. U. S. A. 107 (Suppl. 2) (2010) 8954–8961. N.A. Ellis, S. Ciocci, M. 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Please cite this article as: H. Ostrer, The origin of the p.E180 growth hormone receptor gene mutation, Growth Horm. IGF Res. (2015), http:// dx.doi.org/10.1016/j.ghir.2015.08.003