The Wandering Gene and the Indian Princess

by Jeff Wheelwright

  147The King–Skolnick competition to isolate BRCA1 is detailed in: Curing Cancer: Solving One of the Greatest Medical Mysteries of Our Time, Michael Waldholz, Simon & Schuster, New York, 1997, and Breakthrough: The Race to Find the Breast Cancer Gene, Kevin Davies and Michael White, John Wiley & Sons, New York, 1997. The decisive paper from the Skolnick lab was “A Strong Candidate for the Breast and Ovarian Cancer Susceptibility Gene BRCA1,” Y. Miki et al., Science, Vol. 266, 1994, pp. 66–71.

  Skolnick’s remark about his joking around with Mormons is from my unpublished interview with him in 2005. King’s discovery of her Jewish grandfather is reported by Entine, op. cit., p. 282–89.

  148As to the prevalence and penetrance of 185delAG in Ashkenazi Jews, a number of reports, studies, and commentaries about the mutation followed quickly on the heels of the identification of BRCA1. See, primarily: “BRCA1 Mutations in Ashkenazi Jewish Women” (letter), Patricia Tonin et al., American Journal of Human Genetics, Vol. 57, 1995, p. 189; “A Common BRCA1 mutation in the Ashkenazim,” David Goldgar and Philip Reilly, Nature Genetics, Vol. 11, 1995, pp. 113–14; “The Carrier Frequency of the BRCA1 185delAG Mutation Is Approximately 1 Percent in Ashkenazi Jewish Individuals” (letter), Jeffery P. Struewing et al., Nature Genetics, Vol. 11, 1995, pp. 198–200; “Novel Inherited Mutations and Variable Expressivity of BRCA1 Alleles, Including the Founder Mutation 185delAG in Ashkenazi Jewish Families,” Lori Friedman et al., American Journal of Human Genetics, Vol. 57, 1995, pp. 1284–97; “BRCA1—Lots of Mutations, Lots of Dilemmas,” Francis Collins, New England Journal of Medicine, Vol. 334, No. 3, 1996, pp.186–88; “The Risk of Cancer Associated with Specific Mutations of brca1 and brca2 among Ashkenazi Jews,” Jeffery P. Struewing et al., New England Journal of Medicine, Vol. 336, No. 20, 1997, pp. 1401–8 (the NIH study).

  For a synopsis of Jewish BRCA risk, see “Hereditary Breast Cancer in Jews,” Wendy S. Rubinstein, Familial Cancer, Vol. 3, 2004, pp. 249–57; and the findings of the New York Breast Cancer Study, cited in the note for page 153.

  Because Ashkenazi Jews predominate in Europe and North America, their three founder mutations receive the greatest attention. But from the Israeli perspective, taking into account the Sephardic and Mizrahi populations, there may be as many as seven founder mutations that Jews should recognize. See: “Two BRCA1/2 Founder Mutations in Jews of Sephardic Origin,” Michal Sagi et al., Familial Cancer, Vol. 10, No. 1, 2011, pp. 59–63.

  150On whether Ashkenazi Jewish women have more breast cancer than other women, a small study conducted in Britain found that they did: “A Population-Based Audit of Ethnicity and Breast Cancer Risk in One General Practice Catchment Area in North London, UK: Implications for Practice,” M. Ferris et al., Hereditary Cancer in Clinical Practice, Vol. 5, No. 3, 2007, pp. 157–60.

  150The first major study to establish the young age of 185delAG carriers with cancer was: “Germ-Line brca1 Mutations in Jewish and Non-Jewish Women with Early-Onset Breast Cancer,” M. G. Fitzgerald et al., New England Journal of Medicine, Vol. 334, No. 3, 1996, pp. 143–49.

  151For the greater uptake of BRCA screening by Jewish women, see: “Awareness and Attitudes Concerning BRCA Gene Testing,” Avigyail Mogilner et al., Annals of Surgical Oncology, Vol. 5, No. 7, 1998, pp. 607–12; “Racial Differences in the Use of BRCA1/2 Testing among Women with a Family History of Breast or Ovarian Cancer,” Katrina Armstrong et al., Journal of the American Medical Association, Vol. 293, No. 14, 2005, pp. 1729–36.

  152The Ethical, Legal, and Social Implications (ELSI) Research Program of the National Human Genome Research Institute is still operational. For information on past and current projects, go to: http://www.genome.gov/10001618.

  Late-1990s concerns by Jews about participating in genetic research are explored in: “Judaism, Genetic Screening and Genetic Therapy,” Fred Rosner, Mt. Sinai Journal of Medicine, Vol. 65, Nos. 5 and 6, 1998, pp. 406–13 (available at: http://www.jewishvirtuallibrary.org/jsource/Judaism/genetic.html); “Toward a Framework of Mutualism: The Jewish Community in Genetics Research,” Karen Rothenberg and Amy Rutkin, Community Genetics, Vol. 1, 1998, pp. 148–53; “Jewish Concern Grows as Scientists Deepen Studies of Ashkenazi Genes,” Sheryl Gay Stolberg, The New York Times, April 22, 1998.

  There was evidence that Jewish women avoided BRCA testing because of misplaced fears about discrimination in health-insurance coverage. See, for instance: “Health Insurance and Discrimination Concerns and BRCA1/2 Testing in a Clinic Population,” Emily A. Peterson et al., Cancer Epidemiology, Biomarkers & Prevention, Vol. 11, 2002, pp. 79–87.

  The ELSI paper complaining that Ashkenazim were targeted by BRCA researchers was:“Ashkenazi Jews and Breast Cancer: The Consequences of Linking Ethnic Identity to Genetic Disease,” American Journal of Public Health, Vol. 96, No. 11, 2006, pp. 1979–88.

  153For the findings of the New York Breast Cancer Study: “Breast and Ovarian Cancer Risks Due to Inherited Mutations in BRCA1 and BRCA2,” Mary-Claire King et al., Science, Vol. 302, October 24, 2003, pp. 643–45.

  154On the national surge in BRCA testing, see, for one of many examples: “Jewish Women Change Their Destinies by Testing for Genetic Mutation,” Julie G. Fax, Jewish Journal of Greater Los Angeles, March 27, 2008.

  156For a thorough discussion of prophylactic mastectomy and oophorectomy, see: Positive Results: Making the Best Decisions When You’re at High Risk for Breast and Ovarian Cancer, Joi L. Morris and Ora K. Gordon, MD, Prometheus Books, New York, 2010. For recent evidence that ovarian removal saves lives: “Association of Risk-Reducing Surgery in BRCA1 or BRCA2 Mutation Carriers with Cancer Risk and Mortality,” Susan M. Domcheck et al., Journal of the American Medical Association, Vol. 304, No. 9, 2010, pp. 967–75.

  About the relatively high rate of prophylactic mastectomy in the United States: “Predictors of Contralateral Prophylactic Mastectomy in Women with a BRCA1 or BRCA2 Mutation: The Hereditary Breast Cancer Clinical Study Group,” Kelly A. Metcalfe et al., Journal of Clinical Oncology, Vol. 26, No. 7, 2008, pp. 1093–97.

  159Rubinstein’s estimate of the number of lives to be saved from national BRCA screening for Jews: “Cost Effectiveness of Population-Based BRCA1/2 Testing and Ovarian Cancer Prevention for Ashkenazi Jews: A Call for Dialogue,” Wendy S. Rubinstein et al., Genetics in Medicine, Vol. 11, No. 9, 2009, pp. 629–39.

  160In July 2011 a federal appeals court upheld Myriad’s patents on the BRCA genes. The judicial opinion summarizes the important issues on both sides. See: http://www.cafc.uscourts.gov/images/stories/opinions-orders/10-1406.pdf.

  161BRCA-associated tumors have a poorer prognosis because they tend to be “triple negative”—that is, usually the cancer cells lack estrogen or progesterone receptors while evincing normal amounts of HER2 (human epidermal growth factor receptor-2). As a result, these cancers cannot be attacked by hormone and anti-HER2 therapies. For more information, see: http://www.tnbcfoundation.org/index.html.

  As for the frustrating returns from genomics technology, research on type 2 diabetes offers a telling example. Type 2 diabetes is a widespread disorder of high interest to pharmaceutical companies. Years of searching for predisposing alleles (genetic variants) has produced no fewer than forty candidates across the genome, their functions largely unknown. Regardless, these alleles have very minor impact on the development of the condition, whether individually or in combination. If diabetes genes are not going to be able to “explain” diabetes, lifestyle factors such as diet must assume more importance. See: “Genomics, Type 2 Diabetes, and Obesity,” Mark I. McCarthy, New England Journal of Medicine, Vol. 363, December 2010, pp. 2339–50.

  Scientists used to think that the variants revealed by genomics, even if they turned out to be weak, like the diabetes alleles, at least would pertain to large populations of patients, but even that expectation doesn’t seem to be true. DNA variation is more variable than anyone knew. Uncommon alleles sequestered in th
e world’s ethnic groups appear to hold the keys to genetic risk. See: “Uncovering the Roles of Rare Variants in Common Disease through Whole-Genome Sequencing,” Elizabeth T. Cirulli and David B. Goldstein, Nature Reviews/Genetics, Volume 11, June 2010, pp. 415–26; “Genetic Heterogeneity in Human Disease,” Jon McClellan and Mary-Claire King, Cell, Vol. 141, April 16, 2010, pp. 210–17; “Genomic Medicine—An Updated Primer,” W. Gregory Feero et al., New England Journal of Medicine, Vol. 362, 2010, pp. 2001–11. The latter two papers contrast the potency of BRCA with the alleles implicated in other diseases. A less technical article about the tardy promise of genomics is: “Awaiting the Genome Payoff,” Andrew Pollack, The New York Times, June 14, 2010.

  162A frequently cited critique of DTC gene testing is: “Direct-to-Consumer Genetic Tests: Misleading Test Results Are Further Complicated by Deceptive Marketing and Other Questionable Practices,” U.S. Government Accountability Office (GAO), July 22, 2010, available at: http://www.gao.gov/products/GAO-10-847T. A more sanguine review of “recreational genomics” is: “My Genome, My Self,” Steven Pinker, The New York Times Magazine, January 11, 2009, available at: http://www.nytimes.com/2009/01/11/magazine/11Genome-t.html. For more on the dozen “personal genome pioneers” who gathered in Cambridge, Massachusetts, in 2010, go to: http://www.getconference.org. See also: “Vanity Genomes and the Future of Medical Sequencing,” National Human Genome Research Institute, September 2010 (http://www.genome.gov/27527308).

  163As to MRI (magnetic resonance imaging) screening for high-risk women: Because of their generally younger ages and denser breasts, and because their tumors, if not caught early, can be harder to treat, BRCA carriers are advised to have MRI scans along with or instead of mammograms. For these patients, the sensitivity of MRI is about twice that of mammography, according to several studies, although the cost of MRI can be a deterrent. See: “M.R.I.’s Help Fight High Risk of Cancer,” Denise Grady, The New York Times, November 15, 2010, and Morris and Gordon, op. cit., pp. 186–94.

  CHAPTER 8: LAST DAYS OF THE INDIAN PRINCESS

  PHOTO: Shonnie, Alamosa, Colorado (credit: George Casias).

  169For information and respectful advice about alternative medicine, I recommend the website of the National Center for Complementary and Alternative Medicine, a unit of the National Institutes of Health, at http://nccam.nih.gov.

  CHAPTER 9: WHEN HARRY MET STANLEY

  PHOTO: DNA sampling session, San Pablo, Colorado.

  184The first published report of 185delAG in Hispanos was: “Identification of Germline 185delAG BRCA1 Mutations in Non-Jewish Americans of Spanish Ancestry from the San Luis Valley, Colorado,” Lisa G. Mullineaux et al., Cancer, Vol. 98, No. 3, August 2003. I first learned about the mutation from a talk given by Mary-Claire King in November of that year. King had come across 185delAG in a large Hispano family named Trujillo during the late 1990s but had not reported it formally.

  Sharon Graw, a contributor to the 2003 Cancer paper, performed a molecular analysis of the Hispano mutation and confirmed its Jewish origin. See: “BRCA1:185delAG Found in the San Luis Valley Probably Originated in a Jewish Founder,” I. Makriyianni et al., Journal of Medical Genetics, Vol. 42, 2005, e27 (available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1736052/pdf/v042p00e27.pdf).

  188Hordes published a number of papers on crypto-Judaism in New Mexico, but his thesis is laid out most fully in his book To the End of the Earth: A History of the Crypto-Jews of New Mexico, Stanley M. Hordes, Columbia University Press, New York, 2005, from which I have quoted here.

  190See Chavez, op. cit., for his Hebrew–New Mexico analogy.

  191Two early works by Judith Neulander that disputed Hordes are: “Crypto-Jews of the Southwest: An Imagined Community,” Jewish Folklore and Ethnology Review, Vol. 16, No. 1, 1994, pp. 64–68, and “The New Mexican Crypto-Jewish Canon: Choosing to be ‘Chosen’ in Millennial Tradition,” Jewish Folklore and Ethnology Review, Vol. 18, Nos. 1–2, 1996, pp. 19–58.

  192The magazine article supporting Neulander was: “Mistaken Identity?: The Case of New Mexico’s ‘Hidden Jews’,” Barbara Ferry and Debbie Nathan, The Atlantic Monthly, Vol. 286, December 2000, pp. 85–96. Seth Kunin’s book is cited in the note for page 66.

  193About pemphigus vulgaris in New Mexico: “The Historical and Geomedical Immunogenetics of Pemphigus Among the Descendants of Sephardic Jews in New Mexico,” Kristine Bordenave et al., Archives of Dermatology, Vol. 137, 2001, pp. 825–26. See also Hordes, op. cit, Appendix, pp. 289–95. About Bloom syndrome in New Mexico: “The Ashkenazic Jewish Bloom Syndrome Mutation blmAsh Is Present in Non-Jewish Americans of Spanish Ancestry,” Nathan A. Ellis et al., American Journal of Human Genetics, Vol. 63, 1998, pp. 1685–93, and Hordes, op. cit., pp. 271–72.

  194For two examples of the extensive reporting on Father Bill Sanchez, see: “Hispanics Uncovering Roots as Inquisition’s ‘Hidden’ Jews,” Simon Romero, The New York Times, October 29, 2005, and “The Secret of San Luis Valley,” Jeff Wheelwright, Smithsonian, October 2008, pp. 48–56.

  194The genetic study that Neulander coauthored was: “Toward Resolution of the Debate Regarding Purported Crypto-Jews in a Spanish-American Population: Evidence from the Y chromosome,” Wesley K. Sutton et al., Annals of Human Biology, Vol. 33, January–February 2006, pp. 100–111. In arguing that Hispano males were not different from Iberian males when markers on their Y chromosomes were compared with those of Jews, the authors did not examine the possibility that Sephardic Jewish markers had previously been incorporated in Iberians and by extension New Mexicans, per the admixture study by Adams et al., op. cit.

  Neulander’s complaints about pseudoscience are from “Folk Taxonomy, Prejudice and the Human Genome: Using Disease as a Jewish Ethnic Marker,” Judith S. Neulander, Patterns of Prejudice, Vol. 40, Nos. 4–5, 2006, pp. 381–98. The pemphigus research that she cited was: “Common Ancestral Origin of Pemphigus Vulgaris in Jews and Spaniards: A Study Using Microsatellite Markers,” R. Loewenthal et al., Tissue Antigens, Vol. 63, No. 4, pp. 326–34.

  196Regarding the adjustments made to the Cohan Modal Haplotype, compare and contrast the following papers. The first introduced the CMH concept and the second, by the same team, revised it with new data: “Y Chromosomes of Jewish Priests,” Karl Skorecki et al., Nature, Vol. 385, 1997, p. 32, and “Extended Y Chromosome Haplotypes Resolve Multiple and Unique Lineages of the Jewish Priesthood,” Michael F. Hammer et al., Human Genetics, Vol. 126, 2009, pp. 707–17.

  197Given the well-documented Ashkenazi presence in New Mexico, it might well be asked if this group was the source of 185delAG in Hispanos, rather than the shadowy Spanish conversos. The major argument against the Ashkenazi scenario is that if Eastern European Jews had spread BRCA genes into the local populace, investigators would have detected not only 185delAG but also the other two mutations from the Jewish set: 5382insC in BRCA1 and 6174delT in BRCA2. Together, they are more common in Ashkenazi Jews than 185delAG. Though a rigorous epidemiologic survey is lacking, the other two mutations haven’t turned up in clinical samples in New Mexico and Colorado Hispanos. Nor have they been reported in Spain’s population, although 185delAG has—which is just what you would expect if 185delAG’s transmission was exclusively from Spain. Sources: Mullineaux, op. cit., and Paul Duncan, Hematology-Oncology Associates, Albuquerque, NM, personal communication.

  See also, on this question: “Prevalence of BRCA Mutations and Founder Effect in High-Risk Hispanic Families,” Jeffrey N. Weitzel et al., Cancer Epidemiology, Biomarkers & Prevention, Vol. 14, No. 7, 2005, pp. 1666–71. This study of Hispanics in the Los Angeles area uncovered four instances of 185delAG; none of 6714delT; and one of 5382insC, in a person who had both Mexican and Eastern European ancestry.

  198An account of the kosher beef project in the San Luis Valley appears in “Hard Choices: The Birth and Death of Ranchers’ Choice Cooperative,” David Carter, New Generation Cooperatives: Case
Studies, Illinois Institute for Rural Affairs, Macomb, IL, 2001, pp. 121–31.

  202The newspaper article about Hispano genetic disorders in San Luis Valley, featuring Beatrice, Shonnie, and other patients, was: “Valley Harbors a Tragic Legacy,” Karen Augé, The Denver Post, September 28, 2003, p. A1. The case of Beatrice Martinez Wright subsequently was taken up in Entine, op. cit., chapter 8. I learned of Shonnie Medina’s case during a reporting trip for Smithsonian magazine in 2007. I included Beatrice but not Shonnie in my article (Wheelwright, op cit.).

  205For references on the race concept in science, see notes for chapter 3. In addition, the following articles cover the recent influence of genetics on race: “Genetic Structure of Human Populations,” Noah Rosenberg et al., Science, Vol. 298, December 2002, pp. 2381–85; “Deconstructing the Relationship between Genetics and Race,” Michael Bamshad et al., Nature Reviews/Genetics, Vol. 5, August 2004, pp. 598–609; “What We Do and Don’t Know about ‘Race,’ ‘Ethnicity,’ Genetics and Health at the Dawn of the Genome Era,” Francis S. Collins, Nature Genetics, Supplement, Vol. 36, No. 11, 2004, pp. 513–15; “Genes, Race, and Medicine,” Jeff Wheelwright, a three-part series, Discover, March, April, May 2005; “Looking for Race in All the Wrong Places: Analyzing the Lack of Productivity in the Ongoing Debate about Race and Genetics,” Morris W. Foster, Human Genetics, Vol. 126, No. 3, 2009, pp. 355–62.

  206The estimate that twenty-four million base pairs differentiate one person’s DNA from another’s was taken from Feero et al., op. cit., p. 2003.

  207Regarding the technology of ancestry-testing, direct-to-consumer companies such as 23andMe and Family Tree DNA have started to incorporate more expensive, whole-genome assays in their offerings (i.e., autosomal SNP coverage), the same technology that Ostrer and other scientists use. This is in addition to the standard Y chromosome and mtDNA assays.