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History,Ethnicity, Medicine and Genes: Implication of genomics for community screening and prevention, the case of Ashkenazi • Jewish Populations. Why is history important? • Genomics is a science of populations and their • • diseases. It allows us to understand how disease, history and culture interact It enables us to design rational screening and surveillance programs It enables us to target specific populations and diseases, achieve wide-scale prevention, and avoid cultural and situational barriers to implementation of screening and prevention programs Ideal population for genomic studies • Homogenous, genetically isolated over many generations • Traced to known ancestors or specific small ancestral populations • Accepts and supports genetic research • Geographic proximity to academic resources Ideal populations • • • • Icelanders Amish French Canadians Ashkenazi Jews Ashkenazi populations support and welcome medical research, live in close proximity to major research centers and a substantial proportion of research scientists are of Ashkenazi origin and a part of the communities which they study. Every ethnic group has its own genetic burden • Many of the methods that are now being applied to diverse populations were pioneered in the study of Ashkenazi genetics. • Many advances that intermingle history and medicine Y Chromosome Bears Witness to Story of the Jewish Diaspora By NICHOLAS WADE May 9, 2000 With a new technique based on the male or Y chromosome, biologists have traced the diaspora of Jewish populations from the dispersals that began in 586 B.C. to the modern communities of Europe and the Middle East. The analysis provides genetic witness that these communities have, to a remarkable extent, retained their biological identity separate from their host populations, evidence of relatively little intermarriage or conversion into Judaism over the centuries. Another finding, paradoxical but unsurprising, is that by the yardstick of the Y chromosome, the world's Jewish communities closely resemble not only each other but also Palestinians, Syrians and Lebanese, suggesting that all are descended from a common ancestral population that inhabited the Middle East some four thousand years ago. Gene causes Parkinson's in Ashkenazim Although Parkinson's disease has not generally been regarded as genetic in origin, researchers at Yeshiva University's Einstein College of Medicine and Beth Israel Medical Center in New York have discovered a single gene that is the "major cause" of Parkinson's in Ashkenazi Jews. The report appears as "Correspondence" in the January 26 issue of the prestigious New England Journal of Medicine. NEJM, Volume 354:424-425 January 26, 2006 LRRK2 G2019S as a Cause of Parkinson's Disease in Ashkenazi Jews LRRK2 G2019S as a Cause of Parkinson's Disease in North African Arabs The Lindex – A Pioneering Database • Jacob Jay Lindenthal, Ph.D., Dr. PH, • • Professor,Department of Psychiatry, Director of Public Medical Education,University of Medicine and Dentistry-New Jersey Medical School focuses on North American Jews and consists of approximately 2,400 entries derived from over 1000 studies involving 574 diseases and conditions and classified according to the International Classification of Diseases (ICD9CM). The database allows for review of each disease via literary form, as well as permitting manipulation of the data from the studies so that investigators can examine relationships among diseases. Available through the library The Human Mosaic Jewish Ashkenazi Family American We maintain Complex relationships We all have multiple identity Genes, Self and Group Identity Religious Identification Marriage A species is divided into races when it can be regarded as an essentially discontinuous set of individuals. Jonathan Marks "Despite their long-term residence in different countries -- most Jewish populations were not significantly different from one another at the genetic level.” (M.F. Hammer, Proc. Some cases are easy Nat'l Academy of Science, May 9, 2000) DNA Testing to Determine “Native American Identity” DNA Analysis and the Cultural Affiliation of the Kennewick Man Who gets to decide who is a member of the group? Black Southern African Bantuspeaking population who assert Jewish ancestry: Genes and History Genetic Diseases Brief review of History History Lesson - What happened in 70 CE • • • • 2nd Jewish Temple in Jerusalem destroyed in 70AD dispersal +++, to Europe = Ashkenazim to Spain / Portugal = Sephardim To other countries of the Middle East - Jews of Arab lands • 2,000 years, mixing of populations between communities – communal records ebb and flow of populations in each community Simple genetic markers of populations • The Blood Group story • more complex genetic markers - DNA • ‘Jewish genetic diseases’ • Mitochondrial DNA What does Tay-Sachs tell us? • carried and passed on amongst Ashkenazi Jews • origins in eastern Europe • not found amongst native eastern Europeans or Sephardic populations • must have arisen after Jews moved to Europe • Started in Western Hungary The Tay-Sachs Story • in Jews of Polish and Russian origin • • • • • Tay-Sachs carrier frequency is 0.0324 (1 in 31) no carriers were found amongst near Eastern Jews dating these genetic changes to before 1100 when Jewish migration into Poland & Russia occurred Jews from Austria, Hungary & Czechoslovakia twice as likely to be Tay-Sachs carriers than those with Polish or Russian origin indicates a central rather than eastern European origin difficult to distinguish the causes and influences population bottleneck effects encourage genetic drift versus a potential selective advantage. Illness ‘Inherited Tay-Sachs Familial breast and ovarian Gaucher’s disease cancer Niemann-Pick Hereditory NonPolyposis Dysautonomia Colon Cancer Canavan’s Disease Bloom’s syndrome, Fanconi’s and conditions common Anemia in Sephardim: Factor XI deficiency Familial Mediterranean Fever, Mucolipidosis type IV thalassaemia, G6PD deficiency What happened in eastern Europe? How did Ashkenazim inherit Tay-Sachs? • not from Adam or Eve • Jews in the pale of Settlement from 1264 • since then repeated cycles of growth, variable population loss and migration • ‘ideal environment’ for some genes to reach high frequency • founder effect, genetic drift + endogamy • strong evolutionary pressures • but perhaps also selective pressures What selection pressures may have acted? • genetic drift = random effect • founder effect c.f. the Pilgrim fathers • selective advantage c.f. sickle cell anaemia Genetic Drift • Random fluctuations in the frequency of the • appearance of a gene in a small isolated population, presumably owing to chance rather than natural selection. The effective size of the Ashkenazi population has been estimated by Risch et al. (1995) to have been as small as several thousand people about 500 years ago Evidence in Support of a Founder Effect • Jewish religious & cultural practices • marrying within - endogamy • creates multiple genetically isolated population • • • • • groups does not create genetic diseases but increases recessive gene concentration and expression of recessive conditions this is an ideal environment for founders multiple isolated settlements, multiple founders, many opportunities to concentrate genes multiple examples apart from Tay-Sachs What selective pressures might have acted? • Ashkenazi Jews subject to cycles of political & social upheaval • Matchmaking ethos - scholars married the wealthy and the elite • villages were lost in pogroms whilst others were forced to emigrate • subjected to natural selective pressures – oppression. • epidemics of plague, TB & starvation over-crowded & confined to ghettos • carrying some gene(s) may confer a survival Evidence for Selective Pressure • Average IQ in Ahskenazic (not Sefardic) • • populations is 112 - 115 Visual Spatial scores are lower and incidence of myopia higher than surrounding populations Consistent with 40 generations of narrow sense heritability (each 1 point increase n IQ of parents leads to a 0.3 point increase in the IQ of children) Balance of Evidence The origin of Ashkenazis. Where do Jews fit? Ashkenazim Jews of Arab Lands Russians Armenians Turks Poles Iraqi Jews Byelorussians Portuguese North African Jews Spaniards Muslim Kurds Kurdish Jews North Africans Ashkenazi Jews Palestinians Jordanians Lebanese Syrians Bedouin Genetic evolutionar y tree Genetic Analysis of Populations • DNA markers • Cohen and Levi genes • History, Ethnicity and Health Cohanim and their Genes • the priests of the Temple • • • • responsibility to bless the Jewish community tradition passed by fathers to sons very stringent family / marital rules ‘Cohen’ families descended from Aaron, the High Priest? • Y-borne tradition Cohanim and their Genes • Goldstein & Bradman, UCL London • gathered DNA samples from priests - ‘the Cohanim’ • genetic markers indicate a common genetic origin • regardless of which post-Temple community group but approaches 100% in some communities • consistent with descent from one ancestral Y chromosome Levite Genes • Levites (c.f. Levy) = assistants to the priests • similarly passed father to son • more heterogeneous, more mixed • less strict religious gate-keeping • common Ashkenazi pattern • Mr.Levy@eastern Europe.shtetl.com is ancestor for >50% Ashkenazi Levites • Mitochondrial DNA suggests Levites stem from 4 unique women on the maternal side (?European, Summary • Jews are heterogeneous, but not random • more in common than people realise • documented history reflected in their genes • a large & complex extended family • no single ‘Jewish’ gene • Relevant to understanding and impacting genetic illness Mendelian Disorders in Ashkenazi Bloom Syndrome Canavan Disease Cystic Fibrosis Factor XI Deficiency Familial Dysautonomia (Riley-Day syndrome) Fanconi Anemia Gaucher Disease Mucolipidosis IV Niemann-Pick Disease Non-Classical Adrenal Hyperplasia Nonsyndromic Hearing Loss Tay-Sachs Disease Torsion Dystonia Cancer Predisposition Genes Breast Cancer (BRCA1 and BRCA2) Familial Colon Cancer Clinical Issues and Screening Estimated Risk in BRCA Mutation Carriers – by Age 70 Breast Cancer 36 – 85% Ovarian Cancer 10 – 44% Prostate Cancer 1/9 in general population 1/70 in general population 8 – 16% 3/100 in general population Males with BRCA Mutation • • • • • • Risk of breast cancer – 10% BRCA II – increases prostate cancer risk May increase risk of colon cancer Hereditary non-polyposis colon cancer gene is also higher in the Ashkenazi population Can pass BRCA without being affected –skip generations Some correlation of BRCA with Fanconi anemia Non-Jewish Populatons with BRCA Testing entire populations TSD carrier testing Carrier frequency in the Ashkenazi (Eastern European) Jewish population estimated to be 1 in 25. Various estimates of the carrier frequency in the general population - between 1 in 167 and 1 in 400. Biochemical carrier testing on leucocytes and serum to detect reduced Hex A activity. Normal range: 62-79%. Carrier range: 35-61% Occasionally results are inconclusive and retesting is required. Psychosocial implications No major adverse psychosocial effects have been found in the community but yes in some populations. Depends on how the screening is done. Carriers experience short term shock and anxiety after receiving result Most stressful for couples where already pregnant (a very common situation!) Carriers do not, on the whole, feel stigmatised, even if tested during adolescence. Carriers’ choice of marriage partner is rarely affected (except in the Strictly-Orthodox community). A big issue for shidduchim Dor Yesharim program Current issues Community education – no systematic basis for this. On-going problems with trying to ensure that people get the info they need at the right time for screening. Financial burden on families who have Tay Sachs testing through the Dor Yesharim system. Requires community acceptance and rabbinic approval Current issues cont… Other genetic diseases Gaucher’s disease (1 in 15) – treatment available • Familial Dysautonomia (1 in 30) • Canavans disease (1 in 40) • ‘Jewish’ CF mutations (1 in 30) Other “Jewish” Diseases: • Torsion Dystomia/ Tourette’s Syndrome • Mucolipidosis IV (1 in 50) • Fanconi Anaemia (1 in 80) • Niemann-Pick (1 in 80) • Blooms syndrome (1 in 100) • • • • Higher in Jews: Crohn’s disease Schizophrenia Down Syndrome – older mothers in the Orthodox community ?????????????????????????????? • Should everyone be tested? • Stigmatization • Impact on community image and marital • • • • practices Abortion Counseling Do we screen if we do not know how to treat Community Education Human Genome Project • Initiated 1990 • Completion originally planned for 2005 • Anticipate completion prior to deadline • Results – Complete sequencing of the Human Genome – New branch of science and medicine - What Is a Genome? • Genome: All of the DNA for an organism • Human Genome – Nucleus: 3.2 billion base pairs packaged into chromosomes – Mitochondrion: 16,600 base pairs packaged in one circular chromosome Promise of the Human Genome Project • Improved diagnosis and treatment through the application of genetic information and technologies – Predictive medicine – Individualized medical care – Population screening The Promise of Genomic Medicine • Predictive rather than reactive • Preventive rather than responding only after acute presentation • Screening of populations, subpopulations and individuals • Pharmacogenomics What’s So Different About Genetic Testing for Cancer? • Predictive – Uncertainty • Will the condition develop? • When? • How severe? • Will interventions make a difference? – untested • Direct implications for family members – “If you test positive for a gene then maybe that’s going to have a ripple effect throughout the whole genetic tree.” • Ethical, legal and social issues Public Interest in Genetic Testing • High, even among those at low risk • 2 surveys of women in general population – 82-90% interested in testing for genetic susceptibility to breast cancer Andrykowski 1997, Chaliki 1995 Motivation for Genetic Susceptibility Testing • Desire to reduce uncertainty about risk • To learn about risk for offspring • To learn about other associated risks • To explore further surveillance / treatment options • To make child-bearing and marital decisions • To participate in research Role of Discussion of Risks, Benefits and Limitations of Genetic Testing • Risks – Positive test result • Anxiety • Depression • Guilt • Family issues • Insurance/job discrimination • Confidentiality • Impact on shidduchim – Negative test result • Survivor guilt • Complacency – Uncertain test result Future Directions • Better Surveillance Options • Better Understanding of Transmission Patterns • Delineating how BRCA interacts with other tumor suppressive genes • Chemoprevention • Rational Design of Community Wide Screening Programs “Never make predictions …especially about the future.” Samuel Goldwyn Sr. Hollywood producer