Genetic Diseases Neil Risch, Ph.D. University of California San Francisco 1 Jewish History and Genetics The 3,000+ year history of the Jewish people has been one of expansions and contractions, separations, migrations and coalescence; This unique history has left its mark through the genetic profiles of the various extant Jewish communities of today 2 Jewish Roots and Diaspora Jews are a Middle Eastern people; From the conquest of Joshua in 1,250 BCE and the kingdoms of David and Solomon in 1,000 BCE they grew from a collection of tribes into a single unified nation However, conflicts between the northern provinces (Israel) and southern provinces (Judah) led to a weakening of the state, and subsequently to the conquest and annexation of Israel (northern kingdom) by the Assyrians in 722 BCE 3 The screen versions of these slides have full details of copyright and acknowledgements 1
Babylonian Exile 136 years later, in 586 BCE, the southern kingdom fell to the Babylonians, and the temple in Jerusalem was destroyed; Many Jews were exiled to the Babylonian kingdom (present day Iraq); This was the beginnings of the Jewish diaspora 4 Under the Persians Under the Persians, 200 years later, the Jews were allowed to return to Jerusalem and rebuild the (second) temple; During this period, the Jews in Palestine increased in number and land area nearly to the size under King Solomon; This lasted until the Roman conquests and the destruction of the second temple in 70 CE, and a second phase of Jewish exile and diaspora 5 After the Roman Expulsion For the next 1500 years, Jews migrated and dispersed around the Middle East, West and South Asia, North Africa and Europe; Under varying conditions of acceptance or hostility, they prospered, were forced to assimilate, were killed or were exiled 6 The screen versions of these slides have full details of copyright and acknowledgements 2
Modern Times During the last 500 years, migrations expanded to the New World, South Africa, and Australia During the past 100 years, Jews from around the world have re-congregated in Israel; Currently, North America and Israel have the largest Jewish populations (5.7 million and 5.2 million, respectively) 7 Classification of Jews For the study of genetics, Jews can be categorized into several groups based on geography, history and culture; These groups are not entirely non-overlapping, however, due to historical migrations even during times of separation 8 Jewish Subgroups Ashkenazi Central/Eastern European; Origins in Central Europe (France, Germany) in 10 th century (?) Oriental Middle East, North Africa, India (ancient times) Sephardic Origins in Spain and Portugal (probably from first century or earlier); migrated to Eastern Mediterranean (Turkey) and parts of Europe (Holland, France, Italy), North Africa and America after Spanish and Portuguese Inquisitions (1492 and 1497) 9 The screen versions of these slides have full details of copyright and acknowledgements 3
Genetic Diseases Most genetic diseases found at increased frequency in Jewish populations are recessive, although some are dominant Recessive inheritance means a disease (mutant) allele must be inherited from both parents for disease to be expressed Dominant inheritance means only one mutant copy needs to be inherited (from either parent) 10 Population Distributions The pattern of genetic diseases found in different Jewish populations reflects both their common ancestry and independent developments Some mutations are found in several Jewish groups: The breast cancer mutation BRCA1 185delAG (Ashkenazi Jews, Iraqi Jews, Iranian Jews, Moroccan Jews, Spanish Jews); the colon cancer mutation I1307K (Ashkenazi Jews, Iraqi Jews); Factor XI mutation II (Ashkenazi Jews, Iraqi Jews) 11 Population Specificity Some mutations are population specific (numerous cases in the Ashkenazim) Some mutations that are Jewish population specific have also been found in isolated cases in other groups, probably due to migrants (example of Ashkenazi Bloom syndrome mutation found in American Hispanics) 12 The screen versions of these slides have full details of copyright and acknowledgements 4
Diseases Found in Ashkenazim The Ashkenazi Jewish (AJ) population is known to have a number of genetic diseases at increased frequency Prominent among these are four lysosomal storage diseases (LSDs): Tay-Sachs Disease (TSD), Gaucher Disease (GD), Niemann-Pick Disease (NPD) and Mucolipidosis Type IV (MLIV) 13 Lysosomal Storage Diseases - 1 Recessive inheritance Genetic defects resulting in enzyme deficiency Absence of enzyme prevents the lysosome in the cells of the body from performing its natural recycling function, so various materials are inappropriately stored in the cell 14 Lysosomal Storage Diseases - 2 This leads to a variety of progressive physical and/or mental deterioration over time Some patients survive into adulthood, but others have more severe symptoms and die in their teens or earlier Currently 46 different LSDs, four of which occur within Ashkenazi Jews 15 The screen versions of these slides have full details of copyright and acknowledgements 5
Diseases in Ashkenazim Historically there has been extensive debate over the reason for the increased frequency of four LSDs in the AJ population, between genetic drift (founder effects) versus natural selection (heterozygote advantage) 16 Genetic Drift Change in allele frequencies by random chance alone, due to small population size Can occur during the founding of a population (founder effect) or the dramatic reduction in population size before recovery (bottleneck effect) 17 Heterozygote Advantage (Selection) For a recessive disease, even though it may be serious and even fatal, those who carry a single copy of the mutant allele (heterozygote) may have a survival advantage over those who have a normal genotype If so, the mutant frequency will increase because of the heterozygote advantage, even at the expense of losing the affected homozygotes 18 The screen versions of these slides have full details of copyright and acknowledgements 6
Hemoglobinopathies Classic example is given by the hemoglobinopathies Thalassemia and sickle cell disease These recessive diseases are found at increased frequency in regions of endemic malaria 19 Malaria Thalassemia has high frequency around the Mediterranean; Sickle cell in sub-saharan Africa and parts of the Middle East and India Carriers have milder (and less fatal) malaria infections than non-carriers, especially in childhood 20 Arguments for Selection 1. Frequencies too high for drift alone Statistical analysis shows low probability of such high gene frequencies 2. Four different LSD s unlikely by chance alone 3. Multiple mutations at elevated frequency at same locus 21 The screen versions of these slides have full details of copyright and acknowledgements 7
Small founder population Arguments for Drift Observed diseases are not random but extreme outliers Several historical bottlenecks No selective agent demonstrated No comparable selection operating on neighboring non-jews 22 Other Diseases Affect Ashkenazim The AJ population is also affected by a dozen or more genetic diseases at increased frequency that do not involve lysosomes; These diseases, which are clinically diverse, presumably have been influenced by founder effects and genetic drift 23 Other Diseases in Ashkenazim Bloom Syndrome (BLM), Breast Cancer (BRCA1, BRCA2), Colon Cancer (APC), Canavan Disease (CAN), Deafness (CX26), Cystinuria (CYS), Dysautonomia (DYS), Factor XI deficiency (FXI), Familial Hyperinsulinism (FI), Familial Hypercholesterolemia (FH), Fanconi Anemia Type C (FACC), Glycogenesis type 7 (GLY7), Torsion Dystonia (DYT1) 24 The screen versions of these slides have full details of copyright and acknowledgements 8
Comparing Diseases by Group To address the question of natural selection (heterozygote advantage) for the LSDs, it is relevant to compare the LSDs versus the non-lsds in a variety of ways: 25 LSDs Versus Non-LSDs 1. The number of different mutations found in each gene underlying the disease 2. The frequency distribution of the mutations for LSDs versus non-lsds 3. The ages (coalescence dates) for LSD versus non-lsd mutations, estimated by haplotype analysis 4. The European ancestral geographic distribution of LSD versus non-lsd mutations 26 Expected Patterns Differences between the LSDs and non-lsds for any of the above characteristics would be suggestive of specific selection effects operating on LSDs; on the other hand, similar patterns would argue in favor of founder effect and genetic drift as the primary explanation 27 The screen versions of these slides have full details of copyright and acknowledgements 9
Geographic Disparities Furthermore, disparities in age and/or geographic localization for different mutations within the LSD group would also argue against selection, since the selection would be most likely to occur specifically in time and place 28 Ordered Frequencies for LSD Mutations Disease Mutation Frequency GD 1226.032 TSD 1277.013 NPD 1302.005 MLIV IVS3.004 TSD 1421.003 GD 84GG.002 29 Ordered Frequencies for Non-LSD Mutations Disease Mutation Frequency Disease Mutation Frequency APC I1307K.035 BRCA1 185delAG.006 FXI III.025 BRCA2 6174delT.006 FXI II.022 FI 3992.006 CX26 167delT.020 BLM 2281.005 DYS IVS20.016 CF F508.005 CAN 854.012 CX26 35delG.004 CYS 808C->T.008 FH G197del.003 CF 1282.008 CAN 693.002 FACC IVS4.006 GLY7 Del5.002 30 The screen versions of these slides have full details of copyright and acknowledgements 10
Mutation Frequencies Thus, there is no difference in the frequency distribution for mutations that cause the LSDs and the other non-lsds 31 Dating Mutations It is possible to determine approximately the date of origin of mutations in a population This is done by looking at (neutral) genetic markers near the disease mutation In each generation, there is a certain (low) probability, through the process of genetic recombination, for the nearby markers to recombine with the disease mutation 32 Number of Generations Thus, by examining a group of disease mutation bearing chromosomes for nearby markers with known recombination distance, and seeing how many still have the original marker allele it is possible to calculate approximately the number of generations that have passed 33 The screen versions of these slides have full details of copyright and acknowledgements 11
Dating of Various Mutations Lysosomal storage diseases Other diseases Disease Mutation Gens. Disease Mutation Gens. GD 1226 48 FXI III 31 MLIV IVS3 57 FXI II 120 GD 84GG 55 DYS IVS20 52 BLM 2281 50 BRCA1 185delAG 46 BRCA2 6174delT 29 FH G197del 12 PTD delgag 12 34 Times of Origin Among the mutations found in Ashkenazim two are known to occur at very high frequency in Jews from Lithuania the torsion dystonia mutation delgag and the familial hypercholesterolemia mutation G197; Both mutations date back about 12 generations, or about 300 years ago, and represent founder events in the Lithuanian Jewish population 35 LSD and Non-LSD Are Similar Overall, there is no difference in times of origin of the LSD and non-lsd mutations Most other mutations date to 45-55 generations ago, corresponding approximately to the time of founding of the Ashkenazi population in Europe 1100 years ago 36 The screen versions of these slides have full details of copyright and acknowledgements 12
Geographic Distributions Dor Yeshorim Screening Program, Brooklyn, New York Service to the Orthodox Jewish community around the world Genetic testing of high-school senior girls and boys, prior to marriage Mutation analysis for 7 recessive genetic diseases 37 Diseases Tested Lysosomal storage diseases Tay-Sachs Gaucher Niemann-Pick Non-lysosomal storage diseases Canavan Bloom syndrome Fanconi anemia C Cystic fibrosis 38 Data Analyzed For each testee, geographic origin of four grandparents was obtained, if known Allele frequencies were estimated for geographic areas; The following regions were defined: 39 The screen versions of these slides have full details of copyright and acknowledgements 13
Geographic Categories: Central Europe (Austria, Hungary, Czechoslovakia, Romania) Eastern Europe (Poland, Russia, Lithuania) Mediterranean (North Africa, Greece, Italy, Turkey) Mideast and Southern former USSR 40 Mutation Frequencies for LSDs Mutation Region Gaucher disease NPD Tay-Sachs disease 1226 1604 84GG 1302 1277 1421 G269 C. Europe.0382.0023.0050.0036.0218 0.0003 E. Europe.0303.0032.0006.0010.0175.0041.0010 Mediterr..0028.0006 0 0 0 0 0 Mid East 0 0 0 0 0.0005 0 41 Mutation Frequencies for Non-LSDs Mutation Region BLM Canavan Cystic Fibrosis FACC 2281 693 854 1282 F508 542 IVS4 C. Europe.0030.0023.0110.0117.0085.0007.0085 E. Europe.0181.0008.0107.0096.0056.0010.0056 Mediterr. 0 0 0 0.0085.0011 0 Mid East 0 0 0 0 0.0005 0 42 The screen versions of these slides have full details of copyright and acknowledgements 14
Frequency of TSD 1421 Region Frequency Lithuania.0113 Russia.0067 Poland.0022 43 Conclusions - 1 None of the observed distributions differed between LSDs and non-lsds: number of mutations, frequency distribution of mutations, coalescence dates of mutations, or geographic ancestry of mutations; Some mutations have higher frequency in Central Europe, and others in Eastern Europe; The patterns are not different for LSD versus non-lsd mutations 44 Conclusions - 2 There is a higher frequency of TSD 1277 (and the two GD mutations 1226, 84GG) in Ashkenazi Jews from Central Europe than in those from Eastern Europe 45 The screen versions of these slides have full details of copyright and acknowledgements 15
Conclusions - 3 However, the second most frequent TSD mutation, 1421, is significantly more frequent in Jews from Eastern Europe than those from Central Europe; In fact, the estimated frequency for this mutation in Central Europe is 0; The highest frequency was observed in Jews from Lithuania (1.1%) Russia (0.7%) and Poland (0.2%) 46 Conclusions - 4 This distribution is similar to that observed for primary torsion dystonia and LDL receptor deficiency, both of which have a recent Lithuanian origin; Thus, this TSD mutation is also likely to have a recent Lithuanian origin 47 Conclusions - 5 The (likely) recent Lithuanian distribution of TSD 1421 in contrast to the more central (and likely older) distribution of TSD 1277, and the similarity of mutation distributions overall for LSDs and non-lsds, cast doubt on the theory of heterozygote advantage for the LSD mutations and favors simple founder effect (genetic drift) as the primary explanation for these mutations 48 The screen versions of these slides have full details of copyright and acknowledgements 16
Conclusions - 6 The AJ LSD mutations, with the exception of the GD N370S, are specific to the Ashkenazim; No other neighboring populations of Europe have similarly increased frequencies of LSD mutations; This pattern contrasts significantly from the hemoglobinopathies and G6PD deficiency which affect multiple neighboring populations 49 Bottlenecks Three bottlenecks in Jewish history appear to be important regarding disease alleles in the Ashkenazim 50 Three Bottlenecks The founding of Jews >2500 ybp (e.g., Factor XI II mutation, also found in Iraqi Jews at a similar frequency) The founding of the Ashkenazim ~ 1100 ybp (e.g., GD 84GG, MLIV IVS3 and DYS IVS20) The founding of Lithuanian Jews ~ 500 ybp (e.g., PTD delgag, FH G197del and TSD 1421) 51 The screen versions of these slides have full details of copyright and acknowledgements 17
Selection Versus Drift For the study of natural selection in any population, especially in a founder population, one needs to first consider the potential impact of genetic drift; It is only within that context that arguments about specific selective agents and specific genes can be offered 52 53 The screen versions of these slides have full details of copyright and acknowledgements 18