History,Ethnicity, Medicine and Genes: Implication of genomics for community screening and prevention, the case of Ashkenazi Jewish Populations.

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History,Ethnicity, Medicine and Genes
Implication of genomics for community screening
and prevention, the case of Ashkenazi Jewish
Populations.

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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

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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

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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.

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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

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                Y Chromosome Bears Witness to
Story of the Jewish Diaspora By NICHOLAS WADEMay
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.

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NEJM, Volume 354424-425 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 

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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
  (ICD-9CM). 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

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Genes, Self and Group Identity
We all have multiple identity
We maintain Complex relationships
A species is divided into races when it can be
regarded as an essentially discontinuous set of
individuals. Jonathan Marks
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"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. Nat'l Academy
of Science, May 9, 2000)
Some cases are easy
DNA Testing to Determine Native American
Identity DNA Analysis and the Cultural
Affiliation of the Kennewick Man
Black Southern African Bantu-speaking population
who assert Jewish ancestry
Who gets to decide who is a member of the group?
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Genes and History

• Genetic Diseases

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Brief review of History

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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

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Simple genetic markers of populations

• The Blood Group story
• more complex genetic markers - DNA
• Jewish genetic diseases
• Mitochondrial DNA

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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

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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.

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What happened in eastern Europe?
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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

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What selection pressures may have acted?

• genetic drift
• founder effect
• selective advantage

random effect
c.f. the Pilgrim fathers
c.f. sickle cell anaemia
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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

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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

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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
  benefit

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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)

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Balance of Evidence
Selective Advantage
Founder Effect Random Genetic Drift
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The origin of Ashkenazis.
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Where do Jews fit?

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Genetic evolutionary tree
Russians
Armenians
Turks
Poles
Iraqi Jews
Byelorussians
Portuguese
North African Jews
Spaniards
Muslim Kurds
Kurdish Jews
North Africans
Ashkenazi Jews
Jordanians
Lebanese
Palestinians
Syrians
Bedouin
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Genetic Analysis of Populations

• DNA markers
• Cohen and Levi genes
• History, Ethnicity and Health

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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

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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

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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_at_eastern Europe.shtetl.com
• is ancestor for gt50 Ashkenazi Levites
• Mitochondrial DNA suggests Levites stem from 4
  unique women on the maternal side (?European,
  ?Middle Eastern)

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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

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Clinical Issues and Screening
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Estimated Risk in BRCA Mutation Carriers by Age
70
Breast Cancer 36 85 1/9 in general population
Ovarian Cancer 10 44 1/70 in general population
Prostate Cancer 8 16 3/100 in general population
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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

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Non-Jewish Populatons with BRCA
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Testing entire populations
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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.

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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

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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

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Current issues cont
Other genetic diseases

• Gauchers 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/ Tourettes Syndrome
• Mucolipidosis IV (1 in 50)
• Fanconi Anaemia (1 in 80)
• Niemann-Pick (1 in 80)
• Blooms syndrome (1 in 100)
• Higher in Jews
• Crohns disease
• Schizophrenia
• Down Syndrome older mothers in the Orthodox
  community

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• 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

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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 - Genomics

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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

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Promise of theHuman Genome Project

• Improved diagnosis and treatment through the
  application of genetic information and
  technologies
• Predictive medicine
• Individualized medical care
• Population screening

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The Promise of Genomic Medicine

• Predictive rather than reactive
• Preventive rather than responding only after
  acute presentation
• Screening of populations, sub-populations and
  individuals
• Pharmacogenomics

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Whats 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
  thats going to have a ripple effect throughout
  the whole genetic tree.
• Ethical, legal and social issues

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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

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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

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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

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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

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Never make predictionsespecially about the
future.

• Samuel Goldwyn Sr. Hollywood producer