Transcript grand_rounds

History,Ethnicity, Medicine and
Genes: Implication of genomics for
community screening and
prevention,
the case of Ashkenazi
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Jewish Populations.
Why is history important?
• Genomics is a science of populations and their
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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
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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,
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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
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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
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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
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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
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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)
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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
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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
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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
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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
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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
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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
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Gaucher’s disease (1 in 15) – treatment available
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Familial Dysautonomia (1 in 30)
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Canavans disease (1 in 40)
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‘Jewish’ CF mutations (1 in 30)
Other “Jewish” Diseases:
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Torsion Dystomia/ Tourette’s Syndrome
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Mucolipidosis IV (1 in 50)
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Fanconi Anaemia (1 in 80)
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Niemann-Pick (1 in 80)
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Blooms syndrome (1 in 100)
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Higher in Jews:
Crohn’s 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
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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