Download Scylla and Charybdis - Minority Health Project

Comparison of Human to Drosophila data

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Nei’s genetic distance
v. geographical
distance for D.
melanogaster (dark
circles) and D.
pseudoobscura (light
circles.)
Localized adaptation
and genetic drift
combine to make poor
fit to isolation by
distance model.
Figure 11, Hartl and Clark 1989
How much genetic variation exists within
humans?
Protein electrophoresis
by Lewontin and
Hubby 1967, show
85% of human genetic
variation occurs at the
individual level.
Nei and Roychoudhury
1982, show that protein
variation is greater
Fig. 1, Owens and King, Science
within the so-called
1999 286: 451-453.
“races” than between
Brown 1980 examined
them, 93 - 97% within mitochondrial DNA
and 7 - 3% between..
variation, with same result.
Data from Single nucleotide polymorphisms are
consistent with earlier analyses.
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SNP’s show 85% variation
at the level of the
individual, 10% between
populations on the same
continent, and 5% within
local groups.
Small samples in this
study suggested that
African Americans had
more rare SNP’s. This is
due to anatomically
modern humans orginating
in Africa.
SNP haplotypes
are also
consistent with earlier analyses,
suggest recent, rapid expansion of
anatomically modern humans from
Africa. Fig 1, B. Stephens et al. 2001.
All phenotypic characters together show
the fallacy of racial categories.

The physical features
used to define
America’s social races
are discordant with
our evolutionary
history, Cavalli-Sforza
and Edwards 1964,
and Montagu 1974.
Fig 2.2.3 , Cavalli-Sfroza, Menozzi,
and Piazza., 1994
Criteria for race 4

The failure of phenotypic variation to define
races occurs because that variation is
discordant.
 Discordant variation results from the fact
that different portion of the genome are
responding to non-correlated selection
clines.
Selection and Drift may determine
disease frequency

Monomorphic loci -have one allele at a
frequency > 99%
 This true because
variants at these loci
are highly detrimental
to individual fitness.
 Hemophilia-A
mutation,
q = 2.0 x 10-4

The hemophilia-A is a
large gene containing 26
exons, 186 kbs.
 The mutations at this
locus include both large
and small deletions or
insertions.
 There are 78 large
deletions and 223 point
mutations are known.
Selection and drift 3

Thus, it is likely that
unrelated families
probably carry different
hemophilia-A mutants.
 Their frequencies are
determined by
mutation/selection
balance.
 This means that genetic
drift is most likely to
determine a population’s
frequency.
Figure 1. Apportionment of Human
Genetic Diversity
4
10
86
Alleles found in all world
populations, 86%
Alleles unique to a given continent,
10%
Alleles unique to a specific local
population, 4%
Selection and Drift 4

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Polymorphic loci have
numerous alleles, with
no single allele at a
frequency > 99%.
Phenylketonuria,
q = 0.01
Tay Sachs A, q = 0.017
Cystic Fibrosis,
q =0.022
Distribution of CF D F-508 allele,
Sickle Cell Anemia,
Fig. 2.14.10, Cavalli-Sforza, Menozzi,
q = 0.050
and Piazza, 1994.
Polymorphisms in cytochrome enzymes
Enzyme
Variants
Consequences Euro's Asians W. Africans E. Africans
CYP2A6
CYP2A6*2
CYP2A6*4
Inactive Enzyme 1-3%
No enzyme
1%
0 nd
15 nd
nd
nd
CYP2C9
CYP2C9*2
CYP2C9*3
increased affinity 8-13%
0 nd
altered affinity
6-9% 2-3%
nd
nd
nd
CYP2C19
CYP2C19*2 inactive enzyme
CYP2C19*3 inactive enzyme
13% 23-32%
13% 14-15%
Genetic susceptibility to environmental carcinogens looked at
data from 12, 525 Europeans, 2,136 Asians, 936 African Americans,
& only 60 Africans, as of December 2001.
The small number of Africans means that detecting alleles in this population is
difficult.
Pharmocogenomics analysis should not utilize
“race”, in place of genetic variation.

Percentages of CYP2C19 poor
metabolizer genotypes by
population:
 Euro-American 2%
 Zimbabwe 4%
 Korea 12%
 Japan 19%
 Philippines 23%
 Polynesia (outliers) 51%
 Southern Vanuatu 74%
Kaneko et al (1999)
Pharmocogenetics 9: 581.
Fig. 5, Evans and Johnson
2001.
Distribution of Sickle Cell Anemia Allele is
discordant with “race.”
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The origin of the allele is
uncertain.
However it is distributed
at high frequency in
“Negroids and
Caucasoids.”
High altitude Kenyans
don’t have any sickle cell.
Seen as “Black” disease in
U.S. due to importation of
slaves derived from W.
Africa were malaria was
prevalent.
Fig. 5.8, Ridley 1996
Genetic variation & hypertension
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A number of gene loci
have been associated with
increased risk of
hypertension.
AGT -- which codes for
angiotensinogen a protein
made by the liver and
circulates in excess
ACE – angiotensin
converting enzyme
Fig. 8, Richard Cooper, et al. 1997
Genetic variation & hypertension II
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At the angiotensinogen locus the
235T mutant has tyrosine switched
for methionine.
In Euro-Americans, 235T is
associated with an increased risk of
hypertension.
The 235T allele is found at a
frequency of 85% in African
Americans.
However, 235T is not associated Cooper, Rotimi, Ward 1999, pg. 42.
with increased hypertension risk in
Nigerians (.)
Genetic variation & hypertension III
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At the ACE locus there is a common alu insertion
polymorphism that affects the activity of this enzyme.
The D allele is characterized by an absence of these
alu insertions, and thus have higher enzymatic
activity.
The available evidence shows that the enzymatic
activity of II, ID, and DD genotypes are similar in
Nigerians, Jamaicans, and in the United States (all
populations.)
Hence the deletion genotypic doesn’t seem to be
influenced by “racial” background.
Source: R.S. Cooper (1997).
Hypertension?

Actually, when hypertension rates are
stratified by socioeconomic status, the
differential is located amongst African
Americans in the higher categories.
 This is means that the hypertension
difference results from a biological response
to social/cultural factors (e.g. control
racism, reduce hypertension differential.)
 Neser et al. 1986; Broman 1989; Calhoun
1992; Light 1995.
Individuals may carry genes of diverse
geographic origins

Microsoft Encarta, 1999
We can now prove by
genetic markers that a
Jefferson male fathered at
least Eston Hemings (7/8
Eu.)
 However, Eston Hemings
was a slave, identified as
“Negro”, by Virginia law.
 Beverly Hemings was
freed by Jefferson, moved
to Philadelphia, and
redefined herself, as
“white.”
Jefferson & Hemings

Thus any disease predisposition or resistance gene
in the Hemings…
 had a 7/8 probability of originating in the
European population.
 Hence, a 7/8 probability that the disease
predisposition would have been misidentified.
Jefferson & Hemings

There is a wide variety of admixture percentages
in North Americans with African descent.
 Recent measures suggest that the average African
Americans has on average 17 - 20% European
admixture.
 Also there could be as much as 10% American
Indian admixture.
 Therefore, could be as much as a 30% probability
of African American “disease” predisposition
originating in Asians and Europeans.
Genetic Distance and Disease Differential

The genetic distances
cannot by themselves,
explain the differential in
disease incidence:
 Winkelby 1998, JAMA
suggests genetic causes to
the 37% greater ageadjusted CVD rates.
 However, African
Americans and EuroAmericans are only about
5% different in allele
frequencies.
Cancer Incidence for American Ethnic
Groups, 1996
Ethnic Group
Incidence
Blacks
443
Whites
417.5
Chinese
247.5
Am. Indians
188
Hispanics
281
Source: Miller et al. 1996
Mortality differentials can not be explained
by genetic distance.

Neither single loci or
quantitative traits are
good candidates to
explain the
differential.
Overall

Genetic explanations require
the ability to control
environments
 Permissive mutations
 Environmental effects
phenotypic variance:
Vp = Vg + Ve + Vgxe + Cov (G,E) + Verror
Gene x environment interaction works against
simple racial explanations of disease
prevalence

Common gene, common disease hypothesis.
 Individuals from any socially defined “race” may
have a disease predisposing allele.
 This assumes that the environmental influences on
the gene’s expression are the same in each group.
 However can we assume that safely in the US?
No such equality of environments exists
for minorities in America

The physical environments experienced by
minorities are not equivalent to those of the
majority.
 Greater than 53% of the toxic waste sites located
within one mile of public housing have > 75%
minority occupancy.
Should population categories other than
race/ethnicity be used?

I would argue that we probably have never seen
genetically based, ‘racial’ differences in most disease
categories.
 What we have observed are underlying differences in
the environments of the socially constructed groups that
influence genetic predispositions for disease.
 For example, poor communities often have elementary
schools located by hazardous waste dumps.
 If one “race” has been historically poorer than another,
then they would have seen greater exposure.
Socially constructed races face different
exposure to carcinogens

In a 2000 study of breast cancer risk in women
from NYC:
 DDE levels were highest in African American and
Hispanics.
 DDT highest amongst Hispanics.
 HPCB’s highest in African Americans.
 Trans-nonachlor highest in African Americans,
Wolff, et al. 2000, Environ. Res. 84(2).
The impact of environmental differences
is complex
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Studies of malnutrition in rats
showed that maternal effects on 
adult health extended over
several generations.
We have already seen that
differential stress exposure
plays a role in predisposing
some African Americans to
hypertension.
Offspring of alcoholic mothers
show FA in their teeth, FA has
been linked to lower IQ in
college students.
Numerous studies show
that lasting adult pathology
can result from stress in the
maternal environment:
Desai et al. 1995, Hales et
al. 1996, Napoli et al. 1997,
Waterland and Garza, 1999.
Conclusion: The most insidious impacts of
racism.

African American populations have
maintained historical differences in health
and mortality.
 Biomedical research has focused on innate
or genetic explanations.
 This has been accomplished without
adherence to proper genetic theory or
experimental design.
Conclusion: The most insidious impacts of
racism 2.

By exposing the genetic fallacies operating in the
biological race paradigm the disease mortality
differential becomes problematic.
 Well intentioned researchers who insist that
“special populations” need be included in
biomedical research designs need to be wary of
the “race” industry.
Conclusion: The most insidious impacts of
racism 3.

The remedies we design from the socially
constructed theory of race are radically different,
then from the biological theory.
 The latter, blames the victim for their illness: you
are sick because you have bad genes.
 The former asks why some individuals are more
likely to be exposed to poor diet, stress, &
pollution. How does the legacy of racism
contribute to differential exposure to sources of
disease?