Georgia
M. Dunston,
Ph.D.
Director
|
The
molecular
genetics
research
interests
are in
human
population
genetics,
anthropological
genetics,
immunogenetics,
and the
genetics
of complex
diseases.
Ultimate
goals
surround
elucidating
questions
of human
variation,
the evolutionary
history
of genes
within
populations
and how
these
gene histories
are involved
in the
etiology
of complex
diseases.
While
the laboratory's
research
goals
have shared
consequences
for all
humanity,
specific
interests
focus
on populations
of African
ancestry.
Operational
Objectives:
1.
Develop
a SNP
database
for mapping
functional
mutations
linked
to diseases
common
in African
peoples.
2.
Utilization
of evolutionary
history
of candidate
genes
to identify
polymorphisms
that are
associated
with diseases.
3.
Exploit
the linkage
disquilibrium
generated
by admixture
in the
African
American
population
for gene
mapping. |
|
CURRENT
RESEARCH PROJECTS
The
biological transition
of enslaved
Africans-to-African
Americans is
marked by the
transition of
environmental
stresses from
Africa to those
in the Americas,
and to a lesser
extent, by The
incorporation
of non-African
genes into the
African American
gene pool. The
transition from
the various
African environments
of origin to
the diverse
American environments
is far from
insignificant.
The American
environment
imposed new
selective pressures
on the Africans.
These selective
pressures may
have favored
certain genes
while eliminating
others. This
evolutionary
hypothesis has
been a controversial
explanation
for the high
incidence of
diseases such
as hypertension
in African Americans.
Thus, African
American biology
has been significantly
shaped by periods
of intermixture
creating high
heterogeneity,
and selective
pressures emanating
from the unique
and particularly
adverse social,
economic, and
political conditions
in the US. All
of these factors
might contribute
to the high
incidence of
diseases with
a significant
genetic component
such as type
2 diabetes,
asthma, hereditary
cancer (prostate,
breast and lung),
and hypertension
in African Americans.
Prostate
cancer is
the most common
solid malignancy
among men in
the United States.
African American
men have the
highest incidence
of prostate
cancer compared
to other ethnic
groups. This
cohort also
appears to present
more commonly
at an advanced
stage with aggressive
histology and
increased cancer-related
mortality. Thus,
there is a critical
need to explore
the etiologic
pathways (genetic
and environmental
factors) that
contribute to
this disparity.
In on of our
projects "Genes,
environment
and prostate
cancer in populations
of African descent"
we seek to understand
the relative
contribution
of allelic variations
of candidate
genes and environmental
factors to determine
an individuals
risk of prostate
cancer. The
work is geared
towards the
African American
population,
for whom genomic
studies are
limited. African
Americans share
a common genetic
background with
West Africans
yet vastly different
environments.
Comparative
genetic and
epidemiological
research on
the two populations
reveal potential
risk factors.
This project
will provide
a better understanding
of gene-gene
(epistasis),
and gene-environment
effects on prostate
cancer. At research
sites in Washington,
DC, Chicago,
Illinois, and
Benin City,
Nigeria the
goals of the
project are
to (1) recruit
a well characterized
cohort of 1200
cases and controls
and collect
blood for biochemical
and molecular
assays, along
with diet and
other environmental
information;
(2) use state
of the art DHPLC
technology to
provide a formal
evaluation of
single nucleotide
polymorphism
(SNP) variation
in 22 candidate
genes for prostate
cancer (androgen
associated genes,
apoptosis related
genes, and diet
related genes);
(3) construct
a web-based
database of
the SNPs discovered;
(4) determine
if haplotypic
variation in
candidate genes
accounts for
phenotypic variation
in prostate
cancer, prostate
specific antigen
(PSA) levels,
and disease
progression;
and (5) assess
whether gene-gene
and gene-environment
interactions
exist by examining
if prostate
cancer risk
is modified
after stratification
of genetic and/or
environmental
factors. This
is the first
study which
examines SNP
markers within
the proposed
candidate genes,
diet, and other
environmental
variables in
clinically evaluated
African and
African Americans
and which evaluates
their relative
interactions
and contribution,
if any, to prostate
cancer.
In
another project,
"Haplotype
analyses of
X chromosome
variants: population
genetics and
implications
for prostate
cancer"
the goals are
to (1) provide
a formal evaluation
of X chromosome
variation and
linkage disequilibrium
in the African
American population,
(2) determine
the relationship
of microsatellite
alleles (CAG
and GGN repeats)
within the androgen
receptor with
the risk for
prostate cancer
and (3) exploit
the evolutionary
history of X
chromosome haplotypes
in order to
determine if
differences
in X chromosome
haplotypes account
for phenotypic
variation in
prostate cancer
and prostate
specific antigen
(PSA) levels.
While
the molecular
genetic research
has shared consequences
for all humanity,
our specific
interests focus
on populations
of African ancestry.
Other areas
of immediate
interest are
molecular evolutionary
genetics, and
biological anthropology.
In another project,
"the
genetics of
human pigmentation,"
we seek to understand
the relative
contribution
of allelic variations
of candidate
genes responsible
for variation
in human pigmentation.
Pigmentation
is a classic
anthropological
trait that has
been studied
objectively
using reflectance
spectroscopy
for over 50
years. Skin
pigmentation
is likely the
trait that shows
the largest
degree of variability
among human
populations.
That there are
such dramatic
differences
in the levels
of skin pigmentation
among human
populations
is almost definite
evidence for
the action of
natural selection.
The identification
of the genes
that determine
normal within-population
variation in
pigmentation
and differences
between populations
is the first
essential step
in the elucidation
of the molecular
history of human
pigmentation.
The goals of
this project
are to (1) develop
a database and
sample collection
that will allow
for the delineation
of the genes
that determine
pigmentation,
and (2) genotype
these individuals
for a number
of candidate
genes to identify
those which
determine natural
variation in
pigmentation.
Mutation
analyses of
BRCA1 and BRCA2.
We are analyzing
the breast cancer
predisposing
genes, BRCA1
and BRCA2, for
germline mutations
in African American
families at
high-risk for
hereditary breast
cancer. Patients
are considered
high-risk if
they have a
family history
of the disease,
early onset
breast cancer,
bilateral breast
cancer, breast
and ovarian
cancer, or a
male affected
with breast
cancer. The
entire BRCA1
and BRCA2 coding
and flanking
intron regions
are being examined
for mutation
detection. In
preliminary
studies of BRCA1
using the technique
of single strand
conformation
polymorphism,
we identified
11 different
germline mutations/
variations in
7 patients from
45 high-risk
families. Two
pathogenic,
protein-truncating
mutations were
detected in
exon 11. A ten
base pair tandem
duplication,
943ins10, was
present in a
woman with breast
and ovarian
cancer whose
first-degree
relatives had
prostate cancer.
A four base
pair deletion,
3450del4, was
detected in
a breast cancer
patient with
five cases of
breast cancer
in the family;
two of the proband's
sisters with
breast cancer
also carried
the same mutation.
Four amino acid
substitutions
(Lys1183Arg,
Leu1564Pro,
Gln1785His,
and Glu1794Asp)
and four nucleotide
substitutions
in intron 22
(IVS22+78 C/A,
IVS22+67 T/C,
IVS22+8 T/A
and IVS22+7
T/C) were observed
in patients
and not in control
subjects. One
early onset
breast cancer
patient carried
five distinct
BRCA1 variations,
two amino acid
substitutions
and three substitutions
in intron 22.
An amino acid
substitution
in exon 11,
Ser1140Gly,
was identified
in 3 different
unrelated patients
and in 6 of
92 control samples.
The latter probably
represents a
benign polymorphism.
BRCA1 and BRCA2
analyses for
the detection
of mutations
are ongoing.
Genetic
variation in
asthma.
Asthma families
collected by
HU investigators
were part of
the Collaborative
Study on the
Genetics of
Asthma (CSGA)
genome-wide
search for asthma
susceptibility
loci in ethnically
diverse populations.
Asthma is an
inflammatory
airways disease
associated with
intermittent
respiratory
symptoms, bronchial
hyper-responsiveness
(BHR) and reversible
airflow obstruction
and is phenotypically
heterogeneous.
Patterns of
clustering and
segregation
analyses in
asthma families
have suggested
a genetic component
to asthma. Previous
studies reported
linkage of BHR
and atopy to
chromosomes
5q, 6p, 11q,
14q, and 12q.
One genome-wide
search in atopic
sib pairs had
been reported,
however, only
12% of their
subjects had
asthma. The
CSGA conducted
a genome-wide
search in 140
families with
> or = 2
asthmatic sibs,
from three different
populations
and reported
evidence for
linkage to six
novel regions:
5p15 (P = 0.0008)
and 17p11.1-q11.2
(P = 0.0015)
in African Americans;
11p15 (P = 0.0089)
and 19q13 (P
= 0.0013) in
Caucasians;
2q33 (P = 0.0005)
and 21q21 (P
= 0.0040) in
Hispanics. Evidence
for linkage
was also detected
in five regions
previously reported
to be linked
to asthma-associated
phenotypes:
5q23-31 (P =
0.0187), 6p21.3-23
(P = 0.0129),
12q14-24.2 (P
= 0.0042), 13q21.3-qter
(P = 0.0014),
and 14q11.2-13
(P = 0.0062)
in Caucasians
and 12q14-24.2
(P = 0.0260)
in Hispanics.
Dermatophagoides
pteronyssinus
(Der p) is one
of the most
frequently implicated
allergens in
atopic diseases.
Although HLA
could play an
important role
in the development
of the IgE response
to the Der p
allergens, genetic
regulation by
non-HLA genes
influences certain
HLA-associated
IgE responses
to complex allergens.
To clarify genetic
control for
the expression
of Der p-specific
IgE responsiveness,
a genome-wide
search was conducted
for genes influencing
Der p-specific
IgE antibody
levels by using
45 Caucasian
and 53 African
American families
ascertained
as part of the
Collaborative
Study on the
Genetics of
Asthma (CSGA).
Specific IgE
antibody levels
to the Der p
crude allergen
and to the purified
allergens Der
p 1 and Der
p 2 were measured.
Multipoint,
nonparametric
linkage analysis
of 370 polymorphic
markers was
performed with
the GENEHUNTER
program. The
best evidence
of genes controlling
specific IgE
response to
Der p was obtained
in 2 novel regions:
chromosomes
2q21-q23 (P
= .0033 for
Caucasian subjects)
and 8p23-p21
(P = .0011 for
African American
subjects). Three
regions previously
proposed as
candidate regions
for atopy, total
IgE, or asthma
also showed
evidence for
linkage to Der
p- specific
IgE responsiveness:
6p21 (P = .0064)
and 13q32-q34
(P = 0.0064)
in Caucasian
subjects and
5q23-q33 (P
= 0.0071) in
African American
subjects. No
single locus
generated overwhelming
evidence for
linkage in terms
of established
criteria and
guidelines for
a genome-wide
screening, which
supports previous
assertions of
a heterogeneous
etiology for
Der p-specific
IgE responsiveness.
Two novel regions,
2q21-q23 and
8p23-p21, that
were identified
in this study
merit additional
study. In addition
genome-wide
screening was
conducted for
genes influencing
Dermatophagoides
pteronyssinus-specific
IgE responsiveness
as a part of
the Collaborative
Study on the
Genetics of
Asthma (CSGA).
Evidence for
linkage was
found in some
regions, including
chromosomes
5131-q33 and
11q13 in African
American families.
Plans are underway
to initiate
an international
study of the
genetics of
asthma in collaboration
with medical
scientists in
Ghana and investigators
at the NHGC.
These investigations
will target
regions where
associations
with specific
IgE responses
have been indicated
in African Americans.
top
of page
DEVELOPING
PROJECTS
Characterization
of African American
Ancestral HLA
Haplotypes in
West Africa.
An important
area of investigation
at the NHGC
is the inclusion
of evolutionary
history of genes
as a diagnostic
probe in tracing
the history
of disease in
a population.
This
project builds
upon the foundation
of research
on the genetics
of complex diseases
common in African
Americans already
established
with the NHGRI
in partnership
with the NIH
Office of Research
on Minority
Health. More
specifically,
it would build
upon African
American Diabetes
mellitus (AADM)
an international
human gnome
research initiative
to map genes
for type 2 diabetes
in ancestral
populations
of African Americans.
Because of the
overlap in clinical
phenotype of
some subsets
of types 1 and
2 diabetes,
the rationale
for this study
is that characterization
of HLA class
II haplotypes
in the west
African study
population may
assist in refining
the clinical
phenotype of
a subset of
type 2 diabetes
patients.
The
association
of HLA class
II genes with
susceptibility
|
