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Human
Evolutionary Genetics
We are interested in examining levels and patterns of genetic
variation at the genome level among modern humans and non-human
primates in order to elucidate the evolutionary forces (mutation,
gene conversion/recombination,
migration, drift, selection) that shape and maintain genetic
variation in contemporary populations. These data are being used
to reconstruct
historical demographic and population differentiation events
(including population expansion and contraction, subdivision,
and migration)
and to test hypotheses of modern human origins, including
the possibility of introgression of archaic and modern human
genomes.
African Genetic Diversity Project
Despite the fact that Africa plays a central role in human
evolution, African populations have been greatly underrepresented
in the study of human genetic diversity. Our goal is to establish
a large
database of genetic diversity among geographically, linguistically,
and culturally diverse African populations. The study of African
genetic diversity will be important for reconstructing modern
human origins
as well as recent African and African American population histories.
The study of African genetic diversity will also be important
for the identification of the genetic basis of diseases prevalent
in African
and African American populations (e.g. hypertension, diabetes,
prostate cancer).
To achieve this goal, we and our collaborators
have made several field expeditions to Africa to collect DNA
samples from >7,000 individuals
from > 100 ethnic groups. For many of these samples, we have collected
phenotype data to be used for genotype/phenotype analyses.
We are continuing to collect DNA samples and phenotype information
from geographically
diverse regions of Africa. Great care is taken to conduct this
research in an ethical manner. An additional goal is to help
train African scientists
and to help build resources within Africa for doing human genetic
research.
We are analyzing mtDNA, Y chromosome, and autosomal
variation in these populations, including genome-wide analyses
of resequencing data and of microsatellite, in/del, SNP,
and CNV polymorphism data. From these studies, we will gain valuable
knowledge of
the genetic structure
of African populations and the identification of markers
that will be usefulness in gene mapping studies; we will learn
about
the correlation
of environmental, cultural, linguistic, and genetic variation;
we will be able to obtain highly accurate estimates of demographic
parameters and to test hypotheses of modern human origins
and more recent
population
migration and differentiation events.
Global patterns of
linkage disequilibrium (LD) in the human genome
There is an increasing interest in identifying genes involved
in complex disease (e.g. hypertension, diabetes, obesity,
schizophrenia, and some types of cancer). Gene mapping
approaches for complex
disease often rely on the detection of association between
marker and disease
alleles within populations. The design and effectiveness
of these studies will depend on underlying levels and patterns
of LD in the populations
of interest. Linkage disequilibrium will be influenced
both by locus-specific factors (e.g. mutation and recombination
rates, gene conversion, selection)
as well as by population and demographic history (e.g.
substructure,
admixture, genetic drift, population expansion, and founder
events). Patterns of LD are being examined among ethnically
diverse populations
in order to better understand how locus-specific effects
as well as population and demographic history shape the
distribution of LD in the
human genome and to identify populations that will be particularly
informative for genetic linkage and association studies.
The genetic basis of resistance to infectious disease
It is likely that infectious disease has played a major
role in human evolution and in shaping genetic variation
in the human genome. A current focus of my laboratory is
the study
of human genetic variation
and the evolutionary history of genes involved in resistance
against infectious disease. We are characterizing patterns
of genetic variation
in candidate genes for resistance/susceptibility to malaria
in a set of globally diverse populations, but with an
emphasis on African populations.
Our goal is to identify functionally significant genetic
variation that plays a role in susceptibility to infection.
In addition, we are collaborating
with laboratories that are studying genetic variation
in Plasmodium
falciparum in order to examine co-evolution of infectious
agents and their human hosts.
The genetic basis of adaptation
in humans
We currently know little about how changes at the genetic
level correlate with phenotypic changes and adaptation
to novel environments during recent human evolutionary
history. Additionally, it
has been hypothesized that genetic mutations associated
with common complex diseases
(e.g. hypertension, diabetes, obesity, asthma, arthritis,
allergies,
etc.) may be at high frequency in modern populations
because they were adaptive in ancient environments.
Thus, characterization of signatures
of natural selection in genes that are of adaptive
significance may be of use for identifying functionally significant
variants, some of
which may play a role in human disease. We are particularly
interested in identifying local adaptation in culturally
and geographically diverse
Africans, because of the possibility that selective
forces
may be geographically restricted.
We are using a number
of approaches to identify functionally significant variants
(both coding and regulatory) involved
in adaptation. The first approach is to resequence
candidate genes likely to play a
role in adaptation (for example, genes involved in
food and drug metabolism, sensory perception, and
infectious disease resistance) in a panel of
ethnically diverse humans and non-human primates.
We are also using whole-genome polymorphism data in these
populations
to identify candidate
regions of the genome that may be targets of natural
selection.
Once targets of selection are identified, resequencing,
genotype/phenotype association studies, and in vitro
gene expression assays
can be used
to identify functionally significant variants in
both coding and non-coding regions of the genome.
Genotype/Phenotype
Association Studies
For many of the individuals for which we have obtained
DNA, we also collected phenotype data for traits
likely to play a role in adaptation, some of which
demonstrate a complex pattern of inheritance
and are likely influenced by multiple loci and
environmental factors. In addition to case/control analyses
of
variation
at candidate genes,
we are using whole-genome association studies to
identify novel genes that are associated with these
traits. Together with collaborators, we are also developing
methods
for
mapping
complex traits (including
disease) in highly structured African populations.
Pharmacogenomics
There are currently few studies of variation at
drug metabolism genes across geographically and
ethically diverse African populations. Many of these genes
are likely to play an
important role in
metabolism of drugs that are used to treat infectious
diseases
in Africans (i.e.
HIV, malaria, and TB). Such knowledge is critical
for the development of more effective treatments
for these
devastating diseases that result in millions
of
deaths each
year.
Therefore,
we
are characterizing variation
in Africans at regulatory and coding regions
of genes that are likely to play an important role in metabolism
of drugs used to treat HIV,
malaria, and TB and are collaborating with clinicians
to
determine
the effect of these variants on drug metabolism.
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