Human Genomic Diversity and Disease Research Unit
Current projects
Genetic
variation in sub-Saharan African and Malagasy populations
Our lab
uses several types of genetic markers (mitochondrial DNA, Y chromosome DNA
and autosomal DNA) to examine the genetic structure of sub-Saharan African
and Malagasy populations.
When this research is
used in conjunction with the findings of archaeologists, linguists, anthropologists
and historians, it will contribute to the "writing" of the history
of the peoples of Africa and Madagascar.
Population susceptibility
to disease
Disease occurs in human populations for a variety of reasons, some biological,
some cultural and some due to the interaction of genes with the environment.
Why do some diseases occur
in preference to others and in only some parts of the world? Several factors
need to be taken into account when addressing these issues:
- the kinds of mutations
that lead to the disease;
- the mode of inheritance;
- the rate of mutation;
- the strength of selection
against the disease; and
- the structure of the
population - i.e. is it a large, random-mating population or an isolate?
The growing understanding
of human genetic diversity emphasises the point that, if we are truly to understand
the causes of complex disorders such as hypertension, obesity, diabetics,
auto-immune disorders and alcoholism, we must study all humankind.
We need to understand
the evolutionary histories of allelic variants for normal genetic markers
at candidate loci: if a locus really has genetic variation influencing susceptibility
to a complex trait, that variation also has an evolutionary history and it
will be tied to the history of the adjacent normal DNA sequence variation.
Our understanding of human
population histories also relates to how readily a finding in one ethnic group
or geographical region will generalise to other populations. Only some generalisations
are possible and the causes common to a disorder in one group may not be identical
to those for the same apparent disorder in another group.
In order to comprehend
genetic susceptibility to disease, one therefore needs to understand the history
of affected populations.
Our research on reconstructing
the prehistory of sub-Saharan African populations using "neutral"
gene markers (mtDNA and Y chromosome DNA) has helped us uncover some of the
factors (eg. founder effect, migration, genetic drift) that have shaped the
genetic structure of these populations.
By understanding these
processes at non-disease causing loci, we have gained insight into the mechanisms
influencing genetic variation in Africa.
We are now using this
information to highlight how knowledge of population history could be used
to understand genetic susceptibility to disease.
Mitochondrial DNA
and disease
While the preceding sections have emphasised the importance of mtDNA in population
and evolutionary studies, mitochondria also play a pivotal role in cellular
metabolism and generate energy for cell functions in the form of ATP.
Of the numerous biochemical
reactions that occur within the mitochondria, the oxidative phosphorylation
system (OXPHOS) is the most important in terms of ATP generation and in the
association with disease. Mitochondrial dysfunction has been recognised in
several neurodegenerative diseases, for example:
- Parkinson disease
(PD) - a deficiency of complex I in the substantia nigra of patients with
PD has been described.
- Huntington disease
(HD) - severe deficiencies of complex II and II activity have been described
in the caudate nucleus of HD patients.
- Freidrich Ataxia (FA)
- the defective protein Frataxin, that is associated with FA, is a mitochondrial
protein.
- Alzheimer disease
(AD) - platelet COX deficiency has been described in some cases of AD.
The methodology and tools
for studying mitochondrial genes in neurological disease are readily available
within our group. In collaboration with Prof. G. Modi (Neurology Unit at the
Chris Hani Baragwanath Hospital), we are examining the role of mtDNA in neurodegenerative
diseases. Also, in collaboration with Dr N. Chetty (Molecular Medicine and
Haematology, National Health Laboratory Services (NHLS)/Wits), we are examining
the role of mtDNA in type 2 diabetes.
A host of other diseases,
as well as the aging process, have been attributed to mitochondrial dysfunction.
A systematic study of mitochondrial function at the gene level is therefore
necessary, not only for research, but also diagnostic purposes. |
