Variability in the Androgen Receptor Gene:
Strong Association With Androgenetic
Alopecia, Functional Implications and
Indication For Positive Selection
Hillmer, Axel M.;1 Becker, Tim;2 Myles, Sean;3 Freudenberg,
Jan;4 Brockschmidt, Felix F.;1 Stoneking, Mark;3 Kruse, Roland;5
Nöthen, Markus M.;1
- Dept. of Genomics, Life and Brain Center, University of Bonn,
Bonn, Germany; 2. Inst. for Medical Biometry, Informatics
and Epidemiology, University of Bonn, Bonn, Germany; 3.
Max Planck Institute for Evolutionary Anthropology, Leipzig,
Germany; 4. Dept. of Neurology, Laboratories of Neurogenetics,
UCSC, San Francisco, CA, USA; 5. Dept. of Dermatology,
University of Düsseldorf, Düsseldorf, Germany
Androgenetic alopecia (AGA, male pattern baldness) is
the most common form of hair loss. Its pathogenesis is
androgen dependent, and genetic predisposition is the
major requirement for the phenotype. We have recently
demonstrated that genetic variability in the androgen
receptor gene (AR) is the cardinal prerequisite for the
development of early-onset AGA, with an etiological
fraction estimated at 0.46. The investigation of a large
number of genetic variants covering the AR locus suggests
that a polyglycine encoding GGN repeat in exon one is
a plausible candidate for conferring the functional effect.
The polyglycine tract is located in the transactivating domain
of the androgen receptor protein (AR), suggesting an effect
of repeat length on receptor function. We compared the
functional characteristics of the two most common alleles
(23 and 24 repeats) and two extreme alleles (10 and 27
repeats) in a reporter gene assay in HeLa cells. Our data
provide evidence of functional differences between the
two most common alleles of the AR GGN repeat. The
AR haplotype with the highest frequency (0.45) in the
German population, which confers risk to AGA, seems to
be evolutionarily recent, as indicated by the low sequence
identity with the ancestral haplotype and larger extent
of haplotype homozygosity. This implies that a variant
at the AR locus may have experienced recent positive
selection that led to an increase in frequency of the AGA
susceptibility allele in the European population
Kinda bad news huh?