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CAG repeats on androgen receptor gene and baldness

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

  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

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