Diversity in the androgen receptor CAG repeat has been shaped by a multistep mutational mechanism

Abstract

The androgen receptor (AR) gene encodes a type of nuclear receptor that functions as a steroid-hormone activated transcription factor. In its coding region, AR includes a CAG repeat, which has been intensely studied due to the inverse correlation between repeat size and AR transcriptional activity. Several studies have reported different (CAG)n sizes associated with the risk of androgen-linked diseases. We aimed at clarifying the mechanisms on the origin of newly CAG sized alleles through a strategy involving the analysis of the associated haplotype diversity. We genotyped 374 control individuals of European and Asian ancestry, and reconstructed the haplotypes associated with the CAG repeat, defined by 10 SNPs and 6 flanking STRs. The most powerful SNPs to tag AR lineages are rs7061037-rs12012620 and rs34191540-rs6625187-rs2768578 in Europeans and Asians, respectively. In the most frequent AR lineage, (CAG)18 alleles seem to have been generated by a multistep mutation mechanism, most probably from longer alleles. We further noticed that the DXS1194-DXS1111 haplotype, in linkage disequilibrium with AR-(CAG)n expanded alleles responsible for spinal bulbar muscular atrophy (SBMA), is rare among our controls; however, the haplotype strategy here described may be used to clarify the origin of expansions in other populations, as in future association studies.

Mutational mechanism for DAB1 (ATTTC) n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution

“…Different cellular mechanisms have been associated with gain and loss of genetic material in repeat loci (Gomes‐Pereira et al., ; Martins et al., ; Santos, Pimenta, Wong, Amorim, & Martins, ; Slean et al., ). The repetitive nature of these genomic regions burden normal cell mechanisms such as replication and transcription, leading to an increase in DNA breaks in repeats (Krasilnikova & Mirkin, ; Zhang et al., ).…”

Contraction of fully expanded FMR1 alleles to the normal range: predisposing haplotype or rare events?

“…Indeed, a multistep mechanism involving the gain or loss of several repetitive units during the intergenerational transmission of expanded alleles has been suggested to explain the evolution of other disease-expansion repeats. [34][35][36] Further studies of repeat instability underlying the different groups of normal pure (CGG)n alleles (the unstable ones resulted from large contractions and those, probably more stable, evolved through interrupted repeats) would be of upmost importance for the research of both the mechanistic aspects of repeat instability and the clinical risk-assessment for fragile X syndrome.…”

A Pipeline to Assess Disease-Associated Haplotypes in Repeat Expansion Disorders: The Example of MJD/SCA3 Locus

“…This is also relevant for recessive diseases, since two mutations (expanded alleles) in homozygosity may not share a common ancestral origin. When the gene of interest is on the X chromosome, that allows to infer haplotypes directly in males (e.g., when analyzing the CAG expansion in the androgen receptor , responsible for SBMA) (Santos et al, 2014).…”