Dynamic Nature of the Proximal AZFc Region of the Human Y Chromosome: Multiple Independent Deletion and Duplication Events Revealed by Microsatellite Analysis

The human Y chromosome shows frequent structural variants, some of which are selectively neutral, while others cause impaired fertility due to the loss of spermatogenic genes. The large,scale use of multiple Y-chromosomal microsatellites in forensic and population genetic studies can reveal such variants, through the absence or duplication of specific markers in haplotypes. We describe Y chromosomes in apparently normal males carrying null and duplicated alleles at the microsatellitc DYS448, which lies in the proximal part of the azoospemia factor c (AZFc) region, important in spermatogenesis, and made up of ampliconic repeats that act as substrates for nonallelic homologous recombination (NAHR). Physical mapping in 26 DYS448 deletion chromosomes reveals that only three cases belong to a previously described Class, representing independent occurrences of an similar to 1.5-Mb deletion mediated by recombination between the b1 and B repeat units. The remainder belong to five novel classes; none appears to be mediated through homologous recombination, and all remove some genes, but are likely to be compatible with normal fertility. A combination of deletion analysis with binary-marker and microsatellite haplotyping shows that the 26 deletions represent nine independent events. Nine DYS448 duplication chromosomes can be explained by four independent events. Sonic lineages have risen to high frequency in particular populations, in particular a deletion within haplogroup (hg) C*(xC3a,C3c) found in IS Asian males. The nonrandom phylogenctic distribution of duplication and deletion events suggests possible structural predisposition to such mutations in hgs C and G. Hum Mutat 29(10), 1171-1180, 2008. (c) 2008 Wiley-Liss, Inc.