Divergent outcomes of intrachromosomal recombination on the human Y chromosome: male infertility and recurrent polymorphism

Abstract

The Y chromosome provides a unique opportunity to study mutational processes within the human genome, decoupled from the confounding eVects of interchromosomal recombination. It has been suggested that the increased density of certain dispersed repeats on the Y could account for the high frequency of causative microdeletions relative to single nucleotide mutations in infertile males. Previously we localised breakpoints of an AZFa microdeletion close to two highly homologous complete human endogenous retroviral sequences (HERV), separated by 700 kb. Here we show, by sequencing across the breakpoint, that the microdeletion occurs in register within a highly homologous segment between the HERVs. Furthermore, we show that recurrent double crossovers have occurred between the HERVs, resulting in the loss of a 1.5 kb insertion from one HERV, an event underlying the first ever Y chromosomal polymorphism described, the 12f2 deletion. This event produces a substantially longer segment of absolute homology and as such may result in increased predisposition to further intrachromosomal recombination. Intrachromosomal crosstalk between these two HERV sequences can thus result in either homogenising sequence conversion or a microdeletion causing male infertility. This represents a major subclass of AZFa deletions. (J Med Genet 2000;37:752-758)

The Y chromosome-linked copy number variations and male fertility

“…Complete AZFa deletions occurs after homologous recombination between identical sequence blocks within the retroviral sequences in the same orientation HERVyq1 and HERVyq2 (9)(10)(11). The complete deletion of AZFb is caused by homologous recombination between the palindromes P5/proximal P1 which removes also part of the AZFc region belonging to P1 (8).…”

Apparent intrachromosomal exchange on the human Y chromosome explained by population history

“…DNA sequencing of various length alleles of both loci was performed on ABI Prismt 377 DNA Sequencer (Applied Biosystems) using Big Dye chemistry (Applied Biosystems, Foster City, CA, USA) according to the recommendations of the manufacturer. For DYS385a, five different length alleles were sequenced (11,12,13,16,17), and for DYS385b eight alleles were sequenced (11,12,(14)(15)(16)(17)(18)20 Nei,37 was calculated using the software package Arlequin. 38 …”

“…9 Intrachromosomal exchange between Y-chromosomal copies derived from the HERV15 class of endogenous retroviruses has also been shown to cause deletions at the AZFa region responsible for male infertility. 11,12 Although recombination between segmental duplications also occurs in autosomes and can cause genomic instability and disease, 13,14 the Y chromosome is especially suitable for investigating intrachromosomal rearrangements, because of the absence of interchromosomal processes in the nonrecombining region (NRY).…”

Homozygous deletion of DIS3L2 exon 9 due to non-allelic homologous recombination between LINE-1s in a Japanese patient with Perlman syndrome

“…6 Although Alu-mediated NAHR contributes to a large variety of genetic disorders, L1-mediated NAHR and human endogenous retrovirus-mediated NAHR are very rare causes of human diseases. [9][10][11][12] Only three human diseasesglycogen storage disease type IXb, Alport syndrome-diffuse leiomyomatosis, and Ellis-van Creveld syndrome -have been reported to be caused by L1-mediated NAHR. [13][14][15] To our knowledge, this is the fourth NAHR event to cause human disease, in this case Perlman syndrome.…”