Pseudoautosomal Region 1 Length Polymorphism in the Human Population

The human sex chromosomes differ in sequence, except for the pseudoautosomal regions (PAR) at the terminus of the short and the long arms, denoted as PAR1 and PAR2. The boundary between PAR1 and the unique X and Y sequences was established during the divergence of the great apes. During a copy number variation screen, we noted a paternally inherited chromosome X duplication in 15 independent families. Subsequent genomic analysis demonstrated that an insertional translocation of X chromosomal sequence into theMa Y chromosome generates an extended PAR. The insertion is generated by non-allelic homologous recombination between a 548 bp LTR6B repeat within the Y chromosome PAR1 and a second LTR6B repeat located 105 kb from the PAR boundary on the X chromosome. The identification of the reciprocal deletion on the X chromosome in one family and the occurrence of the variant in different chromosome Y haplogroups demonstrate this is a recurrent genomic rearrangement in the human population. This finding represents a novel mechanism shaping sex chromosomal evolution.
Author Summary The human sex chromosomes differ in sequence, except for homologous sequences at both ends, termed the pseudoautosomal regions (PAR1 and PAR2). PAR enables the pairing of chromosomes Y and X during meiosis. The PARs are located at the termini of respectively the short and long arms of chromosomes X and Y. The observation of gradual shortening of the Y chromosome over evolutionary time has led to speculations that the Y chromosome is “doomed to extinction.” However, the Y chromosome has been shaped over evolution not only by the loss of genes, but also by addition of genes as a result of interchromosomal exchanges. In this work, we identified males with a duplication on chromosome Xp22.33 of about 136 kb as an incidental finding during a copy number variation screen. We demonstrate that the duplicon is an insertional translocation due to non-allelic homologous recombination from the X to the Y chromosome that is flanked by a long terminal repeat (LTR6B). We show this translocation event has occurred independently multiple times and that the duplicated region recombines with the X chromosome. Therefore, the duplicated region represents an extension of the pseudoautosomal region, representing a novel mechanism shaping sex chromosomal evolution in humans.