Abstract for presentation at 11th International Congress of Human Genetics

The constitutional t(11;22)(q23;q11) is the only known recurrent non-Robertsonian translocation in humans. Balanced translocation carriers have no clinical symptoms. While carriers occasionally manifest male infertility or recurrent abortion, they are often identified after the birth of unbalanced offspring with the supernumerary der(22)t(11;22) syndrome. We previously demonstrated de novo t(11;22)s in sperm samples from normal healthy males using translocation-specific PCR. In this study, we show that polymorphisms of the palindromic AT-rich repeat, identified at the t(11;22) breakpoint cluster region on chromosome 11 (PATRR11), affect the frequency of de novo occurrence of the translocation. The typical PATRR11 comprises a perfect palindrome producing de novo t(11;22)s at a frequency of ~10^-5, while a short symmetrical PATRR11 produces at a low frequency (~10^-6). Of note, PATRR11 with asymmetric center do not produce any de novo t(11;22)s at all (<10^-7). We conclude that the size and symmetry of the PATRR11 are the important factors that determine the frequency of de novo t(11;22)s. This is the first report that demonstrates genetic variation over more than three orders of magnitude in the susceptibility for generating this recurrent translocation in humans. Our results show the importance of genome sequence on chromosomal rearrangements, a class of human mutation that is felt by most to be “random”.