Parental origin and timing of de novo Robertsonian translocation formation

Abstract

Robertsonian translocations (ROBs) are the most common chromosomal rearrangements in humans. ROBs are whole-arm rearrangements between the acrocentric chromosomes 13-15, 21, and 22. ROBs can be classified into two groups depending on their frequency of occurrence, common (rob(13q14q) and rob(14q21q)), and rare (all remaining possible nonhomologous combinations). Herein, we have studied 29 case subjects of common and rare de novo ROBs to determine their parental origins and timing of formation. We compared these case subjects to 35 published case subjects of common ROBs and found that most common ROBs apparently have the same breakpoints and arise mainly during oogenesis (50/54). These probably form through a common mechanism and have been termed "class 1." Collectively, rare ROBs also occur mostly during oogenesis (7/10) but probably arise through a more "random" mechanism or a variety of mechanisms and have been termed "class 2." Thus, we demonstrate that although both classes of ROBs occur predominantly during meiosis, the common, class 1 ROBs occur primarily during oogenesis and likely form through a mechanism distinct from that forming class 2 ROBs.

Figure 1

Partial metaphase spreads showing FISH with specific probes for satellite DNA subfamilies. The Robertsonian translocations are indicated by arrows. The same de novo rob(13q14q) is shown in panels A and B. A, FISH with pTRI-6 (green signals), rDNA (red signals), and a 13q subtelomeric probe (Knight et al. ; red signals) shows that the de novo translocation breakpoint is between pTRI-6 (retained) and the rDNA (lost) on chromosome 13. B, FISH with pTRS-47 (green signals), pTRS-63 (red signals), and a 14q subtelomeric probe (Knight et al. ; green signals) shows that the translocation breakpoint is between pTRS-47 (retained) and pTRS-63 (lost) on chromosome 14. For panels C and D, the same de novo rob(14q21q) was used. C, FISH with pTRI-6 (green signals), rDNA (red signals), and a 21q subtelomeric probe (Knight et al. ; red signals) shows that the translocation breakpoint was between pTRI-6 (retained) and rDNA (lost) on chromosome 21. D, FISH with pTRS-47 (green signals), pTRS-63 (red signals), and a 21q subtelomeric probe (red signals) shows that the translocation breakpoint was between pTRS-47 (retained) and pTRS-63 (lost) on chromosome 14. Note that probes pTRS-47 and pTRS-63 cross hybridize to the pericentromeric region of chromosome 9 (yellow signals).

Figure 2

Parental origin determination by PCR analysis using polymorphic markers on somatic cell hybrids. Shown are two markers used to determine the parental origins of the chromosomes involved in this case of a de novo rob(14q15q). The top of the figure shows the idiograms for chromosomes 14 (left), 15 (right), and the rob(14q15q) (middle). The left of the figure shows the results for D14S267 on DNA from the mother (M), child (C) with the de novo rob(14q15q), father (F), somatic cell hybrid carrying the rob(14q15q) (rob), and somatic cell hybrid carrying the free-lying chromosome 14 (fl). The child inherited the upper allele from the father and the lower allele from the mother. The chromosome 14 involved in the rob(14q15q) was derived from the mother, since it shares this lower allele. The free-lying chromosome 14 was inherited from the father. The right of the figure shows the results for D15S979. The child inherited the upper allele from the father and the lower allele from the mother. The chromosome 15 involved in the rob(14q15q) was derived from the father, as it carries the father’s allele. The free-lying chromosome 15 was inherited from the mother. Thus, this rob(14q15q) was derived postzygotically from the maternally derived 14 and the paternally derived 15.