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.
We demonstrate that satellite III (SatIII) DNA subfamilies cloned from human acrocentric chromosomes arose in the Hominoidea superfamily. Two groups, distinguished by sequence composition, evolved nonconcurrently, with group 2 evolving 16-23 million years ago (MYA) and the more recent group 1 sequences emerging approximately 4.5 MYA. We also show the relative order of emergence of each group 2 subfamily in the various primate species. Our results show that each SatIII subfamily is an independent evolutionary unit, that the rate of evolution is not uniform between species, and that the evolution within a species is not uniform between chromosomes.
It has been estimated that a few hundred children are born each year in the United States with translocation Down syndrome. About 5% of the cases with Down syndrome carry a Robertsonian translocation involving chromosome 21. The case described here is a patient with Down syndrome who showed mosaicism for two cell lines. Each cell line contains a different, de novo acrocentric rearrangement. We constructed somatic cell hybrids from the patient's cells and determined the parental origins of the rearrangements by molecular and fluorescence in situ hybridization (FISH) analyses. The analysis showed that the rob(14q21q) formed between a paternally inherited chromosome 21 and a maternally inherited chromosome 14, indicating that this rearrangement formed post-zygotically. Further molecular analysis also determined that the rea(21q21q) is an isochromosome of paternal origin. The cell line containing the isochromosome is unbalanced, resulting in trisomy 21. Because the same paternal chromosome 21 was involved in both the isochromosome and the Robertsonian translocation, we speculate that an unstable chromosome 21 was stabilized either through formation of a rob(14q21q) or through formation of an isochromosome. The mechanism proposed for the formation of the rob(14q21q) in this case is different from that for most de novo rob(14q21q), but similar to a previously reported mosaic case of Down syndrome.
The centromeres and the short arms of the five pairs of acrocentric chromosomes in humans are composed of tandemly ordered repetitive DNA. Previous studies have suggested that the exchanges between acrocentric chromosomes have resulted in concerted evolution of different DNA sequences in their short arms. The acrocentric chromosomes are clinically relevant since they are involved in Robertsonian translocation formation and non-disjunction resulting in aneuploidy. Here we have identified seven new satellite III repetitive DNA subfamilies, determined their nucleotide sequences and established their chromosomal distributions on the short arms of the acrocentric chromosomes. Knowledge of these related sequences may help to elucidate the molecular basis of Robertsonian translocation formation.
Robertsonian translocations (ROBs) are the most common rearrangements in humans, contributing significantly to genetic imbalance, fetal wastage, mental retardation and birth defects. Rob(14q21q) and rob(13q14q), which are formed predominantly during female meiosis, comprise the majority (approximately 85%) of all ROBs. Previous studies have shown that the breakpoints are consistently located within specific regions of the proximal short arms of chromosomes 13, 14, and 21. The high prevalence of these translocations, the consistent breakpoints found, and the fact that roughly 50% of cases occur sporadically suggest that the sequences at or near the breakpoints confer susceptibility to chromosome rearrangement and that the rearrangements occur through a specific mechanism. To investigate this hypothesis, we developed hamster-human somatic cell hybrids derived from de novo rob(14q21q) patients that contained the translocated chromosome segregated from the other acrocentric chromosomes. We determined the physical order of five satellite III subfamilies on 14p, and investigated their involvement in formation of these de novo translocations.
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