Inv Dup Small Marker Chromosomes

SMCs containing two copies of a centromere, arranged in an apparent mirror image symmetry around a central axis, have been referred to as isodicentric (idic), pseudoisodicentric (psu dic) or, more correctly, inverted duplication (inv dup) (Fig. 1). The best studied, recurrent inv dup SMCs are derived from chromosomes 15 or 22. These chromosomes are bisatellited because of an acrocentric p-arm on each end. They also contain two centromeres, usually separated by at least several megabases of euchromatin. Such chromosomes are often stable, presumably because one centromere is inactivated (hence the term pseudoisodicentric). An inv dup SMC associated with an otherwise normal karyotype results in a total of four copies of the excess region, and is therefore a triplication or partial tetrasomy.

inv dup SMCs have been referred to as isodicentric, but this term is appropriate only if the duplications on each side are symmetrical (Fig. 1). inv dup chromosomes have been found often to be asymmetrical, with one side of the chromosome considerably larger than the other. This results in a total of four copies of some regions and only three copies of others (9).

inv dup SMCs can also originate from the other acrocentric chromosomes, but with less frequency and are associated with a less well-defined phenotype than that for chromosomes 15 and 22. Nonacrocentric chromosomes are also a source for inv dup SMCs. These may contain no a-satellite DNA and yet are stable, providing an opportunity to address the question of centromeric function in the absence of the DNA normally present at centromeres (10). These unusual inv dup SMCs are C-band negative, yet have a G-banded primary constriction, which acts as an active kinetochore and reacts with CENP-C antibodies (11). It is presumed that these SMCs activate noncentromeric sequences that function as neocentromeres.

It has long been suggested that inv dup chromosomes are derived from a "U-type" rather than the normal "X-type" exchange between nonsister or sister chromatids at meiosis I (12,13). Mediated by LCRs on chromosomes 15 or 22, a U-type exchange between repeats in opposite

Fig. 1. Structure of bisatellited and dicentric inv dup chromosomes. These chromosomes can have a symmetrical duplication (A) or be asymmetrical, where one side of the duplication is larger than the other (B). In an asymmetric inv dup, the region nearest the centromere is present in two extra copies (light gray), whereas the more distal region is present in only one extra copy (dark gray).

Fig. 1. Structure of bisatellited and dicentric inv dup chromosomes. These chromosomes can have a symmetrical duplication (A) or be asymmetrical, where one side of the duplication is larger than the other (B). In an asymmetric inv dup, the region nearest the centromere is present in two extra copies (light gray), whereas the more distal region is present in only one extra copy (dark gray).

orientation would lead to a dicentric SMC as well as an acentric fragment composed of two copies of the rest of each chromatid. The acentric fragment would be lost, whereas the SMC would be retained through nondisjunction and inactivation of one centromere. Each LCR in chromosome 22q11 is composed of complex blocks of repeats (14). LCR2 and LCR4, in which most rearrangements occur, contain shared repeat blocks in both the same and opposite orientations, which facilitate U-type exchanges. If a U-type exchange occurs between elements of the same LCR (allelic), the resulting inv dup chromosome would essentially be symmetrical. A U-type exchange between similar elements of different LCRs (nonallelic) would produce an asymmetric SMC. Asymmetric inv dup SMCs could also result from a paracentric inversion of a region between LCRs, followed by recombination within the inversion loop (15). This would similarly result in a dicentric SMC and an acentric fragment that is lost.

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