Amplification of a pseudogene cassette underlies euchromatic variation of 16p at the cytogenetic level

Abstract

Euchromatic imbalances at the cytogenetic level are usually associated with phenotypic consequences. Among the exceptions are euchromatic variants of chromosomes 8, 9, 15 and 16, which have each been reported in multiple unrelated families. In this paper, we present a new family and an unrelated individual who have euchromatic variants of 16p. Enhanced hybridisation to the extra material was found by using fluorescence in situ hybridisation with cosmids for both the 16p11.2-specific non-functional immunoglobin heavy chain segments and the pseudogenetic 16p11.2 creatine transporter region. Computerised measurement of the fluorescent signals was consistent with amplification of a pseudogene cassette comprising both these paralogous domains, which were originally transposed from 14q32.3 and Xq28, respectively. Amplification of pseudogenetic sequences is consistent with the normal phenotype in 36/46 carriers from the 18 families reported to date. Inconsistent phenotypic anomalies in the remaining 10 carriers probably reflect bias of ascertainment. These results are analogous to the amplification of the 15q11.2-specific pseudogene cassette in euchromatic variants of chromosome 15. They also suggest that the majority of established euchromatic variants are associated with variation in the copy number of sequences that have been dispersed between pericentromeric and telomeric loci over recent evolutionary time. We propose that constitutional cytogenetic amplification of this kind is part of a more widespread continuum of genomic flux affecting regions in which heterochromatin and euchromatin interpose. Euchromatic sequences that vary in a heterochromatic manner might usefully be termed “hemichromatic”.