The Spreading of X Inactivation into Autosomal Material of an X;autosome Translocation: Evidence for a Difference between Autosomal and X-Chromosomal DNA

Abstract

X inactivation involves initiation, propagation, and maintenance of genetic inactivation. Studies of replication timing in X;autosome translocations have suggested that X inactivation may spread into adjacent autosomal DNA. To examine the inactivation of autosomal material at the molecular level, we assessed the transcriptional activity of X-linked and autosomal loci spanning an inactive translocation in a phenotypically normal female with a karyotype of 46,X,der(X)t(X;4)(q22;q24). Since 4q duplications usually manifest dysmorphic features and severe growth and mental retardation, the normal phenotype of this individual suggested the spreading of X inactivation throughout the autosomal material. Consistent with this model, reverse transcription-PCR analysis of 20 transcribed sequences spanning 4q24-qter revealed that three known genes and 11 expressed sequence tags (ESTs) were not expressed in a somatic-cell hybrid that carries the translocation chromosome. However, three ESTs and three known genes were expressed from the t(X;4) chromosome and thus "escaped" X inactivation. This direct assay of expression demonstrated that the spreading of inactivation from the adjoining X chromosome was incomplete and noncontiguous. These findings are broadly consistent with the existence of genes known to escape inactivation on normal inactive X chromosomes. However, the fact that a high proportion (30%) of tested autosomal genes escaped inactivation may indicate that autosomal material lacks X chromosome-specific features that are associated with the spreading and/or maintenance of inactivation.

A Functional Chromatin Domain Does Not Resist X Chromosome Inactivation: Silencing of cLys Correlates with Methylation of a Dual Promoter-Replication Origin

“…This idea has received support from recent studies showing an especially high abundance of LINE-1 (L1) elements on the mammalian X chromosome (3,49). The involvement of a common repetitive element is consistent with the observation that XCI can sometimes spread considerable distances into X-translocated autosomal segments (72). A few endogenous X-linked genes escape XCI (70), and in translocations its spread into autosomal regions is usually limited, suggesting that some autosomal segments either are resistant to inactivation or lack the elements required to stabilize and/or propagate the inactivating signal (29).…”

X-inactivation by chromosomal pairing events

“…An important clue for solving this problem presents itself when we inspect X-autosome translocations. The heterochromatin generally fails to spread very far into autosomal sequence (Eicher 1970;White et al 1998). However, in a small subset of chimeric chromosomes, inactivation readily spreads across large stretches of autosome (Eicher 1970;Lee and Jaenisch 1997;Lyon 1998).…”

Two Classes of Dosage Compensation Complex Binding Elements along Caenorhabditis elegans X Chromosomes

“…When a portion of the X not containing the XIC/Xic region is translocated to an autosome, this chromosomal region will not be bound by Xist and will not be subjected to dosage compensation. However, when the X-inactivation center is moved adjacent to autosomal sequences (either on X-autosomal translocations, or Xic transgenes inserted on autosomes), variable and incomplete spreading into the autosomal region has been observed (8,20,30,32,33,35). These types of observations led to the "way station" hypothesis, originally proposed by Gartler and Riggs (12).…”