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

• Published in: American journal of human genetics Vol. 63; no. 1; pp. 20 - 28
• Main Authors: White, Wendy M., Willard, Huntington F., Van Dyke, Daniel L., Wolff, Daynna J.
• Format: Journal Article
• Language: English
• Published: Chicago, IL Elsevier Inc 01.07.1998; University of Chicago Press
• Subjects: Adult; Biological and medical sciences; Chromosome aberrations; Chromosome Mapping; Chromosomes, Human, Pair 4 - genetics; CpG Islands - genetics; DNA - genetics; Dosage Compensation, Genetic; Female; Gene Expression Regulation - genetics; Humans; Hybrid Cells - metabolism; Karyotyping; Medical genetics; Medical sciences; Microsatellite Repeats - genetics; Polymerase Chain Reaction; RNA - genetics; Somatic-cell hybrids; Transcription, Genetic - genetics; Translocation, Genetic - genetics; X autosome translocation; X chromosome; X inactivation; X autosome translocation; X inactivation; Somatic-cell hybrids; X chromosome; Chromosomal aberration; Human; Long arm; Abnormal X chromosome; Asymptomatic; Autosome; Gene expression; Inactivation; Genetic determinism; Case study; Gene; Abnormal chromosome B4; DNA; Abnormal chromosome; Female; X-Chromosome; Structural analysis; Chromosome translocation
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/301922

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.