Absence of correlation between late-replication and spreading of X inactivation in an X;autosome translocation

Abstract

We have analysed the spread of X inactivation in an individual with an unbalanced 46,X,der(X)t(X;10)(q26.3;q23.3) karyotype. Despite being trisomic for the region 10q23.3-qter, both the proband and her aunt with the same karyotype presented only with secondary amenorrhoea and lacked any features normally associated with trisomy of distal 10q. Cytogenetic and molecular studies showed that the derivative X;10 chromosome was exclusively inactive. Transcribed polymorphisms were identified in five genes contained within the translocated region of chromosome 10 and were used to perform allele-specific transcription studies. We showed that four of the genes studied are inactive on the derivative chromosome, directly demonstrating the spread of X inactivation over some 30 Mb of autosomal DNA. However, the most distal gene examined remained active, indicating that this spreading was incomplete. In contrast to the gene expression data, replication timing studies showed no spreading of late replication into the translocated portion of 10q. We conclude that silencing of autosomal genes by X inactivation can occur without a delay in the replication timing of the surrounding chromatin. Our findings support the hypothesis that autosomal chromatin lacks certain features present on the X chromosome that are required for the effective spread and/or maintenance of X inactivation.

Skewed X-Chromosome Inactivation in Scleroderma

“…Numerous studies conducted in different control populations indicate that extremely skewed X-inactivation is a rare event not exceeding 3-5 percent. ( 15,16,17 ) For the current study, extremely skewed X-inactivation was present in 44 of 149 patients (29.5%) but in only 3 controls (2.4%) and the OR was 16.9 (95% CI 4.8-70.4, P<0.0001).…”

“…Whereas, ratios in the range of 50-79 percent is usually regarded as normal variation, deviation from this range in 80-89 percent of cells is defined as skewed, and above 90 percent of cells as extremely skewed X-inactivation. ( 15,16,17 ) Fisher's Exact test was used for statistical analyses.…”

An ectopic human XIST gene can induce chromosome inactivation in postdifferentiation human HT-1080 cells

“…Because recent results demonstrate that replication timing is not strictly correlated with transcriptional inactivation (17), the most direct test for the final outcome of the inactivation process is to examine transcription more directly. Transcription of the neomycin resistance gene (neo R ) located in the integrated cosmid, adjacent to the XIST gene, was assessed.…”

Early-replicating heterochromatin

“…These examples include (1) early initiation of replication within bovine satellite I, which comprises 5% of bovine genomic DNA and is located in the centromeric heterochromatin of most chromosomes (Matsumoto and Gerbi 1982); (2) early initiation of replication in the pericentric heterochromatin and centromeres of mouse chromosomes (Holló et al 1996); (3) early replication of some human telomeres (Wright et al 1999), despite the fact that human telomeres exhibit TPE (Baur et al 2001); (4) occasional early replication of autosomal genes inactivated by spreading of heterochromatin from a translocated human X chromosome (Sharp et al 2001); (5) early replication of inner centromeres in Drosophila (Ahmad andHenikoff 2001, 2002;Sullivan and Karpen 2001); and (6) early replication of Drosophila ␤-heterochromatin (the form of heterochromatin containing occasional expressed genes and located immediately distal to pericentric ␣-heterochromatin; Schü beler et al 2002).…”