Word frequency analysis reveals enrichment of dinucleotide repeats on the human X chromosome and [GATA]_nin the X escape region

Abstract

Most of the human genome encodes neither protein nor known functional RNA, yet available approaches to seek meaningful information in the "noncoding" sequence are limited. The unique biology of the X chromosome, one of which is silenced in mammalian females, can yield clues into sequence motifs involved in chromosome packaging and function. Although autosomal chromatin has some capacity for inactivation, evidence indicates that sequences enriched on the X chromosome render it fully competent for silencing, except in specific regions that escape inactivation. Here we have used a linguistic approach by analyzing the frequency and distribution of nine base-pair genomic "words" throughout the human genome. Results identify previously unknown sequence differences on the human X chromosome. Notably, the dinucleotide repeats [AT] n , [AC] n , and [AG] n are significantly enriched across the X chromosome compared with autosomes. Moreover, a striking enrichment (>10-fold) of [GATA] n is revealed throughout the 10-Mb segment at Xp22 that escapes inactivation, and is confirmed by fluorescence in situ hybridization. A similar enrichment is found in other eutherian genomes. Our findings clearly demonstrate sequence differences relevant to the novel biology and evolution of the X chromosome. Furthermore, they implicate simple sequence repeats, linked to gene regulation and unusual DNA structures, in the regulation and formation of facultative heterochromatin. Results suggest a new paradigm whereby a regional escape from X inactivation is due to the presence of elements that prevent heterochromatinization, rather than the lack of other elements that promote it.

Characterization of simple sequence repeats (SSRs) from Phlebotomus papatasi (Diptera: Psychodidae) expressed sequence tags (ESTs)

“…Dinucleotide repeats are typically more frequent in noncoding regions [28-30]; however, they occur occasionally in coding regions as well [31]. Some dinucleotides, such as (AG)n/(CT)n, are not selectively neutral and may have functional roles.…”

Characterization of the bovine pseudoautosomal boundary: Documenting the evolutionary history of mammalian sex chromosomes

“…A high density in LINE sequences alone is thus certainly not a sufficient condition for the spreading of X inactivation. It will be interesting to compare the word composition of inactivated portions of the X chromosome with the PAR in bovine, as was recently performed for inactivated segments versus segment escaping inactivation on the human X chromosome (e.g., Carrel et al 2006;McNeil et al 2006). Note that the bovine PAR is also enriched in SINE elements, which were shown to be enriched in regions of the X chromosome escaping X inactivation in human (Carrel et al 2006).…”

The X chromosome is organized into a gene-rich outer rim and an internal core containing silenced nongenic sequences

“…We speculate that it is the ability of XIST RNA to bind and condense the repetitive heterochromatin found in the inner core of Xi that results in chromosome-wide silencing, an idea consistent with both evidence that gene-poor DNA is found more interior to chromosome territories (38) and that noncoding repetitive motifs may be involved in X inactivation (14, 39, 40). Although Alu and LINEs are prominent components of the Cot-1 DNA, of particular interest would be the involvement of LINE transcription because this sequence is enhanced on Xi (14,39).…”

“…Occasionally, MIC2, which resides in the pseudoautosomal region, seemed to be expressing from a ''gap'' in the XIST RNA signal, raising the question of whether XIST RNA may associate less tightly with that region. We mapped the interphase location of a probe to GATA repeats, which we have recently shown to be strikingly enriched throughout the psuedoautosomal region (14). The pseudoautosomal region was found primarily to border the XIST RNA (Fig.…”