James Turner group

Sex chromosomes in development and disease

Males and females differ fundamentally in their sex chromosome make-up: females have two X chromosomes (XX), while males have one X chromosome and one Y chromosome (XY). The sex chromosomes are highly enriched in genes functioning in germ cell and neural development, and they influence male-female differences in growth, behaviour and susceptibility to a variety of diseases, e.g. hypertension and cancer.

The imbalance in dosage for X genes between females and males also presents unique challenges for the developing embryo that are overcome by X chromosome inactivation; the silencing of one X chromosome in each female cell by the non-coding RNA Xist. Our lab studies the epigenetics, evolution and cell biology of the sex chromosomes from a variety of organisms, including mammals, in order to understand how these chromosomes influence human health and disease.

Previous work from our lab has shown that the mammalian X chromosome is dominated by genes involved in spermatogenesis, with around eighteen percent of all X-genes being expressed in developing sperm. We have identified Rsx, an Xist-like RNA with features suggestive of a role in X chromosome inactivation in the second largest class of mammals, the metatherians. Our studies have also identified a surveillance mechanism, meiotic silencing, that inactivates genes on unpaired meiotic chromosomes, and is mediated by the DNA damage proteins BRCA1, ATR and histone H2AFX. This surveillance mechanism is likely to play a major role in the infertility phenotypes seen in patients with chromosome abnormalities.

Figure 1

Figure 1

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Identification of Rsx, a non-coding RNA involved in metatherian X chromosome inactivation. Left: The Rsx RNA molecules (green) form a localised cloud in female opossum cells. Right: the area covered by the cloud is the inactive X chromosome, identified by enrichment for the inactivating histone mark H3K27me3 (red).

Figure 2

Figure 2

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An enrichment of multicopy male germ cell genes on the mouse X chromosome. The figure shows the positions and copy number of the multicopy genes on the X chromosome. These multicopy gene families form complex structures, as shown by sequence similarity plots at the top of the figure.

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