Inactivation status of PCDH11X: sexual dimorphisms in gene expression levels in brain
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Genes escaping X-inactivation are predicted to contribute to differences in gene dosage between the sexes and are the prime candidates for being involved in the phenotype observed in individuals with X chromosome aneuploidies. Of particular interest is ProtocadherinX (PCDH11X or PCDHX), a recently described gene expressed in brain. In humans, PCDH11X has a homologue on the Y chromosome and is predicted to escape from X-inactivation. Employing bisulphite sequencing analysis we found absence of CpG island methylation on both the active and the inactive X chromosomes, providing a strong indication that PCDH11X escapes inactivation in humans. Furthermore, a sexual dimorphism in levels of expression in brain tissue was observed by quantitative real-time PCR, with females presenting an up to 2-fold excess in the abundance of PCDH11X transcripts. We relate these findings to sexually dimorphic traits in the human brain. Interestingly, PCDH11X/Y gene pair is unique to Homo sapiens, since the X-linked gene was transposed to the Y chromosome after the human–chimpanzee lineages split. Although no differences in promoter methylation were found between humans and chimpanzees, evidence of an upregulation of PCDH11X in humans deserves further investigation.
KeywordsMethylation Level Lymphoblastoid Cell Line Human Female Female Chimpanzee Inactivation Status
The authors would like to acknowledge Patricia Blanco-Arias and Carole Sargent for their valuable contribution to this work. We also would like to thank Luís Teixeira da Costa and Raquel Seruca for scientific advice and Luís Cirnes and Marta Novais for technical support. We are grateful to Dr. P. Khaitovitch, Dr. P. A. Morin and Dr. S. Paabo for kindly providing chimpanzee samples. We also thank the anonymous reviewers for their comments, which have contributed to the improvement of the manuscript. This work was partially supported by Fundação para a Ciência e Tecnologia (through grant SFRH/BD/7006/2001 and POCTI, Programa Operacional Ciência, Tecnologia e Inovação). Norman Ross, James Close, Adam Dagnal and Tim Crow are grateful to the UK Medical Research Council, TJ Crow Psychosis Research Trust, Stanley Foundation and SANE for support.
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