Pseudoautosomal gene SHOX exhibits sex-biased random monoallelic expression and contributes to sex difference in height

Hattori, A.; Seki, A.; Inaba, N.; Nakabayashi, K.; Takeda, K.; Tatsusmi, K.; Naiki, Y.; Nakamura, A.; Ishiwata, K.; Matsumoto, K.; Nasu, M.; Okamura, K.; Michigami, T.; Katoh-Fukui, Y.; Umezawa, A.; Ogata, T.; Kagami, M.; Fukami, M.

doi:10.1101/2021.08.23.457290

bioRxiv · 10.1101/2021.08.23.457290

Pseudoautosomal gene SHOX exhibits sex-biased random monoallelic expression and contributes to sex difference in height

Hattori, A.·Seki, A.·Inaba, N.·Nakabayashi, K.·Takeda, K.·Tatsusmi, K.·Naiki, Y.·Nakamura, A.·Ishiwata, K.·Matsumoto, K.·Nasu, M.·Okamura, K.·Michigami, T.·Katoh-Fukui, Y.·Umezawa, A.·Ogata, T.·Kagami, M.·Fukami, M.

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Abstract

Adult men are, on average, [~]13 cm taller than adult women. Although previous studies have suggested a significant contribution of sex chromosomal genes to sexual dimorphism in height, all attempts to identify a male-specific growth gene have failed. In the present study, we analyzed transcripts from cartilage tissues, and found that the expression of SHOX, a growth-promoting gene in the pseudoautosomal region on the X and Y chromosomes, was lower in females than in males. DNA methylation analyses showed that SHOX has some characteristics of genes subjected to X chromosome inactivation (XCI). These findings indicate that sex difference in human height is mainly ascribed to incomplete spreading of XCI on a pseudoautosomal gene. More importantly, RT-PCR of fibroblast clones revealed XCI-independent random clonal monoallelic expression of SHOX. We presume that during eutherian evolution, SHOX translocated from an autosome to the proto-sex chromosome without losing the epigenetic memory of random clonal monoallelic expression and subsequently underwent partial XCI. This study provides a novel model of epigenetic gene regulation leading to phenotypic diversity in humans.

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Hattori, A., Seki, A., Inaba, N., Nakabayashi, K., Takeda, K., Tatsusmi, K., Naiki, Y., Nakamura, A., Ishiwata, K., Matsumoto, K., Nasu, M., Okamura, K., Michigami, T., Katoh-Fukui, Y., Umezawa, A., Ogata, T., Kagami, M., Fukami, M.. 2021-08-23. Pseudoautosomal gene SHOX exhibits sex-biased random monoallelic expression and contributes to sex difference in height. https://doi.org/10.1101/2021.08.23.457290

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