Table 2.

Imprinted genes linked to fertility and menopause

Gene	Imprint status-Fertility-Imprint prediction	References
GNAS1	Direct evidence shows that gene GNAS1 is imprinted in some human tissues, in particular maternally expressed and paternally silenced in the pituitary gland and ovaries.	(Hayward et al. 1998; Mantovani et al. 2002; Wilkins & Úbeda 2011)
	A loss-of-function mutation of GNAS1 results in follicle-stimulating hormone (FSH) resistance (among other symptoms) when the gene is MI but not when it is PI. FSH resistance results in reduced ovarian follicle stock and premature ovarian failure. Thus a loss-of-function mutation of GNAS1 results in premature ovarian failure when MI but not when PI. Greater expression of GNAS1 contributes to greater fertility thus acting as a fertility enhancer.	(Nakamoto et al. 1998; Weinstein et al. 2001; Persani et al. 2010)
	Our model predicts that GNAS1 will be paternally silenced in tissues affecting fertility, prediction supported by the evidence of imprinting in GNAS1.
DLX5	Direct evidence shows that DLX5 is imprinted in humans; maternally expressed and paternally silenced.	(Horike et al. 2005; Miyano et al. 2008)
	Mutant mice that are monoallelic for DLX5 experience reduced fertility and early follicular exhaustion that results in premature ovarian failure. Given that expression of DLX5 contributes to greater fertility, this locus can be classified as a fertility enhancer.	(Bouhali et al. 2011)
	Our model predicts that DLX5 will be paternally silenced, prediction supported by the evidence of imprinting in DLX5.
WT1-AS	The antisense transcript of gene WT1 (WT1-AS) is imprinted in humans, in particular paternally expressed and maternally silenced. The antisense transcript antagonises the sense transcript of the same parental origin.	(Dallosso et al. 2004)
	WT1 knockout mice develop without the establishment of an ovarian reserve and are non-viable. Given that expression of WT1 contributes to establishing an ovarian reserve, this locus can be classified as a fertility enhancer and its antisense as a fertility inhibitor.	(Wilhelm & Englert 2002; Monget et al. 2012)
	Our model predicts that WT1-AS will be maternally silenced, prediction supported by the evidence of imprinting in WT1-AS.

Summary of the evidence linking imprinted genes to menopause.