Variation in BMPR1B, TGFRB1 and BMPR2 and Control of Dizygotic Twinning

Abstract

Genes in the TGF9 signaling pathway play important roles in the regulation of ovarian follicle growth and ovulation rate. Mutations in three genes in this pathway, growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15) and the bone morphogenetic protein receptor B 1 (BMPRB1), influence dizygotic (DZ) twinning rates in sheep. To date, only variants in GDF9 and BMP15, but not their receptors transforming growth factor ß receptor 1 (TGFBR1), bone morphogenetic protein receptor 2 (BMPR2) and BMPR1B, have been investigated with respect to their roles in human DZ twinning. We screened for rare and novel variants in TGFBR1, BMPR2 and BMPR1B in mothers of dizygotic twins (MODZT) from twin-dense families, and assessed association between genotyped and imputed variants and DZ twinning in another large sample of MODZT. Three novel variants were found: a deep intronic variant in BMPR2, and one intronic and one non-synonymous exonic variant in BMPRB1 which would result in the replacement of glutamine by glutamic acid at amino acid position 294 (p.Gln294Glu). None of these variants were predicted to have major impacts on gene function. However, the p.Gln294Glu variant changes the same amino acid as a sheep BMPR1B functional variant and may have functional consequences. Six BMPR1B variants were marginally associated with DZ twinning in the larger case-control sample, but these were no longer significant once multiple testing was taken into account. Our results suggest that variation in the TGF9 signaling pathway type II receptors has limited effects on DZ twinning rates in humans.

Population structure, genetic diversity and selection signatures within seven indigenous Pakistani goat populations

“…Variants of this gene are related to reproductive traits in multiple species (Luong et al . ; Marchitelli & Nardone ; Ahlawat et al . ).…”

Using sheep lines with mutations in single genes to better understand ovarian function

“…However, association between these mutations and twinning could not be established (Zhao et al 2008). Similarly, while mutations in BMPR1B were observed in MODZT, they were only marginally associated with increased twinning (Luong et al 2011). Similar to the increased responsiveness to gonadotrophins observed in sheep heterozygous for a BMP15 mutation or homozygous for the BMPR1B mutation (McNatty et al 2006a), mutations in the human population in BMP15 have also been linked weakly to a higher response to FSH (Moron et al 2006, Hanevik et al 2011.…”

BMP15 regulates the inhibin/activin system independently of ovulation rate control in sheep

“…In sheep, heterozygous carriers of various missense mutations affecting BMP15 or GDF9 or carriers of a partial loss-of-function mutation in their receptor BMPR1B, exhibit systematically increased ovulation rates and litter sizes (reviews: Montgomery et al 2001, McNatty et al 2003, Fabre et al 2006, Persani et al 2014. Polymorphisms in GDF9, BMPR1B and SMAD3 (encoding a BMP15/ GDF9 signaling factor) have also been shown to occur among human cohorts with a propensity for dizygotic twins (Palmer et al 2006, Hoekstra et al 2008, Luong et al 2011, Mbarek et al 2016, and the presence of non-synonymous substitutions in BMP15 or GDF9 genes has been recently associated with twinning in callitrichine primates (Harris et al 2014). From a phylogenetic analysis comparing mono-and polyovulating mammalian species, high variations have been observed in specific areas of BMP15 and GDF9, which are able to modify the biological activity of the proteins in poly-ovulating mammals (Monestier et al 2014).…”