Biology subjects

Muglia, L.

Publications and source records attributed to Muglia, L..

3 recordsLinked to original sources

bioRxiv2022

A SNP affects Wnt4 expression in endometrial stroma, with antagonistic implications for pregnancy, endometriosis and reproductive cancers

The common human single nucleotide polymorphism rs3820282 is associated with multiple phenotypes ranging from gestational length to likelihood of endometriosis and ovarian cancer and can thus serve as a paradigm for a highly pleiotropic genetic variant. Pleiotropy makes it challenging to assign specific causal roles to particular genetic variants. Deleterious mutations in multifunctional genes may cause either the co-occurrence of multiple disorders in the same individuals (i.e., syndromes), or be repeatedly associated with a variety of disorders in a population. Moreover, the adverse effects can occur in combination with advantages in other traits, maintaining high frequencies of deleterious alleles in the population. To reveal the causal role of this specific SNP, we investigated the molecular mechanisms affected by rs3820282 in mice. We have shown previously that rs3820282 introduces a high affinity estrogen receptor 1 binding site at the Wnt4 locus. Having introduced this nucleotide substitution into the homologous site of the mouse genome by CRISPR/Cas 9 we show that this change causes a specific upregulation of Wnt4 transcription in the endometrial stromal cells during the preovulatory estrogen peak in late proestrus. Transcriptomic analysis of the whole uterus reveals broad systemic effects on uterine gene expression, including downregulation of proliferation and induction of many progesterone-regulated pro-implantation genes. The effect on proliferation is limited to the luminal epithelium, whereas other effects involve the uterine stromal compartment. We suggest that in the uterus, these changes could contribute to increased permissiveness to embryo invasion. Yet in other estrogen-responsive tissues, the same changes potentially lead to decreased resistance to invasion by cancer cells and endometriotic foci. A single molecular effect of rs3820282 on Wnt4 expression may thus underlie the various associated phenotypic effects.

genetics↗

bioRxiv2020

Deciphering the evolution of the transcriptional and regulatory landscape in human placenta

In mammals, the placenta mediates maternal-fetal nutrient and waste exchange and provides immunomodulatory actions that facilitate maternal-fetal tolerance. The placenta is highly diversified among mammalian species, yet the molecular mechanisms that distinguish the placenta of human from other mammals are not fully understood. Using an interspecies transcriptomic comparison of human, macaque, and mouse term placentae, we identified hundreds of genes with lineage-specific expression - including dozens that are placentally-enriched and potentially related to pregnancy. We further annotated the enhancers for different human tissues using epigenomic data and demonstrate that the placenta and chorion are unique in that their enhancers display the least conservation. We identified numerous lineage-specific human placental enhancers, and found they are highly overlapped with specific families of endogenous retroviruses (ERVs), including MER21A, MER4A/B and MER39B that were previously linked to immune response and placental function. Among these ERV families, we further demonstrate that MER41 insertions create dozens of lineage-specific Serum Response Factor (SRF) binding loci in human, including one adjacent to FBN2, a placenta-specific gene with increased expression in humans that produces the peptide hormone placensin to stimulate glucose secretion and trophoblast invasion. Our results demonstrate the prevalence of lineage-specific human placental enhancers which are frequently associated with ERV insertions and likely facilitated the lineage-specific evolution of the mammalian placenta.

evolutionary biology↗

bioRxiv2020

Detection of complex genetic architecture using two-locus population differentiation: modeling epistasis

Recent advances in genetics have increased our understanding of epistasis as important in the genetics of complex phenotypes. However, current analytical methods often cannot detect epistasis, given the multiple testing burden. To address this, we extended our previous method, Evolutionary Triangulation (ET), that uses differences among populations in both disease prevalence and allele frequencies to filter SNPs from association studies to generate novel interaction models. We show that two-locus ET identified several co-evolving gene pairs, where both genes associate with the same disease, and that the number of such pairs is significantly greater than expected by chance. Traits found by two-locus ET included those related to pigmentation and schizophrenia. We then applied two-locus ET to the analysis of preterm birth (PTB) genetics. Using ET to filter SNPs at loci identified by genome-wide association studies (GWAS), we showed that ET derived PTB two-locus models are novel and were not seen when only the index SNPs were used to generate epistatic models. One gene pair, ADCY5 and KCNAB1 5’, was identified as significantly interacting in a model of gestational age (p as low as 3 × 10−3). Notably, the same ET SNPs in these genes showed significant interactions in three of four cohorts analyzed. The robustness of this gene pair and others, demonstrated that the ET method can be used without prior biological hypotheses based on SNP function to select variants for epistasis testing that could not be identified otherwise. Two-locus ET clearly increased the ability to identify epistasis in complex traits.View Full Text

genetics↗