Harley, V. | bioRxiv Science

bioRxiv2023

Genetic Association Studies in Transgender Cohorts: A Systematic Review and Meta-Analysis

According to twin studies, there is a heritable contribution to gender incongruence, but the genetic mechanisms of this are unknown. Recent efforts to identify an aetiology of gender incongruence have focused on the hypothesis that sex hormones establish gender identity through influencing the development of neuroanatomy. Candidate gene studies that have sought to elucidate whether polymorphisms in sex steroidogenesis genes are overrepresented in transgender populations have been equivocal. A systematic search for case-control genetic association studies in transgender populations was conducted. Mean (+SD) or allele frequencies were extracted and combined quantitatively in random effects meta-analysis, summarised as standardised mean difference for continuous alleles or odds ratios for allele frequencies. Eight studies were included in the analysis. These studies spanned polymorphisms in five genes; the CAG repeat in androgen receptor (AR), the TA repeat in estrogen receptor 1 (ESR1), the CA repeat in estrogen receptor 2 (ESR2), the TTTA repeat in cytochrome P450 family 19 subfamily A member 1 (CYP19), and the T>C SNP in cytochrome P450 family 17 subfamily A member 1 (CYP17). Pooled estimates indicated that transgender women have a significant overrepresentation of short ESR1 alleles compared to cisgender men (OR = 1.23, 95% CI: 1.06, 1.44, p = 0.0089). This may contribute an increased likelihood of developing gender incongruence amongst natal males. Future investigations into gender incongruence should use genome-wide methods.

genetics↗

bioRxiv2022

Reprograming human fibroblasts into Sertoli cells: a tool for personalized medicine

Disorders/Differences of Sex Development (DSD) are congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical. With overlapping phenotypes and multiple genes involved, poor diagnostic yields are achieved for many of these conditions. The current DSD diagnostic regimen can be augmented by investigating transcriptome/proteome in vivo, but it is hampered by the unavailability of affected gonadal tissue at the relevant developmental stage. We try to mitigate this limitation by reprogramming readily available skin tissue-derived dermal fibroblasts into Sertoli cells (SC), which could then be deployed for different diagnostic strategies. SCs form the target cell type of choice because they act like an organizing center of embryonic gonadal development and many DSD arise when these developmental processes go awry. We employed a computational predictive algorithm for cell conversions called Mogrify to predict the transcription factors (TFs) required for direct reprogramming of human dermal fibroblasts into SCs. We established trans-differentiation culture conditions where stable transgenic expression of these TFs was achieved in 46, XY adult dermal fibroblasts using lentiviral vectors. The resulting Sertoli like cells (SLCs) were validated for SC phenotype using several approaches. SLCs exhibited Sertoli-like morphological and cellular properties as revealed by morphometry and xCelligence cell behavior assays. They also showed Sertoli-specific expression of molecular markers such as SOX9, PTGDS, BMP4, or DMRT1 as revealed by IF imaging, RNAseq and qPCR. The SLC transcriptome shared about two thirds of its differentially expressed genes with a human adult SC transcriptome and expressed markers typical of embryonic SCs. Notably, SLCs lacked expression of markers of other gonadal cell types such as Leydig, germ, peritubular myoid or granulosa cells. The trans-differentiation method was applied to a variety of commercially available 46, XY fibroblasts derived from patients with DSD and to a 46, XX cell line. The DSD SLCs displayed altered levels of trans-differentiation in comparison to normal 46, XY-derived SLCs, thus showcasing the robustness of this new trans-differentiation model.

cell biology↗