User:Cluffa/New sandbox

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Sources for Evolution
Bakloushinskaya, I. Y. (2009). Evolution of sex determination in mammals. Biology Bulletin, 36(2), 167–174. https://doi.org/10.1134/S1062359009020095 Secondary (review) article - this is almost certainly acceptable.

Hanhua Cheng, Xuan Shang, Yan He, Tao Zhang, Ya-Ping Zhang, & Rongjia Zhou. (2007). Insight into human sex ratio imbalance: the more boys born, the more infertile men. Reproductive BioMedicine Online (Reproductive Healthcare Limited), 15(5), 487–494. https://doi.org/10.1016/S1472-6483(10)60378-1 This is kinda both - it has primary research but a huge lit review. Maybe? Also, it’s got both evolutionary information and potential information about role in disease, so it might help Emma too.

Katsura, Y., Kondo, H. X., Ryan, J., Harley, V., & Satta, Y. (2018). The evolutionary process of mammalian sex determination genes focusing on marsupial SRYs. BMC Evolutionary Biology, 18, 1–N.PAG. https://doi.org/10.1186/s12862-018-1119-z Primary research article - this is interesting but should probably be a last resort.

Graves, J. A. M. (2015). Weird mammals provide insights into the evolution of mammalian sex chromosomes and dosage compensation. Journal of Genetics, 94(4), 567–574. https://doi.org/10.1007/s12041-015-0572-3 Secondary (review) article - this is almost certainly acceptable.

Evolution
SRY may have arisen from a gene duplication of the X chromosome bound gene SOX3, a member of the Sox family. This duplication occurred after the split between monotremes and therians. Monotremes lack SRY and some of their sex chromosomes share homology with bird sex chromosomes. SRY is a quickly evolving gene and its regulation has been difficult to study because sex determination is not a highly conserved phenomenon within the animal kingdom. Even within marsupials and placentals, which use SRY in their sex determination process, the action of SRY differs between species. The gene sequence also changes; while the core of the gene, the High-mobility group (HMG) box, is conserved between species, other regions of the gene are not. SRY is one of only four genes on the human Y chromosome that have been shown to have arisen from the original Y chromosome. The other genes on the human Y chromosome arose from an autosome that fused with the original Y chromosome.

Action in the nucleus
The TDF protein consists of three main regions. The central region encompasses the HMG (high-mobility group) domain, which contains nuclear localization sequences and acts as the DNA-binding domain. The C-terminal domain has no conserved structure, and the N-terminal domain can be phosphorylated to enhance DNA-binding.[11]The process begins with nuclear localization of TDF by acetylation of the nuclear localization signal regions, which allows for the binding of importin β and calmodulin to TDF, facilitating its import into the nucleus. Once in the nucleus, TDF and SF1 (steroidogenic factor 1, another transcriptional regulator) complex and bind to TESCO (testis-specific enhancer of SOX9 core), the testes-specific enhancer element of the SOX9 gene in Sertoli cell precursors, located upstream of the SOX9 gene transcription start site.[5] The HMG region of TDF that binds to the minor groove of the DNA target sequence, causing the DNA to bend and unwind. The establishment of this particular DNA “architecture” facilitates the transcription of the SOX9 gene.[11] In the nucleus of Sertoli cells, SOX9 directly targets the Amh gene as well as the prostaglandin D synthase (Ptgds) gene. SOX9 binding to the enhancer near the Amh promoter allows for the synthesis of Amh while SOX9 binding to the Ptgds gene allows for the production of prostaglandin D2 (PGD2). The reentry of SOX9 into the nucleus is facilitated by autocrine or paracrine signaling conducted by PGD2. SOX9 protein then initiates a positive feedback loop, involving SOX9 acting as its own transcription factor and resulting in the synthesis of large amounts of SOX9[11].

Role in other diseases
SRY has been shown to interact with the androgen receptor and individuals with XY karyotype and a functional SRY gene can have an outwardly female phenotype due to an underlying androgen insensitivity syndrome (AIS).[19] Individuals with AIS are unable to respond to androgens properly due to a defect in their androgen receptor gene, and affected individuals can have complete or partial AIS.[20] SRY has also been linked to the fact that males are more likely than females to develop dopamine-related diseases such as schizophrenia and Parkinson's disease. SRY encodes a protein that controls the concentration of dopamine, the neurotransmitter that carries signals from the brain that control movement and coordination.[21] Research in mice has shown that a mutation in SOX10, an SRY encoded transcription factor, is linked to the condition of Dominant megacolon in mice. This mouse model is being used to investigate the link between SRY and Hirschsprung disease, or congenital megacolon in humans. There is also a link between SRY encoded transcription factor SOX9 and campomelic dysplasia (CD). This missense mutation causes defective chondrogenesis, or the process of cartilage formation, and manifests as skeletal CD [28]. Two thirds of 46,XY individuals diagnosed with CD have fluctuating amounts of male-to-female sex reversal.

27. Herbarth, B., Pingault, V., Bondurand, N., Kuhlbrodt, K., Hermans-Borgmeyer, I., Puliti, A., … Wegner, M. (1998). Mutation of the Sry-related Sox10 gene in Dominant megacolon, a mouse model for human Hirschsprung disease. Proceedings of the National Academy of Sciences, 95(9), 5161–5165. https://doi.org/10.1073/pnas.95.9.5161

28. Pritchett, J., Athwal, V., Roberts, N., Hanley, N. A., & Hanley, K. P. (2011). Understanding the role of SOX9 in acquired diseases: lessons from development. Trends in Molecular Medicine, 17(3), 166–174. https://doi.org/10.1016/j.molmed.2010.12.001