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Write an introduction about the significance and background, focusing on the role of X-inactivation in disease, specifically how patterns of X-inactivation in the placenta may affect gene expression that correlates with autism pathogenesis.

Write an introduction about the significance and background, focusing on the role of X-inactivation in disease, specifically how patterns of X-inactivation in the placenta may affect gene expression that correlates with autism pathogenesis.
Follow the outline:
1. The role of serotonin in autism pathology
2. Gene expression in the placenta
a. Between patient/control
b. Between male/female offspring
c. Across species
3. X-inactivation and autism predisposition or development
4. Patterns of X-inactivation in the placenta (this is what we want to do this research about)

The following papers are sources that you can read and add on to this. You need to include the main related significant information that I wrote below:

Individuals with Autism Spectrum Disorder had more mono-allelic expression on both autosomes and the X chromosome than controls (Ben-David, Shohat, and Shifman, 2014)
Methods
X-inactivation informs variance-based testing for X-linked association of a quantitative trait (Ma, Hoffman, Keinan, 2015).

A sensitive assay for not only the presence/absence of X-chromosome inactivation, but also the level of escape from inactivation of a particular allele can be incorporated into tests for associations of X-linked alleles with quantitative traits (Ma, Hoffman, Keinan, 2015).

Using next-generation RNA sequencing to identify imprinted genes – Wang and Clark, 2014
Lays out problems with differential allele expression – READ THIS (important)

A study of human embryonic stem cells, those with skewed X-inactivation showed preference towards X-chromosomes with the wild-type allele (Liu et al, 2015).

Whole transcriptome RNA analysis may be more sensitive than detection of only the XIST allele, given evidence that gene reactivation on the inactive X chromosome precedes loss of XIST coating (Vallot et al, 2015).

Allelic imbalance is a prevalent and tissue-specific feature of the mouse transcriptome (Pinter et al, 2015)
As many as 20% of genes in the mouse genome exhibit some level of allele-specific expression, in addition to known imprinted genes (Pinter et al, 2015).

Specifically, allelic imbalance across mouse populations is primarily attributed to genomic variation (Pinter et al, 2015); similar population-specific variation is expected across humans.

Analysis of X chromosome inactivation in human embryonic stem cells reports that the average size of Copy Number Variants was twice as high in cell lines with skewed inactivation (Luo et al, 214).

Although genetic males (with one hemizygous X chromosome) are more often susceptible to X-linked disorders than genetic females (who have two copies of the X chromosome), equal susceptibility can occur in genetic females who exhibit extreme skewing of the X-chromosome and are only able to express the disease-causing allele (Holle et al, 2015).

Single-cell XIST expression in human preimplantation embryos: oocyte through embryo transition.
“We show that XIST is first expressed beginning at the 4-cell stage, coincident with the onset of embryonic genome activation in an asynchronous manner. Additionally, we report that mRNA reprogramming produces iPSCs that initially express XIST transcript; however, expression is rapidly lost with culture. Loss of XIST and H3K27me3 enrichment at the inactive X chromosome at late passage results in X chromosome expression changes.” – Briggs and Dominguez, 2015

Individuals with Autism Spectrum Disorder had more mono-allelic expression on both autosomes and the X chromosome than controls (Ben-David, Shohat, and Shifman, 2014)

Brooks and Renaudineau, 2015

From TCGA dataset, Loss of XCI is common in high grade serious ovarian adenocarcinomas, and loss of XCI results in aberrant expression of cancer-testis antigenes, which may play a role in increased tumor aggression (Kang et al, 2015).

Loss of XCI is thought to have an oncogenic effect in hematologic malignancy in mice [2]. It is also observed in human breast and ovarian cancers [3–5].

[2]
Yildirim E, Kirby JE, Brown DE, Mercier FE, Sadreyev RI, Scadden DT, et al. Xist RNA is a potent suppressor of hematologic cancer in mice. Cell. 2013;152(4): 727–42. doi: 10.1016/j.cell.2013.01.034. pmid:23415223

[3-5]
3. Pageau GJ, Hall LL, Ganesan S, Livingston DM, Lawrence JB. The disappearing Barr body in breast and ovarian cancers. Nature reviews Cancer. 2007;7(8):628–33. doi: 10.1038/nrc2172. pmid:17611545

4. Cheng PC, Gosewehr JA, Kim TM, Velicescu M, Wan M, Zheng J, et al. Potential role of the inactivated X chromosome in ovarian epithelial tumor development. Journal of the National Cancer Institute. 1996;88(8):510–8. pmid:8606379 doi: 10.1093/jnci/88.8.510

5. Benoit MH, Hudson TJ, Maire G, Squire JA, Arcand SL, Provencher D, et al. Global analysis of chromosome X gene expression in primary cultures of normal ovarian surface epithelial cells and epithelial ovarian cancer cell lines. International journal of oncology. 2007;30(1):5–17. pmid:17143508 doi: 10.3892/ijo.30.1.5

Timing of X chromosome inactivation
The pattern of XCI is remarkably different between humans and mice (reviewed in Fan and Tran, 2011).
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3965368/

Patterns of X chromosome inactivation vary significantly across undifferentiated female human embryonic stem cells derived from inner cell mass of the blastocyst stage embryo, but this may be due to selection of the cell line (Dvash, Lavon and Fan).


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