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The last chapter of Xinxin’s thesis is now on @biorxivpreprint. 1/n https://twitter.com/biorxivpreprint/status/1297409581342167040">https://twitter.com/biorxivpr...
It describes a follow-up to @ClarissaCParker’s GWAS in outbred CFW mice, which identified a locus for methamphetamine sensitivity that colocalized with a cis-eQTL for the gene Azi2. 2/n https://pubmed.ncbi.nlm.nih.gov/27376237/ ">https://pubmed.ncbi.nlm.nih.gov/27376237/...
In this paper, XInxin used CRISPR/Cas9 to make a frameshifted (null) Azi2 allele and found that additional copies of the null allele were associated with greater sensitivity to methamphetamine. Those data support the GWAS data, right? 3/n
Well, almost.
The trouble is, the eQTL allele that caused increased Azi2 expression caused increase methamphetamine sensitivity. But we found that killing Azi2 increased sensitivity, that’s backwards. 4/n
The trouble is, the eQTL allele that caused increased Azi2 expression caused increase methamphetamine sensitivity. But we found that killing Azi2 increased sensitivity, that’s backwards. 4/n
Some of you will remember that we (and many others) have previously shown that strain background can flip the effect of an allele. In this case, we discovered Azi2 in CFW but made the mutant on B6. I don’t like it, but I don’t have anything better... 5/n https://youtu.be/x0wNnN7gEgA ">https://youtu.be/x0wNnN7gE...
We also went down a rabbit hole trying to replicate previously reported inhibition of Slc6a3 by Azi2 (Slc6a3 encodes the the dopamine transporter, which is the target of methamphetamine). Sadly, we didn’t see any correlation between the two. 6/n https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886844/">https://www.ncbi.nlm.nih.gov/pmc/artic...
We used RNASeq to explore gene expression differences in Striatum and VTA in the Azi2 mutants. As you’d expect, some other genes are impacted, some interesting pathways, but no smoking gun. 7/n
So, does showing that Azi2 alters methamphetamine sensitivity support the GWAS finding, even if the direction is opposite? How much less convincing is it when the direction is opposite? Or is opposite worse than no effect? I don’t think I have formed an opinion yet. 8/n
I think more whole animal studies following up on mouse and human GWAS are critical for harvesting biological insights.
Congratulations to Xinxin Zhou, who defended last week.
Thanks also to @TeleseFrancesca who is a coauthor and was one of Xinxin’s committee members. 9/9
Congratulations to Xinxin Zhou, who defended last week.
Thanks also to @TeleseFrancesca who is a coauthor and was one of Xinxin’s committee members. 9/9
*please forgive me! “...following up on mouse, RAT, and human...”
http://www.ratgenes.org"> http://www.ratgenes.org
http://www.ratgenes.org"> http://www.ratgenes.org
