Genetics: RABGAP1L

[wastwater]

I may have interaction with RAB3GAP and RAB1A does it do a similar thing I wonder,the paper mentions Rapamycin

RAB3GAP1 and RAB3GAP2 modulate basal and rapamycin-induced autophagy - PMC

Macroautophagy is a degradative pathway that sequesters and transports cytosolic cargo in autophagosomes to lysosomes, and its deterioration affects intracellular proteostasis. Membrane dynamics accompanying autophagy are mostly elusive and depend ...

pmc.ncbi.nlm.nih.gov

https://www.sciencedirect.com/science/article/pii/S0006349525000839

Rab3gap1 palmitoylation cycling modulates cardiomyocyte exocytosis and atrial natriuretic peptide release​

 

[ME/CFS Science Blog]

I initially thought that the causal gene(s) for this region on chromsome 1 are too uncertain given how many protein-coding genes are packed in this region. I still think this is the case.

But zooming out, it seems that there might be two independent signals close to each other. A small group of SNPs that is near the significance threshold, but then there's also a longer structure around 10^-6 that seems to correspond to the length of RABGAP1L.



The ones in the RABGAP1L region are no longer in strong LD with the top hit. So perhaps this 'dragon-like figure' of SNPs with p-values around 10^-6 point to the RABGAP1L gene, even if the SNPs with the lowest p-values close to it point to another gene?

 

[forestglip]

A small group of SNPs that is near the significance threshold, but then there's also a longer structure around 10^-6 that seems to correspond to the length of RABGAP1L.

Hmm, I'd be cautious about ascribing similarities in length between a gene and a signal as more than a coincidence.

Here's that area except with LD colors in reference to the top SNP (purple diamond) of that little length of SNPs:


It looks like that's just a stretch of SNPs that are in strong LD with each other, so if one is significant, the rest are as well.

Edit: Corrected chart to use European LD.

 

[ME/CFS Science Blog]

It looks like that's just a stretch of SNPs that are in strong LD with each other, so if one is significant, the rest are as well.

Yes but perhaps they are in strong LD because they are related to the long RABGAP1L gene?

It also looks different from the SNPs that hit the significance threshold close by and which seems more ambiguous (not sure which gene it points to). But the dragonlike-SNPs at 10^-6 probably point to RABGAP1L or GPR52.

 

[forestglip]

Yes but perhaps they are in strong LD because they are related to the long RABGAP1L gene?

I think generally LD is related to where DNA tends to be cut when DNA shuffling is happening during cell division. I'm not sure if there's any relation between regions that tend to stay together and the locations of specific genes, but maybe it happens. I don't know enough to say it's not possible.

Even if that was the case, a significant SNP in that region would make the whole long region significant whether it's causally related to RABGAP1L or any other gene.

It also looks different from the SNPs that hit the significance threshold close by and which seems more ambiguous (not sure which gene it points to). But the dragonlike-SNPs at 10^-6 probably point to RABGAP1L or GPR52.

It's possible. I wouldn't discount that it might just be LD with the same signal as the main locus though.

 

[jnmaciuch]

It also looks different from the SNPs that hit the significance threshold close by and which seems more ambiguous (not sure which gene it points to).

The most significant hit there (1:173,846,152 / rs12071663 ?) seems to sit pretty comfortably in an intronic region of DARS2, looking at UCSC genome browser

I'm not sure if there's any relation between regions that tend to stay together and the locations of specific genes, but maybe it happens. I don't know enough to say it's not possible.

That happened to be a topic for one of the lectures I attended earlier this year--certain regions of the genome can be more or less prone to crossover events due to having a sequence that facilitates things like recruitment of certain DNA excision & repair proteins, or formation of 3D structures in the DNA itself that encourage/discourage crossover. It's definitely possible that certain genes/regions of the genome evolved to have sequences that discourage crossover within that region--which could be because it was advantageous to keep those regions together transcriptionally, or because that sequence happens to create a protein with a certain advantageous structure.

Yes but perhaps they are in strong LD because they are related to the long RABGAP1L gene?

So I think you'd be right to suspect that something about the RABGAP1L gene causes the "dragon" shape. Molecularly, there are probably two "stable" regions there (denoted by the two different LD colors in the dragon) with a small stretch more prone to crossover right between them.

Even if that was the case, a significant SNP in that region would make the whole long region significant whether it's causally related to RABGAP1L or any other gene.

And you'd be right to conclude that as well. We just know that at least one thing in that general region is associated with ME/CFS--best candidate would be the most signficant hit in DARS2, but it could be any of the stretches all in LD with eachother. Looking at the supplementary tables, it seems like the final gene annotation chosen for DecodeME's top SNPs was heavily influenced by number of tissues in the coloc data.

 

[Hutan]

Thanks for the interesting discussion. What do the arrows beside gene names signify in the charts? Some go right and some go left.

 

[jnmaciuch]

Thanks for the interesting discussion. What do the arrows beside gene names signify in the charts? Some go right and some go left.

The arrows indicate which strand of the DNA the gene is actually on, since both strands of DNA encode genes. Sometimes genes can even overlap in the same position on opposite strands, so a given sequence (e.g. ATTACGCA) belongs to gene 1 but the complementary nucleotides for that sequence belong to gene 2 (i.e. TAATGCGT--actually it would be the reverse complement TGCGTAAT because transcription happens in the opposite direction on the opposite strand)

[Edit: More specifically, the arrows indicate which way DNA polymerase travels when the gene is being transcribed, which differentiates the strands]

 

[forestglip]

But the dragonlike-SNPs at 10^-6 probably point to RABGAP1L or GPR52.

Linking to the thread for a fibromyalgia GWAS since there was a signal in the same region and they believe it may be related to GPR52:

The strongest association was with a coding variant in HTT , the causal gene for Huntington's disease. Gene prioritization implicated the HTT regulator GPR52 ,

The two relevant loci in DecodeME, showing that there may be a signal in the HTT region in ME/CFS as well (black triangles are locations of top hits from fibromyalgia):