CASP12 is a pseudo gene in a large part of the population because of a premature stop codon. But some populations in Africa still have the active version without this stop codon. They also have a frameshift in exon three on UCSC Genome Browser that's shared with primates but nonetheless they say it still works. How can this gene still function with a very obvious frameshift (single nucleotide indel) inside the exon? Instead they say the stop codon was the killer a few codons upstream.
- Just an interested citizen scientist.
2 answers
The frameshift is after the stop as I understand your explanation, so the stop would take precedence.
Generally, a frameshift might not affect gene function if it is a false positive (not real, just a technical artifact), or is heterozygous as Pierre says, or maybe not if it at the end of the reading frame. The last depends on the organism with nonsense mediated decay occurring in some.
According to AI - gemini in this case - this CASP12 is a textbook example of alternative splicing with biological tradeoffs (selective advantage) between the various isoforms. So the effect you describe is down to alternative splicing.
gnomAD shows a shorter isoform that would shift the frame-shift into the 3’UTR. Also the gene goes right to left.
Interesting observation nonetheless would be nice to confirm with RNA-seq exactly what is going on.
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could be heterozygous, could be a functional protein that doesn't have an active region in the COOH part of the peptide, could be a non-essential protein ...
Interesting, but I don't believe it could be heterozygous because it seems to be fixed across humans chimps and gorillas. It also seems to be more towards the NH2 part. It could be nonessential but it seems the exon is essential for making the protein because when it has the polymorphic stop codon it stops pumping out proteins, but when it doesn't, it keeps working. But both alleles of the stop codon still have this protein with the frameshift, in the same exon, one works one doesn't.