Lycanthropy—the sudden transformation of individuals into wolf-human chimeras during full moon periods—remains one of the least understood medical conditions persisting today. Researchers find investigation of the phenomenon doubly confounded by social stigma (who wants to tell a scientist that they are a werewolf?) and sampling difficulty (how many werewolves will actually sit still for a medical examination during the full moon?). The consequent lack of scientific information about the condition prevents the development of anti-lycanthropic therapies.
Here I present a list of mRNA splice variants which have plausible connection to werewolf phenotypes, and summarize the hypothesis and analysis used to generate the list. Though the work is conjectural, it offers researchers an a priori estimate of the werewolf transcriptome to support and motivate future investigation.
Competing Interests Statement
To construct a parsimonious hypothesis for the werewolf phenotype:
Assume a werewolf’s genome is indistinguishable from a normal human genome, save for possibly a few small retrovirus-related insertions. This reflects the thinking that a lycanthrope requires a human genome to experience “normal” human phenotypes when the nighttime full moon is absent (the majority of their lives).
Assume a werewolf’s mRNA expression outside of nighttime full moon periods is indistinguishable from “normal” human mRNA expression, with the possible exception of mRNA that codes for a protein-based nighttime full moon sensor. I base this on the idea that “normal” phenotypes experienced by lycanthropes during the day can only result from “normal” mRNA expression.
Assume that during the nighttime full moon, a werewolf’s mRNA transcription emits from the same genes as it does during other times. This reflects the idea that a change in how the genes are expressed is a more succinct explanation for the phenomenon than a change in which genes are expressed. This leads us to alternative splicing:
Suppose that for each gene in a subset of human genes there exists a splice variant that is more “canine” than the other splice variants associated with the gene.
Hypothesis: When the more “canine” splice variants of each of these genes express simultaneously and abundantly, the werewolf phenotype appears. One or more molecular mechanisms which respond to lunar phase and the absence of daylight modulate the overall expression of these particular splice variants.
At present, the lack of measured werewolf transcriptome data due to the research challenges listed above prevents testing of the hypothesis. However, since the idea is one of the few available scientific conjectures on the subject, I’ll call it “expert opinion” and build an a priori transcriptome estimate out of it:
Retrieved a list of human and canine gene IDs from NCBI’s “gene info” file, matched by gene symbol:
Retrieved all the “NM” mRNA transcripts associated with these gene IDs from RefSeq. Ignored “XM” transcripts since they are predicted sequences rather than verified ones (but who am I to talk?!?).
Ignored all gene symbols having only one human “NM” transcript associated with it, since this leaves no splice variants to sort by how “canine” they are.
Ignored all gene symbols having two or more canine “NM” transcripts associated with it (nine out of 1087 total gene symbols having at least one canine “NM” met this condition). Made this decision for computational convenience, given that this work is very “back of the envelope” in style. Future investigation should include these cases.
For each canine/human homologous gene pair (from the gene symbol match described above), I locally aligned each of the human NM transcripts associated with the gene symbol to the canine NM transcript associated with the gene symbol, and then ranked the human transcripts by their similarity to the canine transcript. Measured relative sequence similarity by bit score ratio, the bit score of each alignment divided by the bit score of the canine NM transcript aligned with itself. Demonstrating this process for gene ANKHD1:
If the highest similarity human splice variant for the gene had an alignment bit score ratio exceeding the next highest human splice variant’s bit score ratio by 0.25 (chose this value arbitrarily), I selected the variant as a plausible member of the set responsible for lycanthropic transformation.
Using this method, I identified 35 genes having a human mRNA splice variant that is measurably more “canine” than the other human mRNA variants in the gene model:
Future Directions for this Research
I highly encourage Big Pharma to drop everything they are working on, synthesize molecules designed to specifically attenuate each of these 35 splice variants, and ship them to my house before November 10th.