Crowdfunded whole-genome sequencing of the celebrity cat Lil BUB identifies causal mutations for her osteopetrosis and polydactyly
Preprint posted on February 22, 2019 https://www.biorxiv.org/content/10.1101/556761v1
(This preprint was highlighted by Jesus Victorino with the help of Gabriel Aughey)
Rare diseases are a group of disorders that have a low incidence in the population, which often implies reduced interest from public and private entities and, therefore, limited diagnosis and treatment of affected patients.
In this study, Bridavsky et al. describe the genome sequence of Lil BUB, a celebrity feline with almost 3 million Facebook followers. Lil BUB has a unique appearance thought to be due to her diagnosed osteopetrosis: a diminutive stature, a distinctive protruding tongue together with a form of polydactyly that makes her have 6 toes on each front paw – all of which contribute to her mass appeal (Fig.1).
Whole-Genome Sequencing (WGS) was performed thanks to a crowdfunding initiative to fund the study while engaging the public. After sequencing, the authors were able to identify two different mutations, showing that Lil BUB presented not one but two different rare diseases: a homozygous allele for the osteopetrosis phenotype and a polydactylyl allele in heterozygosis.
In this preprint, the authors discover the genetic basis of Lil BUB’s unique phenotypes and furthermore, demonstrate the power of crowdfunding in not only accomplishing scientific goals, but also for public engagement and science dissemination.
Figure 1. Lil BUB complex phenotype showing dwarfism (A), short skull and tongue (B), polydactyly (C) and bone defects in forelimbs (D)(taken from figure 1 of the preprint).
Successful crowdfunding campaign
Whilst the majority of scientific funding is obtained from competitive grants, Lil’ Bub’s status amongst the internet’s most venerated cats afforded the authors an opportunity to experiment with alternative funding streams for this project. Therefore, the authors embarked on a crowdfunding campaign to cover the costs of sequencing Lil Bub’s genome. Not only was the crowdfunder financially successful (raising over $8000), the opportunity to effectively engage the public with science was also exploited. The authors communicated the aims and progress of the project via various social media platforms, thereby demonstrating that the crowdfunding model can come with societal benefits beyond just the funding of novel research.
Lil BUB phenotype is caused by two independent mutations
Osteopetrosis and polydactyly are both rare diseases that have not been linked to one another in humans or cats. Whether Lil-BUB had been affected by an unusual case of osteopetrosis that included polydactyly or by two different rare diseases at the same time was uncertain and this study aimed to answer this and find the genetic causes of her symptoms.
Whole-Genome Sequencing (WGS) was performed and revealed a heterozygous mutation in the limb enhancer of the Sonic hedgehog gene, already known to be linked to dominant polydactyly in mammals. Osteopetrosis, however, seemed to be caused by a homozygous recessive allele in the TNFRSF11A gene encoding a truncated version of the transmembrane receptor RANK.
Why we like this preprint
The identification of causal mutations in precision medicine constitutes the ultimate goal of NGS-mediated personalized diagnosis. However, due to our restricted knowledge of the genome, determining the clinical significance of mutations in probands is limited to previous reports on similar cases.
We chose this preprint because it is an example of how precision medicine can help fine-tuning a phenotype-based diagnosis thus leading to a more accurate description of a patient’s disease and, if possible, an improvement in the treatment. In this case, Lil BUB’s acute phenotype was the result of two different rare diseases.
Moreover, this work is a beautiful combination of how the creativity and enthusiasm of a committed group of scientists took over possible money burdens and launched an initiative that allowed them not only to fulfill their research purposes, but to reach an audience of tens of thousands of people, who they kept engaged and updated with their scientific advances.
Questions for the authors
– Lil Bub’s celebrity status was clearly important for a successful crowdfunding campaign. Do you think it would be possible to fund a project like this without the existing fanbase that Lil Bub brought with her?
– Are you considering crowdfunding as a periodic way of funding some of your research projects? Would there be a potential danger for projects to become too biased on mediatic research?
– After the success of this research, how do the authors envision the future of crowdfunding in science? Could there be too many projects trying to use this strategy and, thus, many of them fail to succeed?
– What would be the advice for young motivated researchers who want to get both funding and public engagement?
– Many different mutations affecting the ZRS limb enhancer cause ectopic anterior expression of the Shh gene and UK1, UK2 and Hemingway mutations are examples of that . Is it known which transcription factor/s bind the ZRS enhancer? Do the authors think the different mutations affect the same putative binding site?
– ZMPSTE24 is a metalloprotease involved, among other things, in Lamin A maturation and knockout mice have been studied due to the similarities with phenotypes of patients with Progeria syndrome, showing strong phenotypes in mice when in homozygosis . In Hutchinson-Gilford Progeria Syndrome (HGPS), a heterozygous point mutation affecting a splicing site in LMNA gene that impairs correct Lamin A maturation and causes premature aging. However, while in humans this mutation appears spontaneously and causes severe phenotypes in heterozygosis, the equivalent mutation in mice confers the strong phenotype when the animals are homozygous . Due to the differences in the phenotype effect of heterozygous and homozygous mutations in human and mouse, we were wondering whether the heterozygous loss-of-function allele of ZMPSTE24 has been reported in cats and if the allele found in Lil BUB’s genome could be contributing to her congenital malformations.
- Lettice LA, Hill AE, Devenney PS and Hill RE. 2008. Point mutations in a distant sonic hedgehog cis-regulator generate a variable regulatory output responsible for preaxial polydactyly. Hum Mol Genet. 17, 978-985.
- De la Rosa J, Freije JMP, Cabanillas R, Osorio FG, Fraga MF, Fernandez-Garcia MS, Rad R, Fanjul F, Ugalde AP, Liang Q, Prosser HM, Bradley A, Cadiñanos J, Lopez-Otin C. 2013. Prelamin A causes progeria through cell-extrinsic mechanisms and prevents cancer invasion. Nat Comm. 4:2268.
- Osorio FG, Navarro CL, Cadiñanos J, Lopez-Mejia IC, Quirós PM, Bartoli C, Rivera J, Tazi J, Guzman G, Varela I, Depetris D, de Carlos F, Cobo J, Andres V, De Sandre-Giovannoli A, Freije JMP, Levy N, Lopez-Otin C. 2011. Splicing-Directed Therapy in a New Mouse Model ofHuman Accelerated Aging. Sci Transl Med. 3, Issue 106, pp. 106ra107.
Posted on: 21st March 2019 , updated on: 23rd March 2019Read preprint
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