Lil Bub is a star on social media due to her idiosyncratic looks. Now a US-German team of biologists reports that a combination of two rare genetic changes has been discovered in the cat’s genome. The sequencing of the genome was financed by crowdfunding.
Lil Bub has her own website and Instagram channel. Probably thanks to its unusual appearance, millions of people want to participate in the life of the small cat. Their growth stopped at the age of seven months. Her snout is shortened, her tongue hangs out and she has extra toes on each paw. She has also been diagnosed with “marble bone disease” (infantile malignant osteopetrosis), a rare condition in which bone density increases with age. This notoriety is used by the team behind Lil Bub to raise money for animal shelters, animal welfare organizations and cats to help in need.
The money for the sequencing of the cat’s genome was also collected by fans through crowdfunding. More than 7,000 euros were donated over 45 days. The results have been available on the bioRxiv preprint server since the end of February in the form of a non-externally peer-reviewed specialist article. The peer review process, including publication in an open access journal, is to follow soon. The researchers from the Max Delbrück Center for Molecular Medicine in Berlin, the Max Planck Institute for Molecular Genetics in Berlin and the University of Pennsylvania in the USA also report on their work in a blog they have set up for this purpose.
The genetic analysis revealed that the cat has two different, rare changes in its DNA. One is responsible for the development of the extra toes (polydactyly), the other for the bone disease (osteopetrosis) that also results in their small size and short snout. The first change is known in cats. It affects the regulation of the so-called Sonic Hedgehog gene. The cats of the writer Ernest Hemingway also have an identical variant of this gene. They are famous for having six toes on their front paws. About fifty descendants of these cats still live in the Ernest Hemingway Museum in Key West, Florida, USA.
Finding the genetic change that causes Lil Bub’s osteopetrosis took a little longer: an initial analysis of her genetic material revealed around six million possible differences between Lil Bub’s genome and the cat reference genome. Normally, in a second step, the researchers would have compared Lil Bub’s genome with that of her healthy relatives – but that was not possible in this case: she is an orphan. With the help of experts specializing in diseases of the human skeletal system, the number of variants was later narrowed down. Eventually, it turned out that a single base was missing from a gene that had previously been linked to osteopetrosis in humans and mice. The frameshift affects a gene called RANK/TNFRSF11A, which is required for proper osteoclast function. This is one of the two types of cells responsible for remodeling bones throughout life. The mutation creates an imbalance between bone formation and bone resorption, so that ultimately too much and too dense bone tissue is formed.