Animal research is vital for understanding and treating diseases in humans, and we’re not just talking about preclinical drug trials. Studying diseases in animals can provide important insights into their mechanisms, help us understand their environmental and genetic risk factors, and provide clues as to how they can be tackled in humans. Such research is more valuable in species that are similar to humans, both physiologically and genetically. Organisms that share the same set of organs and suffer from the same diseases as us are more valuable for obvious reasons.
At least as far as mammals go, mice have been the stars of scientific animal research. They are small, easy to maintain, have a short life cycle, and share many genetic similarities with humans. On average, the mouse genes that code for proteins are 85% identical to those of humans, with some genes being up to 99% identical. However, shared genetic sequences aren’t everything. The way in which the genome is organised (factors such as the order of genetic elements within the genome, their division into chromosomes, as well as the regions of non-coding DNA separating them) has important effects on how genes are expressed.
It turns out that mouse genomes are organised very differently to our own. During the 80 million years since our common ancestor, the mouse has ‘shuffled’ its genome like a pack of cards, rendering it quite unusual compared with most other mammals. Furthermore, mice and humans share only around 50% of their non-coding DNA, which makes up about 95% of the human genome. Most lab mice are far less genetically diverse than humans due to many generations of controlled breeding. All this isn’t to say that mice aren’t still excellent models for studying human disease, but they are not ideal genetic counterparts, making them less useful for helping us understand how our own DNA is packaged and how this can affect our health.
The genomes with the most similar organisation to our own can unsurprisingly be found among non-human primates. Besides these, cats are one of the closest organisms to humans in terms of how their genomes look and behave – closer than dogs which, like mice, have seen their genomes ‘reshuffled’ during their evolutionary past. This means that if we can understand how genetic traits of the cat affect its health, that understanding is more likely to translate to humans, as are drugs aimed at treating diseases common to both cats and humans. One existing example of this is remdesivir, an important drug for fighting COVID-19 that was first successfully used against a cat disease caused by another coronavirus.
Such studies don’t necessarily require cats to be kept in a lab, as a blood sample or cheek swab is often all that is required for genomic research. Like dogs, cats living alongside humans are exposed to very similar environmental factors, making them even closer analogues of human disease (though dogs do admittedly tend to be more eager to work with humans). There is therefore plenty to be learnt simply by studying the diseases that domestic cats develop naturally during their lives. For example, cats develop cancer less frequently than dogs and humans, and there may be clues in the cat genome as to why this is the case.
Cat’s have typically been undervalued in science in favour of mice and dogs. While unlikely to ever surpass the mouse, cats have been catching up to their canine rivals thanks to the efforts of the small but efficient cat research community. The 99 Lives Cat Genome Sequencing Initiative recently produced the most detailed domestic cat genome to date, surpassing that of the dog. Leslie Lyons, the director of the initiative, also just wrote a paper on the value of cat genomics. The eventual goal is to understand the genetic basis for all traits in the cat, producing a complete ‘encyclopaedia’ of the cat’s DNA.
Cats have already helped us to figure out the details of a fascinating genetic phenomenon called lyonization. Named after its discoverer Mary Lyon, lyonization is more commonly known as X chromosome inactivation, and occurs in almost all female mammals (including humans). Females inherit two copies of the X chromosome, but only one is active within each cell. Tortoiseshell and calico cats are perfect examples of lyonization, as their fur patterning is the result of the inactivation of X chromosomes carrying genes that determine fur colour. Each cat X chromosome can carry a gene variant encoding either black fur or orange fur, leading to the following three combinations:
The first two combinations will result in orange fur and black fur respectively, regardless of which X chromosome is inactivated. However, the the third combination will result in a pattern of orange and black patches, since which gene variant is expressed varies throughout the cat – this is called a tortoiseshell pattern.
A calico cat is a specific type of tortoiseshell that also has white fur – this is due to a separate autosomal gene (not located on a sex chromosome) that supresses fur colouration by slowing the migration of the pigment-producing cells.
Calico cats have helped establish two important components of Lyon’s theory: that lyonization is very stable (inactivated X-chromosomes don’t reactivate, including when they are replicated during cell division), and that it occurs early during embryonic development. This is why calico cats have reasonably large, separate patches of fur colour, rather than an even mix of colours across their coats.
The stability of X inactivation is also evident in the first cloned cat, CC (for Copy Cat or Carbon Copy, depending on who you ask). CC was cloned by taking the nucleus of a cell from a calico cat named Rainbow, and transferring it into an egg cell, which was then implanted into a surrogate mother. Despite being a genetically identical copy of rainbow, CC was not born a calico, having no orange patches at all. This was because the X chromosome carrying the orange fur variant happened to be inactivated in the nucleus used to clone rainbow, and that inactivation was conserved throughout the entire cloning process and embryonic development.
Understanding the cat’s genome could tell us a lot about our own genetic makeup and how we might treat diseases in humans, but it’s worth stressing that such research won’t just benefit us, but our cats as well. We want our pets to live healthier and longer lives too, and a better understanding their genetic makeup will only improve veterinary medicine.
Why Mouse Matters: https://www.genome.gov/10001345/importance-of-mouse-genome
The Genetics of Calico Cats: http://www.bio.miami.edu/dana/dox/calico.html
X-INACTIVATION - A CAT STORY: https://kalantry.lab.medicine.umich.edu/research/calico-cat
The Unappreciated Importance of Cats (to Medical Science): https://www.nytimes.com/
A new domestic cat genome assembly based on long sequence reads empowers feline genomic medicine and identifies a novel gene for dwarfism: https://doi.org/10.1371/journal.pgen.1008926
One More Thing We Have in Common With Cats: https://www.theatlantic.com/science/archive/2021/07/cat-genomes/619587/
Cats – telomere to telomere and nose to tail: https://doi.org/10.1016/j.tig.2021.06.001
A cat cloned by nuclear transplantation: https://doi.org/10.1038/nature723
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