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Cats’ Genomes Make Them Good Models for Human Disease

Over the years, I’ve shared my home with 17 felines. Several have perched on my printer while I cranked out many articles and books on genetics.

Little did I know that the genome of Felis catus is subtly similar to my own. Now, the aptly named Leslie Lyons, an associate professor at the University of Missouri Department of Veterinary Medicine & Surgery, has published an article in Trends in Genetics, “Cats – telomere to telomere and nose to tail, that makes the case for cats as models of human disease. (Telomeres are chromosome tips.)

“Approximately 33% of households in the USA own a cat, and as pets, cats have evolved from vermin control to beloved family members,” Lyons writes. In the US, 42.7 million households include at least one feline.

Cats Are More Genetically Diverse Than Us

I’ve always been amazed at genome analyses that indicate species that are more genetically diverse than we are, when one chimp looks more or less like another to us. Cats are more genetically diverse than us, too.

The first genome sequence of a domestic cat was published in 2007. That individual was a 4-year-old Abyssinian named Cinnamon, whose lineage traces back several generations to Sweden.

Human and cat genomes each have about 20,000 protein-encoding genes, of which nearly 16,000 are nearly identical between them and us. That correspondence reflects descent from a shared mammalian ancestor from which all cats and humans diverged about 65 million years ago. Forty-two cat species exist today.

Domestic cats have 19 pairs of chromosomes to our 23. Cat chromosomes have distinctive sizes, so they’re easier to study than human chromosomes, several of which are the same size and challenging to distinguish. But comparing chromosomes isn’t really informative – they’re just the structures that carry genes. It’s a little like comparing buildings by their appearance rather than by the characteristics of their occupants.

More informative than aligning chromosomes from the two species is analysis of sites in the genomes where the DNA base could be any of the four building blocks A, T, C, or G. These points of variation are called single nucleotide polymorphisms (SNPs) or single nucleotide variants (SNVs). One study of the genomes of 54 unrelated cats revealed high genetic diversity, with each animal’s genome harboring about 10 million SNPs. A human genome has only 4 to 5 million. So anyone who thinks all tabbies look alike isn’t appropriately appreciating the genetic variability of the species.

Similar Genome Organization

Similarities between cat and human genomes are subtle. “The dog or mouse genome has rearranged chromosomes that are quite different than humans, but the domestic cat has genes that are about the same size as humans, as well as a genome that, like humans, is very organized and conserved,” said Lyons. Cat and human genes are also similarly spaced along their chromosomes.

In evolutionary biology, “conserved” DNA sequences are those that are identical, or almost identical, in two species. The fact that these gene sequences have not changed much over time means that they are essential – if it ain’t broke, evolution doesn’t fix it. Individuals with mutations in those genes don’t survive to reproduce, so the conserved sequences persist.

Considering cat genomes could be especially important in mining the so-called “genetic dark matter” that makes up the bulk of our genomes. Dark matter includes vast stretches of short repeated DNA base sequences, which don’t encode protein, as well as sequences that control a protein’s production or interrupt coding sequences as introns. Some genetic diseases of our feline friends arise from the dark matter and so the animals could serve as models of corresponding human diseases. For example, cats that have white spots and are deaf harbor bits of inserted DNA in a non-coding part of a gene called KIT. The human version of the gene is an oncogene (causing cancer when over-expressed). Dark matter also determines how chromosomes fold, which regulates gene expression.

From Rare Single-Gene Diseases to Cat Alzheimer’s

Cats have already left their mark on human health. For example, a coronavirus infection in cats causes feline infectious peritonitis, which leads to an overwhelming, fatal immune response in about 10 percent of cases. Research on the cat condition led directly to the development of remdesivir to treat COVID.

The 99 Lives Cat Genome Sequencing Consortium has identified 88 feline genes that are associated with diseases, about a dozen of which are known to cause rare genetic conditions in people. These include:
• A form of dwarfism
• A form of retinal blindness
• Polycystic kidney disease
• Several types of mucopolysaccharidoses
• Niemann Pick disease type C1
• Glycogen storage disease IV
• Porphyria
• Leukocyte adhesion deficiency

More common conditions may affect cats and us too. “The domestic cat as a natural animal model of Alzheimer’s disease” in a neurology journal caught my attention. The brains of people with Alzheimer’s disease have abundant amyloid-beta plaques and neurofibrillary tangles, but most other mammals have the first but not the second. Cats develop both amyloid-beta plaques and neurofibrillary tangles, plus a pattern of nerve cell loss that is similar to the situation in people with Alzheimer’s.

Dementia in cats is called “feline cognitive dysfunction.” Our Babycat received that diagnosis not based on his plaques or tangles, but on the observation that each night he’d howl piteously at a corner of our bedroom ceiling.

Cats Won’t Let It Happen

Lyons thinks cats would make valuable model organisms. “Working with a primate is on the expensive side, but a cat’s affordability and docile nature make them one of the most feasible animals to work with to understand the human genome.”

I’m not so sure about that. My youngest feline, Milton, would go ballistic if a white-coated human attempted to stuff him into a box or approached him with a needle. Are anyone’s kitties “docile” when visiting the vet, unless they are catatonic with terror? Lyons also helpfully points out that cats have been cloned, which might be valuable for repeating experiments, but I don’t imagine we would ever face a shortage of felines requiring intervention to mass-produce them.

So will cats replace mice, monkeys, and lab rats? From the 17 felines I’ve lived with, I can’t imagine how this would ever happen.

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