貓科基因組醫學能夠解讀人類不確定意義的變異（VUSs）。端粒到端粒的基因組組裝技術適用於所有貓科物種，這支持了遺傳進化與物種形成的研究。與人類相比，貓科動物高度保守的基因組結構表明，牠們可能也能解讀影響三維染色體結構並調控基因的基因間變異。
https://www.cell.com/trends/genetics/fulltext/S0168-9525(21)00142-6
Keywords
Semidomesticated hypercarnivores (see Glossary), domestic cats are bioproxies for human agricultural development and our postagrarian migrations. These critters are often underfoot but are also the keynote predatory species and at the top of the food chain in diverse ecological niches, whether wild, rural, or urban. Darwin, Haldane, Searle, and other early geneticists recognized that cat pelage phenotypes supported Mendel’s laws and other basic genetic principles. Cats have also helped decode more complex genetic concepts including lyonization, X-inactivation, and methylation because of their X-linked Orange coat coloration and since the first cloned cat, Cc, did not come out as the expected coat coloration [1]. The coat patterns and colors of domestic and wild species of cats exemplify intricate biological pathways, demonstrating that not one of the ~20 000 genes in our mammalian genomes stands alone. Feline leukemia virus gave us our first clues into cancer etiology and the consideration of hybrid cats nearly a half century ago [2], and more recently, the nucleoside-analog-based remdesivir proving highly effective in combating the COVID pandemic was firstly shown to cure a previously fatal coronavirus-induced disease in cats, feline infectious peritonitis [3]. Quelled enthusiasm by the scientific community has historically meant cats have been perhaps a pace behind with their genetic and genomic resources. However, the cat research community may be small but is efficient and has, for arguably fewer funds and personnel, helped cats to effectively leap forward in genomics, showing new promise in supporting genomic medicine, gene regulation, and speciation studies and the development of therapeutics for use by humans and animals.
Precision/genomic medicine is now feasible in veterinary healthcare, especially for domestic cats. Approximately 33% of households in the USA own a cat, and as pets, cats have evolved from vermin control to beloved family members. With increasing vigilance, cat owners are escalating their expenditures for their cats’ veterinary care, whether the cat is one of the 10% representing a fancy breed or the 90% representing a randomly bred alley cat. Whole genome sequencing (WGS) and whole exome sequencing (WES) are available for domestic cats as genomic diagnostic tools for their healthcare via the community-based 99 Lives Cat Genome Sequencing Consortium [4,5]. Consortium studies are defining new disease variants for well-recognized disease genes, thereby supporting established biomedical models, such as Niemann–Pick disease type C [6]; new variants in new genes for known diseases, such as disproportionate dwarfism, thereby providing new genetic considerations for undiagnosed patients [7]; and new variants for new diseases of conserved biological processes, such as brain development or cell migration and differentiation [8]. The cat’s genomic tools and the 99 Lives Consortium have led to more rapid identification of causal disease and trait variants in cats, hence naturally occurring biomedical models, with ~84 mutations causing diseases under negative selection and 44 desired variants under positive selection in cats and at least seven variants influencing one blood group (https://omia.org) (Figure 1). Analyses of only 54 unrelated cat genomes and the production of the cat reference assembly V9.0 suggests cats have high genetic diversity, with 36.6 million biallelic single nucleotide variants (SNVs) in which individuals carry ~9.6 million SNVs each. Conversely, humans roughly carry 4 to 5 million SNVs per individual [4]. Variant effect prediction shows that 128 844 SNVs of the 36.6 million are synonymous, 77 662 missense, and 1179 loss of function (LoF). With hundreds of thousands of human genome sequences for comparison, deciphering DNA variants causal for diseases, traits, conditions, and behaviors is still an elusive process, leading to a plethora of VUSs that mar the decoding of causal variants. The vast cat genetic variation should be used in a comparative genetics approach. Genetic constraint can be expressed as the probability of LoF intolerance (pLI), implying specific genes have more or less tolerance to variants causing a significance loss of their protein’s function. The 15 962 direct cat–human orthologs share similar levels of pLI, suggesting variant prediction combined with pLI could support VUS prioritization [4]. The increasing DNA variant WGS and WES datasets produced during veterinary healthcare not only support the discovery of the feline causal variants for traits, conditions, and biomedical models, but their innocuous variants also have value and can be compared to human VUS databases, potentially deciphering VUS functions and influencing their priority for further investigation.
‘Dark matter’ – whether 85% of the universe or 98% of mammalian genomes – clouds the understanding of our state of being. Approximately 10% of the noncoding regions within the ‘dark matter’ of the genome are conserved across species, suggesting these sequences have some control over form and function, biology and physiology, and behavior and temperament. Besides decrypting VUSs, cross-species genomic comparisons are enlightening some of the functions of noncoding sequences, supporting the identification of regulatory sequence motifs. For an example in cats, dominant White, which is associated with deafness and white Spotting, which is associated with domestication, are traits caused by an ~800 bp and ~8 kb insertion into intron 1 of the KIT gene, respectively (OMIA 001737-9685, 000209-9685, 001580-9685). Although not an intergenic variant, the disruption of intronic sequences and noncoding sequences suggests that this variant influences gene regulation and overall melanocyte production and migration. Since hundreds to thousands of genome sequences are now being produced for many species, including domestic cats, pangenome assemblies [9], which represent both SNV and structural variation, will help decipher inter- versus intraspecies genomic variation and whether the variation controls interspecies evolution and speciation versus intraspecies phenotypes and diseases.
Cats, felids, the family Felidae, are represented by ~42 species, diverging from other mammals, including humans, ~65 million years ago (www.iucnredlist.org). Cats have easily distinguishable chromosomes that can be readily flow sorted, thus facilitating somatic cell hybridization mapping and chromosome painting [10]. These gross mapping techniques demonstrate the cat genomic organization is a strong proxy for most feliform carnivores [11]. Syntenic blocks of genes on the 23 human chromosomes are more extended in the 19 cat chromosomes in comparison to other common mammalian model organisms such as mice, rats, dogs, and pigs. Additionally, the first phased, haploid-based genome assemblies of F1 hybrid felids highlight the potential of the genomic investigation of the family Felidae, particularly for evolution and speciation [12]. Genome assemblies for the domestic cat and the Asian leopard cat (Prionailurus bengalensis) are robust with N50 scaffolds of 147.6 and 148.6 Mb and 71 and 83 total scaffolds, respectively, indicating the success of the assembly of complex repeat regions. A variety of hybrids produced by natural matings of domestic cats are available, such as crosses with the Geoffroy’s cat, (Oncifelis geoffroyi), servals (Leptailurus serval), and jungle cats (Felis chaus) or lions (Panthera leo) crossed with tigers (Panthera tigris), producing the liger, suggesting many felid phased genome assemblies are possible. In addition, reproductive techniques developed for wild felid conservation could support additional cat genome assemblies since any felid sperm will fertilize a domestic cat oocyte; thus, hybrid cell lines from disrupted embryos could be expanded to provide sufficient DNA for WGS. Thus, like the human telomere-to-telomere consortium (sites.google.com/ucsc.edu/t2tworkinggroup/home), even longer-read technologies suggest assembly scaffolds will soon encompass complete chromosomes, telomere-to-telomere. Since haploid-based phased genome assemblies are feasible for every cat species, telomere-to-telomere genome assemblies may cover the family Felidae – nose to tail.
People tend to either love them or hate them, and cats are often underappreciated by the scientific community. Will the species with conserved genomic organization with humans, or the species with less genome conservation, help resolve gene regulation via the similarities and differences in the 3D structures created in the intergenic or intragenic sequences? Felids could be the optimal species to enlighten the human genome’s dark matter. Does the dark matter hold more keys to evolution of form and function and speciation? The assisted reproductive technologies have produced both RFP and GFP transgenic cats. Thus, genome-edited cats are feasible, allowing the production of a large animal biomedical model for disease studies, understanding basic biology and physiology, and providing an alternative for long-term model therapeutic trials. New genomic technologies are allowing cats to develop new avenues for understanding evolution, domestication, and adaptation. Feline genomics holds great potential and promise for advancing human medicine and mammalian biology.
