Cat Genetics 101 Part 1: The Basics

Cat Genetics 101 Part 1: The Basics

DNA? RNA? Gene? Allele? Chromosome? PCR? Sex-linked? Trait? Dominant? Recessive? Partial dominance? Hereditary? Environmental? Phenotype? Genotype? sNP?

The first time you read an article on feline genetics (as most serious cat breeders and exhibitors will do early on in their career), it’s very likely that your head will start spinning as you try to understand what looks like a foreign language – especially if your last biology class is a distant memory. In a three-part series, Cat Talk will try to take some of the mystery out of basic genetics, particularly as it relates to Felis catus. In part one, we will discuss some basic concepts and definitions that every cat fancier should know. In part two, we cover the “who, what, where, when, and how’s” of feline genetic testing – e.g., who should do it, what is it, where can you get it, when it should be done, and how it’s performed. In part three, we will look to the future, and what exciting new tests may be available to help take the guesswork out of breeding and promote a healthier feline population.

Basic Feline (and Human) Genetics

Phenotype vs. Genotype

One of the first concepts a breeder needs to get straight in their mind is the difference between a phenotype and a genotype. A phenotype, quite simply, is the observed state of a trait – a trait being some aspect of an organism that can be observed and measured. The phenotype has three basic underlying factors: environment, which are non-inherited factors that impact the trait; epigenetics, which are factors that are inherited but not controlled by our genes as far as we know; and genotype, which are factors that are controlled by the DNA sequences contained in our cells.

Dominance

Now that you have phenotype and genotype straight in your mind, let’s talk about the concept of genetic dominance. To understand genetic dominance, one needs to understand the concept of a gene.³We hear that term used all the time, but what IS it, really? Truth is, as a greater understanding is gained of molecular biology and genetics, the definition of “gene” has evolved over time. But for the purposes of a discussion on cat genetics, a gene is a locus (region) of DNA that is made up of nucleotides (a type of organic molecule), and is the molecular unit of heredity. The majority of DNA in both cats and humans is in the nucleus of the cell, and arranged in long strands of DNA called chromosomes. Nearly all mammals are diploid organisms, meaning they have two copies of each chromosome … usually one copy from the mother and one from the father. Humans have 23 pairs of chromosomes – 22 pairs of autosomes (any chromosome other than a sex chromosome), and a pair of sex chromosomes (two X chromosomes in females, and an X and the shorter Y chromosome in males). Cats have 19 pairs of chromosomes, 18 pairs of autosomes and one pair of sex chromosomes.¹ The chromosomes in a matching pair are considered homologous, meaning they are very similar structurally to each other, and the gene controlling a trait on one chromosome lines up with the same gene on the other. Genes that are basically the same but can produce measurable differences (e.g., long hair vs. short hair) are called alleles of that gene.

However, since one chromosome is contributed by each parent, and most mammals exhibit a great deal of phenotypic diversity in a species, there may be some slight variations in the biochemical makeup of the gene for each parent. If the allele is the same on both chromosomes for that gene, then the genotype for the trait it controls is referred to as homozygous. If they are different, the genotype is heterozygous. So what happens if a gene is heterozygous? Which allele wins? In the example above, is the cat long-haired or short-haired?

The concept of genetic dominance describes the process that determines how the gene expresses the trait it controls.² A thorough discussion of dominance is too long for an article of this nature; however, understanding some of the basic concepts of dominance is extremely helpful to cat breeders. One of those concepts is autosomal dominance versus sex-linked dominance (This has zero to do with whether a man or a woman should be in charge!)Autosomal dominance is a bit easier to understand, since autosomes structurally are basically the same – they usually have the same number of genes in the same position on the chromosome controlling the same traits, i.e., the gene(s) controlling the length of a cat’s hair are on the same chromosome in the same location. Like most things that use the word dominance, there are varying degrees. The easiest to understand is complete dominance. In our longhair/shorthair example, if cats who are heterozygous for hair length always have a phenotype of shorthair, then the shorthair allele expresses complete dominance over the longhair allele. The longhair allele is referred to as recessive. While there are three genotypes for the gene that controls hair length (homozygous short hair, homozygous long hair, and heterozygous – one of each allele), there are only two phenotypes: long hair and short hair. Keep in mind, though, that genetic dominance only refers to the relationship between two alleles. If there are more than two alleles, the dominance relationships can be like a game of rock, paper, scissors: rock dominates over scissors, scissors dominates over paper, paper dominates over rock. There is no one allele that wins all the time, which can make things quite unpredictable.

Things get even more unpredictable when you throw in the concepts of incomplete dominance and co-dominance. To keep things simple, we’ll use the time-honored Genetics 101 example of snapdragon color to explain incomplete dominance. One color allele expresses red, one does not, and the flower is white. If you cross a homozygous red snapdragon with a homozygous no red (white), you will get all pink plants – a distinctively different phenotype. The red does not fully express. If you cross two of those pink offspring, statistically, you will get homozygous red (RR), which is a red phenotype, a heterozygous red (Rr and rR), which is a pink phenotype, and homozygous no red, which is a white phenotype. When incomplete dominance is in play, there are three genotypes and at least three phenotypes. Yes, I said at least. There could be other factors controlling how much the red is expressed, and there could be multiple shades of pink expressed. The expression of white in bi-colored cats is a good example of a co-dominant gene. When a cat with no white is crossed with a “high white” bi-color, all of the cats will have at least some white on their feet, face and chest. If one of the offspring is crossed back to a non-white cat, some of the cats will have white feet, and some will not. None of them will have high white because none of them have two copies of the white allele. If those same offspring are crossed to another high white cat, they will have some cats with white feet and some with high white, because none of them have two copies of the non-white allele. Yes, I know there are multiple genes controlling the expression of white in cats – we’ll dive into that topic more completely in part two. Right now, we’re just doing the x’s and o’s.

Co-dominance is a bit different and occurs when both alleles are seen fully expressed in the phenotype. If red and non-red were co-dominant in our snapdragons, we would see either a snapdragon with red flowers and white flowers or flowers with splotches of red and white. We would not see pink. Co-dominance gets interesting when there are more than two alleles, and some are co-dominant and some are not. One of the best examples of this is human A-B-O blood types. There is a gene that produces a certain type of glycoprotein (“H”) on the surface of a red blood cell that is biochemically slightly different. There are three alleles of this gene – one produces a modification to the H protein that we call blood group “A,” one produces another modification we call blood group “B,” and one produces no modification and we call that blood group “O.” But here’s where it gets tricky: The A and B alleles are completely dominant over the O allele, but A and B are co-dominant to each other. So now we have six genotypes produced by the three alleles and four phenotypes: A, B, AB, and O. See if you can figure out what the six genotypes are. I’ll post the answer in the next article.

Now that we know what co-dominance is, a person in the cat fancy might be tempted to proclaim that a patched, tortoiseshell, or calico cat are an example of co-dominance. Well, not really. What we have here is an X-linked trait – meaning a gene on the X chromosomes.⁶ If you recall from earlier in this article, there is one pair of chromosomes that’s not really a pair, and under an electron microscope the X and Y chromosome look radically different – they get their names from their shape under the microscope. The gene that controls whether the hair is red or brown comes in two alleles – red and no red. We’ll get into more detail on cat color genetics in the next article, but for now, we’re keeping this very simple: Only the X chromosome has this gene, and there is no corresponding gene on the Y chromosome that controls the red color. Since the male has only one copy of the X chromosome from their mother, they only get one allele – red or no red, red or brown. There is no confusion, unless the male has a genetic defect called Klinefelter Syndrome, where the mother contributes an egg with two X chromosome rather than one … More about this later. A trait expressed by only one allele is referred to as hemizygosity (from the Greek “hemi” meaning half and “zygote” referring to the fertilized egg).

Fine for the males, but isn’t the red and brown female an example of co-dominance? Again, not really. A female may have two X chromosomes, but only one of them is fully active. (The theories on why this happens for the X chromosome and not the autosomes are interesting but out of the scope of this article, and still very much theoretical). In the early stages of pre-embryonic development, a cell undergoes a process called Lyonization (No, this is not named after the Dr. Lyons we know – it’s named after British geneticist, Mary Lyon, who first proposed the theory of X-chromosome inactivation in 1951). One of the copies of the X chromosome is seemingly randomly inactivated.⁷ So, if a female has inherited a red gene from one parent and a non-red gene from another, some cells will express the red pigment and other won’t – they will be brown. The closer to fertilization the X chromosome inactivates, the bigger the patches of color. Once Lyonization occurs, the same X chromosome is inactivated when that cell replicates. Big, distinct patches of color signify early Lyonization. Small intermixed patches of color signify late Lyonization. Curiously, the same thing happens in males with two X chromosomes – one of the X chromosomes is inactivated. However, males with two X chromosomes are still generally unable to reproduce, as the odd number of chromosomes (even if one is inactivated) make it difficult for the cell division required to produce viable sperm to occur.

Gene Expression and Activation

Like electronic devices, genes have biological on and off switches. Just because a gene can do something doesn’t mean it does. Our entire biological life cycle is encoded in our cells, but if every gene carried out its instructions whenever it felt like it, ours and our cats’ bodies would likely be a puddle of unstructured goo. The timely expression of our genes is where the real miracle of life occurs, and scientists have only begun to scratch the surface in understanding how that is done. Does the gene lie dormant, or does it somehow work differently in different environments?

A very simple example of this concept occurs in pointed cats. Pointed cats carry a mutation of the enzyme tyrosinase, an enzyme critical to melanin production, which produces the pigment in the hair shaft.¹The mutated form of the enzyme does not work at body temperature, so the cat is unable to produce melanin in hair at their body temperature. Pointed cats are born almost completely white, and stay that way when they are kept close to the warm body of their mothers. But as they grow up and begin to venture out, the temperature lowers, the tyrosinase works as designed, and melanin is produced in the hair shaft, starting with the tips of the ears, tail, and feet. (This creates a dilemma for some breeders of long-haired cats: keep the cat warm and inhibit color production, or keep the cat cold and stimulate coat production?)

While the tyrosinase mutation is basically harmless, unless your breed standard encourages clear coats in your pointed cat, understanding this activation process is also key to defeating cancer and other diseases where cells start to divide and grow in an uncontrolled manner, or diseases where processes critical to life shut down, such as diabetes and many degenerative diseases. As we begin to test for genetic markers for certain diseases in cats (and humans) that appear – at least in part – to be inherited, it is critical that we understand the concept of gene expression. While researchers may have identified an allele of a gene that everyone with a certain disease carries, not everyone who carries that particular flavor of the gene may develop the disease. There are cats who carry two copies of the gene associated with PKD, yet live long and healthy lives. How does that happen? Why does a gene activate (or not activate) to produce an active disease state? There is no one answer to that question. It could be environmental. It could be activator genes. It could be both. The appearance of a genetic marker is not necessarily a death sentence for your cat (or for you), and a test result needs to be viewed in context. The FDA now heavily regulates human genetic testing when it involves predicting the likelihood of an individual to develop an inherited disease, but there is not the same kind of regulation in the veterinary world. The information obtained from genetic testing is invaluable to a breeder, but when undesirable results are obtained from markers that predict the health of a cat, your veterinarian should always be consulted before taking any action, particularly if your cat appears healthy.

Genetic Mutations

Mutations are simply a permanent change in the nucleotide (building blocks of genes) sequence of genetic material. Although mutations are often thought of as exclusively detrimental events, that is not always the case. While it is true that 70% of mutations involved in the production of an organism’s proteins are fatal, the other 30% are neutral or of some benefit.⁴Mutations can be part of a normal biological process, they can be produced by environmental factors, or they can be produced when the body’s natural ability to repair its DNA doesn’t get it quite right. An example of a mutation that occurs as part of the normal process is antibody formation. The DNA in the cells that produce antibodies to fight foreign organisms is basically the result of a change in the nucleotide sequence, which enables the antibody to be specific to the antigen (a molecule that stimulates an immune response, such as a virus, bacteria, or foreign substance). An environmental mutation with a negative impact is overexposure to sunlight. In susceptible individuals, the radiation from sunlight alters a skin cell’s normal replication process and produces abnormal cells that grow rapidly, either producing a localized tumor or a cancer capable of spreading throughout the body. Sometimes a mutation is a mixed bag, such as the one that produces the abnormal hemoglobin S found in sickle cell anemia, which primarily affects populations of African descent. An individual who has two copies of the Hemoglobin S gene develops a disease that produces a severe anemia. However, a person with only one copy of the hemoglobin S gene produces enough normal hemoglobin (incomplete dominance or co-dominance?) to mitigate the effects of hemoglobin S, so that a person with one copy does not know unless it is uncovered in laboratory testing. The presence of one copy of the gene has a beneficial effect; however, it makes those persons’ red blood cells less vulnerable to attack by the parasites that cause malaria, thereby increasing the overall survival rate from malaria in those populations.

Genetic Testing

Since its development in 1983, Polymerase Chain Reaction (PCR) testing of DNA has made the testing for specific DNA markers (pieces of DNA associated with a specific trait) easy, relatively cheap, and accessible.⁵This has become an invaluable tool for cat breeders, as they can screen and select their breeding cats for desirable and undesirable inheritable traits. However, caution must be exercised when requesting these types of tests. PCR testing does not require large amounts of DNA to produce a result; however, because of this sensitivity the procedure is also extremely vulnerable to contamination from prior samples if the equipment is not properly cleaned and maintained, or from spurious organic material obtained during the collection process. Testing should be done at labs which have a good reputation, and care must be exercised not to introduce contaminants from other cats or even your own fingers when collecting samples, as these stray cells can interfere with the testing process and produce inaccurate results.

Looking Ahead

Hopefully, we haven’t made your head spin too much with our Genetics 101 lecture. Perhaps you have gained some basic understanding of genetic concepts if this was a foreign language to you before. In our next article, we will discuss what types of genetic testing can be done today, when this type of testing should and should not be performed, and the significance of the tests performed.