In most cases, the genetic interactions listed in Table 2 occur because the interacting genes are participating in a single biochemical pathway. Let’s look at a simple example of a pathway where two genes, A and B, act in sequence to produce a purple pigment (Figure 10).

So how does this all work for fur color in dogs? It all comes down to the molecular function of the genes. Let’s start with some basic biology.

Pigmentation in mammals (including humans!) is primarily a result of two different forms of melanin: eumelanin is black or brown in color, while pheomelanin is reddish gold. Both eumelanin and pheomelanin are produced in specialized organelles called melanosomes within cells called melanocytes. Melanocytes are specialized cells with long arm-like projections that extend through the epidermis and contact many other cells (Figure 10). Melanosomes are transported to other cells in hair follicles and skin, giving hair (or fur, in the case of dogs) and skin its pigment. The ratio of eumelanin to pheomelanin, the amount of melanin in each melanosome, and the number of melanosomes produced by each melanocyte all influence overall pigmentation.

Each of the genes in Table 1 contributes to a different step of the pigmentation process. The B locus corresponds to a gene called TYRP1. This gene encodes an enzyme that catalyzes one of the first steps in synthesizing eumelanin from the amino acid tyrosine. In dogs, the B and b alleles produce slightly different forms of the enzyme. The enzyme variants produce slightly different eumelanin structures, which then appear either black or brown.

The melanosomes are transported through the branches of the melanosomes toward target cells in the epidermis, including hair follicles. A protein called melanophilin, encoded by the D locus, plays a role in this process. Different forms of the protein affect how many melanosomes are transported. Black or brown dogs with a dd genotype appear lighter in color because fewer melanosomes are transported. Which form of eumelanin (black or brown) is produced does not affect the action of melanophilin, which is why the B and D loci show no gene interaction in a dihybrid cross.

From the extensions of the melanocytes, melanosomes are targeted to other cells in the epidermis. The process is regulated by interactions between the melanocytes and the target cells. The E locus encodes a protein called MC1R. MC1R is a receptor protein found on the surface of melanocytes. In response to a signaling molecule called ASIP from hair follicles, MC1R triggers a switch between eumelanin and pheomelanin production in melanosomes destined for the fur. Variations in MC1R result in predominantly pheomelanin production (as can certain variations in the ASIP gene, also called the A locus)^[1]. The reddish-color pheomelanin makes a dog appear yellow, cream, or red.

Do you have a yellow, cream, or red dog? Interestingly, you can tell your dog’s genotype at the B locus by looking at their nose! Although the e allele prevents eumelanin from being deposited in the fur, the black or brown pigment is still present in the skin of the nose. If your dog has a brown or pink nose, they have a bb genotype. If your dog has a black phenotype, they have at least one B allele, genotype B_^[2].

As mentioned previously, dogs are a very powerful model organism because they are one of the most visibly variable species, but individual breeds may have very little genetic variation due to inbreeding. This makes it easier to identify genetic variants that correspond to traits, and it gives geneticists a “way in” to understanding human health as well. Many of the genes mentioned in this chapter perform similar functions in other mammals: including humans! Table 3 lists some of the genes controlling appearance in dogs, along with gene function and known phenotypic variations in humans.

More than two genes

In most cases, the genetic interactions listed in Table 2 occur because the interacting genes are participating in a single biochemical pathway. But biochemical pathways often include far more than just two genes! The next sections look at how different forms of gene interaction influence phenotype when more than two genes are involved.