The genetics of the calico cat

In an earlier post, I detailed the life and work of Nettie Maria Stevens, the namesake of our new calico cat. Nettie Stevens is known for her discovery of the X and Y chromosomes as the basis for sex determination. While researching the post, I found myself in another internet rabbit hole and I wanted to share some of the things I learned about cat genetics because, it turns out, calico cats are an excellent lesson in genetics.

The genetics of cat fur color (like the genetics of human hair color) are rather complex. There are many different genes that create the spectrum of coat colors and patterns found in domestic cats. In other mammals, white fur color alone has been linked to at least six genes (MITF, EDN3, EDNRB, PAX3, SOX10, and SNAI2). For this discussion, I will focus only on the gene loci that create the calico pattern: agouti (A), orange (O), and spotted (S). Based on the combined expression of these genes, some cats are tortoiseshell, a mix of black and orange and some cats are calico, a mix of black, orange, and white. Because the Orange gene is on the X chromosome, most torties and calico cats are female. There are rare cases of male cats with Klinefelter syndrome (XXY) that can have these fur color variants.

Figure 1 Schmidt-Kuntzel, et al., 2009

Agouti (gene name ASIP) encodes a protein that inactivates the melanocortin receptor and thus controls the distribution and amount of pigment cells (melanocytes) in the hair. The Orange gene has not yet been identified, but its position on the X chromosome has been mapped. Interestingly, the MC1R gene, which has been linked to red hair in humans and other mammals, is not involved in the coloring of calico cats because it isn't on the X chromosome. A recent study of the Syrian hamster, which shows sex-linked inheritance of yellow fur color, described the sex-linked yellow gene (Sly) as being independent of MC1R function and not likely homologous to the Orange gene in cats. However, recessive versions of the MC1R allele create orange/amber fur color in Norwegian forest cats. The gene for white spotting (S) has been linked to the KIT locus; more recent publications have shown that a retroviral insertion in the KIT oncogene caused white spotting, with a full insertion leading to the recessive all white mutation.

The genetics of the tortoiseshell/calico cat

If fur color followed the rules of Mendelian genetics, you would expect cats to be only black and white or orange and white, not two or three colors at once. The patterns observed in calico and tortoiseshell cats can be explained by a phenomenon called X chromosome inactivation. Somatic chromosomes come in even pairs, but the sex chromosomes are not created equal. The Y chromosome is rather small and does not encode many genes. In contrast, the X chromosome contains lots of protein-encoding genes. If an XX individual expressed all the genes on both X chromosomes, they would have a huge imbalance in protein expression in comparison with someone with XY. Organisms have different ways to level the compensate for these differences. In mammals, this involves silencing one of the X chromosomes in each cell with the XX genotype. In organisms like the fruit fly, the XY males just double the expression of the genes on the X chromosome.

The specifics of how this happens is actually pretty amazing. (For further details of the process, check out my post on Nessa Carey's book Junk DNA.) In short, a long non-coding RNA known as Xist (X-inactive specific transcript) turns off one copy of the X chromosome in each cell; on the opposite strand of DNA, a gene called Tsix is found. Xist and Tsix have mutually exclusive expression, which ensures that only one X chromosome is inactivated in each cell. X chromosome inactivation occurs at the 8 cell stage of the embryo. Different cells inactivate different copies of the X chromosome, which means some cells express alleles for orange and white and other cells express black and white alleles. These 8 cells then divide and produce the millions of cells that make up a cat. This random pattern of gene inactivation leads to the pattern observed in Nettie and other calicos.

Carbon copy (left) is a clone of Rainbow (right)

Importantly, because these traits are not strictly inherited by classic Mendelian patterns, it makes cloning cats a bit trickier than other animals. As highlighted in the book Frankenstein's Cat, scientists were disappointed when the cloned cat Carbon Copy ended up looking quite different from its clone mother. Had they thought more carefully about the genetics of calico cats, they might have picked a different breed for their experiment!

maneki-neko calico cat figurines are
thought to bring good luck

Calico cats like our Nettie offer excellent lessons in genetics as they higlight X-linked genes and dosage compensation. After all this reading, I think I will take advantage of cat genome sequencing to discover the specific mutations in our cat. I learned more than expected about cat genetics and hope to share these lessons with you soon. For now, if you want to learn more about the genetics of cats, you should check out Herding Hemingway's Cats by Kat Arney.

Caesar's Last Breath: Sam Kean brings his keen eye for storytelling to explore the air around us

I just finished reading Sam Kean's new book Caesar's Last Breath: Decoding the secrets of the air around us. I wasn't planning to write a review, but when I realized my blog has covered every other book by Sam Kean (including Dueling Neurosurgeons and The Violinist's Thumb), I felt like it deserved some attention.

The theme of the book is understanding the molecules that make up our air. Each chapter is devoted to a component or two that is found in the air we breathe. This approach means there is some overlap with Kean's brilliant debut, The Disappearing Spoon. Luckily, the overlap seems only to include the best stories in the history of chemistry and Kean is able to explore the stories further. For example, we get more background on the German chemist Fritz Haber inventor of the process to make ammonia from nitrogen and hydrogen, thus spurring the development of agriculture and chemical weapons. I don't want to spoil it, but if you want a taste, you can check out Kean discussing the story on Radiolab.

Not all of the stories are as serious as Haber's. For example, Kean's chapter on methane allows a moment of silliness in the details of the life of the French performer Le Pétomane, a man who trained himself to fart at will. At his peak, he was the highest paid performer in France, bringing bigger crowds to the Moulin Rouge than even Sarah Bernhardt. 

It is difficult to choose a favorite among the chapters, but if I had to pick just one, it would probably be "Controlled Chaos", which focuses on water and its role in the Industrial Revolution, through the work of James Watt and others to develop steam power and the work of Alfred Nobel to make explosives. Nobel's legacy now is pretty securely tied to the prizes bearing his name. However, during his life time, Nobel's work cost many lives and left him in poor health, guilty and haunted by his reputation as a merchant of death. In fact, this guilt was the impetus for his starting the Nobel prize, much to the chagrin of his family who fought to inherit the wealth.

Because I read so many science books, I often have a sense of déjà vu when reading. However, Caesar's Last Breath included lots of new and interesting tidbits, like the surprising connection between Albert Einstein and refrigerators and the strange history of the manipulation of the weather. Perhaps my only complaint with the book would concern the final chapter on the air on other planets, which felt a bit disconnected both in subject and style.

I highly recommend Caesar's Last Breath for people interested in chemistry or the periodic table as well as those interested in the history of science.

How to Tame a Fox (and Build a Dog): a long term experiment and a story of perseverance and hope

The story of Dmitry Belaraev's long-term experiment in fox domestication was beautifully covered by Scientific American and The Discover Blogs as well as on Radiolab. I found the story and the science behind it fascinating, but I wasn't sure a book was needed to delve further in the story. After I read How to Tame a Fox (and Build a Dog), I learned how wrong I was.

Lee Alan Dugatkin co-authored the book with one of the original researchers, Lyudmila Trut. The authors are able to tell the story of Belaraev's seemingly Quixotic plan to tame foxes in a way that is compelling, even when I knew the major plot points.

The project's hypothesis was simple: continuous breeding of the tamest/gentlest foxes would lead to foxes that behaved like dogs. I found it amazing that they were so committed to scientific rigor that they ran a parallel experiment where they chose the most aggressive foxes. At the time, Belaraev faced obstacles from the ruling Communist party. Today, scientists would also question funding such a long-term experiment. Most geneticists use animals with short lifespans (e.g. fruit flies, C. elegans, yeast) so they can get results quickly and at lower costs. The experiment started producing results far earlier than even the principal investigators would have guessed. Even after a few generations, they found that the foxes showed more dog-like traits (floppy ears, tails, and other classic signs of neotony.) After 10 generations, they found that females went into estrus earlier and some male pups showed changes in fur color.

These changes were all predicted by Belaraev, who had a pretty revolutionary idea at the time, which he called "destabilizing selection". He suggested that the changes that occur in the course of domestication aren't simply due to the accumulation of mutations, but rather changes in the expression of existing genes.

Graphical Abstract from Parker et al Cell Reports 2017

Once genome sequencing arrived on the scene, the domesticated foxes were soon the subject of several studies. The first approach was to compare 700 genetic markers that had been used in the initial dog genome sequence with both the wild and domesticated foxes.  The researchers found several cases of convergence between the two domestication events, which included genetics variations that would ultimately lead to changes in the appearance and behavior of the tame animals. In 2010, a paper in Nature reported the genomic changes that accompanied the domestication of dogs from wolves.  Of course, the research is still in progress. One recent paper in Science suggests that dogs were domesticated in Eurasia and Eastern Asia from 14000 to 6000 years ago. The most recent data (published in my journal Cell Reports) suggest that different breeds of dogs had origins in different geographical locations. Importantly, the work published so far suggests that Belaraev was right: changes in gene expression not just mutations were key to domestication.

Perhaps the most fascinating parts of the book were the details concerning the barriers to science in Soviet-era Russia. These included the domination of genetics by a non-scientist named Trofim Lysenko, who was staunchly opposed to the ideas of Darwin and Mendel; these ideas were gaining acceptance at the time in the West. Lysenko even convinced Lenin that putting seeds in the cold would make crops grow better at low temperatures (they don't). Lysenko fabricated data to support his ideas and those of the party, which devastated Soviet agriculture for decades. Lysenko was celebrated by the Communist party simply for being a peasant and for going against "bourgeois Western science".  Interestingly, Khrushchev's daughter Rada, a journalist who trained as a biologist, argued against Lysenkoism and fought to protect science and the work of Belaraev. I think this serves as another example of why it's best to keep politics out of science (but not science out of politics!) The stories of the suppression of science in the height of soviet Russia are evocative of current anti-science rhetoric in these United States.

One of the reasons that Belaraev was able to persevere in the face of such odds was his enthusiasm and charisma. Belaraev was a social chameleon, who could easily adapt to his audience. These traits made people gravitate towards him and helped him argue for the benefits of the fox experiment to the powers that be. Officially, the rationale of the experiment was to breed foxes that would have more variety in their colors, which would help fetch higher prices for their fur. The domestication experiment was funded despite the crackdown on work in genetics. This isolationism crippled Russian scientists, who were cut off from the science in the rest of the world.

In the late 1980s the fox experiment was 30 years old. The farm started to have some trouble with funding and the researchers had to scale back the experiment. The situation was made worse in 1998 when the Russian economy collapsed. The scientists started sacrificing some of the foxes and selling their pelts. Shortly after this, they contacted a few select media outlets to cover the story, which helped them secure some funding for the project. Today, the experiment has been going on for 60 years, which is a long time for a laboratory experiment, but a short time frame for evolution.

How to Tame a Fox (and Build a Dog) was a fascinating and ultimately hopeful story. Even in such a difficult political climate, this scientist and his visionary experiment were able to persevere with some patience and ingenuity, a message that I think will resonate with scientists that are struggling to stay afloat in 2017.