JOIN USThere was very little that was safe or conventional in Ernest Hemingway’s life. “Moderation” appears to have been one word lacking from his otherwise superb vocabulary, even when it came to cats.
But of course, such an extraordinary man would not be associated with just ordinary cats; about half of the animals bear extra toes, typically on their forepaws. Most cats are, like humans, pentadactyls. That is, they have five digits on their forepaws. The so-called Hemingway cats have six digits, with the extra digit the homolog of the human thumb, which gives the paw a mittenlike appearance. When found in felines, the condition, known as preaxial polydactyly, is now commonly referred to as a “Hemingway cat.”
While the origins of the Hemingway House cats remains murky, the cause of their polydactyly is no longer a mystery. Researchers have recently pinpointed the precise mutation in the cats’ DNA responsible for the formation of the extra digit. The story of the origin of Hemingway’s cats is one of finding deep genetic connections among very different animals – from fruit flies to chickens, mice, cats, and yes, even humans.
In the late 1970s, one of the most challenging puzzles in all of biology was that of embryonic development – how a complex creature formed from a single fertilised egg cell.
Experiments with the fruit fly
Two researchers, Christiane Nuesslein-Volhard and Eric Wieschaus, led a bold undertaking to identify all of the genes responsible for the process in fruit flies, then and now one of the main workhorses of basic genetic research. They identified scores of genes that played roles in building the fruit fly body and its body parts, work that led to their sharing of the 1995 Nobel Prize in Physiology or Medicine with the late Edward B Lewis, another pioneer fruit fly geneticist.
One of the reasons for that honour was the discovery that, contrary to all biologists’ expectations, similar sets of genes to those involved in building fruit flies were also involved in building the bodies of such different animals as mice, frogs and other vertebrates, including humans.
Indeed, by the 1990s, one common strategy for discovering genes involved in building vertebrate bodies, organs or body parts was to look for the counterparts of fruit fly genes in those vertebrates. That was the approach taken by one team led by Professor Cliff Tabin at Harvard Medical School that was eager to find the genes responsible for the formation and patterning of vertebrate limbs. Decades of research on the chicken wing had shown that the formation of the pattern of digits across the entire structure depended on some signal produced by cells in the most posterior part of the developing embryo’s wing bud.
Blame it on the hedgehog
Tabin’s team sought to identify that signal by isolating the chicken’s counterparts of certain fruit fly genes. They isolated a chicken homolog of a fruit fly gene called “hedgehog.” The name had been given by Nuesslein-Volhard and Wieschaus because mutations in the fly gene caused the fruit fly larva to be covered with fine hairs, like a hedgehog.
Tabin’s team was stunned and delighted to find that the chicken gene, dubbed “Sonic hedgehog” after the video game character, was turned on in the posterior of the limb bud, right where the digit-patterning activity was also located. They then found that the Sonic hedgehog protein was indeed the long-sought digit-patterning signal.
For instance, they demonstrated that turning Sonic hedgehog on in the anterior part of the limb bud had the same effect as transplanting posterior tissue to the anterior part of the limb – it caused the formation of extra digits. The induction of polydactyly by Sonic hedgehog in laboratory experiments raised the possibility that inherited cases of polydactyly might be caused by mutations in the Sonic hedgehog gene.
Polydactyly is well known in mice and in humans, as well as cats, and sure enough, cats, mice and humans all have Sonic hedgehog genes. But inspection of the Sonic hedgehog genes of polydactyl individuals did not reveal any mutations that would cause the Sonic hedgehog signal to be defective. So what role, then, does Sonic hedgehog play in the syndrome?
It turns out that polydactyly is not due to disruptions of Sonic hedgehog function, but of its regulation. In order to make the proper five-digit, pinky-to-thumb pattern, the production of the Sonic hedgehog protein must be restricted to posterior cells. The pattern depends on the relative concentration of Sonic hedgehog, which is greatest in the posterior (where the pinky will form) and lowest in the anterior where the thumb will form.
Mutations that disrupt Sonic hedgehog regulation such that some protein is made in the anterior of the limb bud cause the formation of an extra thumb. These mutations were difficult to find in DNA at first because they were not located in the part of the gene that encodes the protein. Rather, they occurred far away in a stretch of DNA sequence that acts like a switch to turn Sonic hedgehog on in the posterior part of the limb bud and to keep the gene off in cells in the anterior part of the limb bud.
A team led by Robert Hill of the Medical Research Council Human Genetics Unit in Edinburgh showed that the Sonic hedgehog switch that controls gene activity in the limb is located about one million base pairs from the part of the gene encoding the Sonic hedgehog signal.
When the switch is scrambled...
Mutations that scramble the switch are responsible for polydactyly in mice and humans. But further work has shown that even slight mutations substituting just a single letter of the DNA sequence can also cause the syndrome, not only in mice and humans, but in Hemingway’s cats.
Hill’s team analysed one line of affected Key West cats and found a perfect association between polydactyly and a substitution at one position in the cat’s Sonic hedgehog gene switch.
They also examined other unrelated polydactylous North American cats and found the same substitution, which indicates that all North American polydactylous cats may be descended from one polydactylous ancestor.
Like Hemingway’s cats and the writer himself, we all have our quirks, some more visible than others. Genetics has made huge strides in understanding the basis of many characteristics like extra toes and fingers.