Body-Altering Mutations In Humans and Flies

I became a science writer, circa 1980, because I didnt think flies with legs growing out of their heads my PhD research had much to do with human health or biology. So when I spied the words A Human Homeotic Transformation way down on the Table of Contents in the May issue of the American Journal of Human Genetics, I was as riveted as a normal person would be getting a copy of People with a celebrity on the cover.

Of Homeotic Mutations and The X-Files

Mutations in four genes give the fly in the lower right an extra pair of wings (Credit: FlyBase)

A homeotic mutation mixes up body parts, so that a fly grows a leg on its head, antennae on its mouth, or sports a double set of wings. Designation of body parts begins in the early embryo, when cells look alike but are already fated, thanks to gradients of morphogen proteins that program a particular region to elaborate particular structures. Mix up the messages, and a leg becomes an antenna or, as in the AJHG article, a child develops two upper jaws, instead of an upper and a lower.

I once knew the homeotic mutants of Drosophila melanogaster intimately, as I archaically mapped their genes. Shortly after I left Thom Kaufmans lab at Indiana University (where I penned a fruit fly romance novella, in addition to my thesis), post-doc Matt Scott and fellow grad student Amy Weiner were homing in on the homeobox, a 180-base-sequence that encodes a protein part that binds other proteins that turn on sets of other genes crafting an embryo, section by section.

Soon, homeoboxes turned up in all manner of genomes, affecting the positions of petals, legs, and larval segments, the genes mysteriously arrayed on their chromosomes in the precise order in which theyre deployed in development. Homeotic mutants even starred in an episode of the The X-Files.

Homeotic mutations cause a few human diseases. In lymphomas, white blood cells detour onto the wrong lineage, and in DiGeorge syndrome, the missing thymus and parathyroids and abnormal ears, nose, mouth, and throat echo the abnormalities in Antennapedia, the legs-on-the-head fly in the photo. Extra and fused fingers and various bony alterations also stem from homeotic mutations.

Alas, no human homeotic seemed as compelling to me as a double-winged fly until I saw photos of the tiny faces of the children with upper lower jaws.

Two Upper Jaws

3D CT scan of child with ACS. Lower jaw is small and malformed (left); same aged child with normal jaw (middle); lower jaw of child with ACS inverted over upper jaw of normal skull (right). (Credit: Image courtesy of Seattle Childrens).


Body-Altering Mutations In Humans and Flies

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