Question: When a baby is developing, how do the different parts of it's body know what they are? A little finger and a thumb are made up of exactly the same cells, e.g. blood cells, bone cells etc, but what makes the little finger a different shape to the thumb?

Susan Cartwright answered on 22 Jun 2015:

This is controlled by various genes which produce regulatory proteins (which, as the name suggests, regulate whether particular genes are turned on or off). The main genes involved are called homeobox or Hox genes, from a particular sequence of DNA that they all have in common.

All multicellular animals descend from something like a segmented worm. In some animals, e.g. insects, the segments are still very apparent (consider a caterpillar) – in other animals, such as us, not so much (though the spinal column still looks vaguely segmented). What Hox genes used to do is produce gradients of increasing or decreasing concentration from head to tail, causing different genes to turn on in different segments.

The action of Hox genes has been well mapped in the geneticists’ favourite animal, the fruit fly Drosophila melanogaster. Mutations in Hox genes typically cause features to differentiate as though they were in a different segment from where they actually are. For example, one such mutation causes the unfortunate fly to develop an extra pair of legs where its antennae ought to be (legs and antennae start from the same basic structure), and another causes it to develop an extra pair of wings (the wings come from the second thoracic segment, and this mutation causes the third thoracic segment to think it’s the second thoracic – hence, extra wings).

Hox genes tend to live clustered together, and often the order in which they lie on the chromosome is the same as the order in which they are expressed from head to tail as the embryo develops. They are very ancient, and their sequences are closely related in animals as diverse as fruit flies and humans. However, they can get duplicated in the course of evolution, and the originally identical duplicates gradually diverge in structure and function. Flies have 8 Hox genes, neatly lined up; vertebrates like us have 39 in total, divided into 4 separate clusters on different chromosomes (HOXA to HOXD, on chromosomes 7, 17, 12 and 2).

Hox gene mutations in humans have been shown to cause a variety of malformations, not as obviously related to misidentified segments as in fruit flies, but then the segmentation of vertebrates is much less obvious than that of insects. To take one of your examples, a mutation in HOXA13 can cause, among other things, abnormally short thumbs, and mutations in HOXD13 can cause fingers to fail to separate (so you get one fat finger with two sets of finger-bones inside it, for example), or extra fingers or toes to form. The paper I read does say that the ordering of human Hox genes, as with flies, seems to map to the expression: those nearer the top end of the chromosome, when mutated, cause problems broadly speaking in your upper body, and those nearer the bottom end cause problems in your lower body.

It is a very complicated procedure, and Hox genes were only discovered in 1978. It will take time to sort it all out!