Homologs

I discussed in a previous post the relevance of the genetic concept, heterogeneity, to EHE. Specifically, the two most common types of EHE-causing genetic alterations involve transcription co-activators, YAP and TAZ. These two genes are very similar, making them homologs. There are two types of homologs: paralogs and orthologs.

Paralogs: a pair of genes that derives from the same ancestral gene and now reside at different locations within the same genome. Gene duplication is a very common evolutionary event that allows variation by mutation within a particular gene without losing its (possibly essential) function. There are many examples: hemoglobin is made of a tetramer of globin proteins, two each of Hb A and Hb B. These are each synthesized from the Hb A and B gene templates: closely related but diverged from one another at some point as a result of duplication of an ancestral globin gene and subsequent mutations in each daughter gene. Hb A and B are paralogs, just as YAP and TAZ are. 

Similar to globin, YAP and TAZ are highly conserved throughout evolution - they are transducers of a signal system, Hippo, that is well known and first described in detail in Drosophila (fruit flies). The Hippo system is responsible for controlling organ size by causing cells to stop proliferating when they touch each other (contact inhibition). YAP and TAZ are the vertebrate versions (orthologs) of the Drosophila gene, Yorkie. Orthologs are genes in different species that evolved from a common ancestral gene by speciation. So, orthologs and paralogs are closely related gene sequences (homologs), separated by speciation and therefore are in different species (orthologs) or duplication and mutation but in the same species (paralogs).

You might think this is way too much detail about EHE. But a better understanding the biology of this disease will help us get more quickly to the goal of a cure.