In my January column (“Fishing Expeditions and Autism: A Big Catch for Genetic Research?” Psychiatric Times, January 2009, page 12), I described the great difficulties researchers face characterizing the genetic basis of the disease. Complexities range from trying to establish a stable diagnostic profile to making sense of the few isolated mutations that show clear associations (either with disease or syndrome variants).
Using the metaphor of a fishing net, I discussed 2 overall research strategies that geneticists commonly use to catch these elusive sequences of interest. One strategy is to cast nets that act like large purse seiners to collect many sequences in a single (and usually quite expensive) effort. The other strategy is akin to dropping a single fishing line into the genetic waters to see if anything “bites.” In Part 1, I described one particularly successful strategy that snagged a large number of useful sequences.
Here, the focus narrows: I will not describe the isolation of many sequences, but rather only one. Our “catch” is called MeCP2, a gene whose mutations can give rise to a wide spectrum of related postnatal neurodevelopmental disorders—including autism spectrum disorders. I will start with some background regions about gene regulation, move to the biological functions of MeCP2, and then focus on studies in animal models that provide tantalizing hints about the origins of autistic behavior. My goal is to show that research progress in autism is a continuum of efforts, ranging from large projects with lots of identifiable sequences to small projects that focus on the properties of single genes.
Gene typologies and their regulation
There is a lot of heavy-duty molecular biology behind MeCP2. Getting the clearest view requires us to review 4 pieces of background information. Feel free to skip to the section “MeCP2 and Rett syndrome” if Class II genes and CpG islands are working parts of your vocabulary.
Gene classes. As you recall from your undergraduate days, genes are broken down into 3 classes. Class I genes encode the information necessary to make ribosomal RNAs. Class II genes encode the information to make mRNA, and these genes are in the distinct minority (only about 2% of activatable sequences). Class III genes encode transfer RNAs.
Class II genes can be broken down into 2 functional parts. The first part includes the nucleotides that are necessary to encode the protein, which are called the “structural sequences.” The second part, which often lies in front of the gene, is called the “promoter.” Promoters act like tiny on-off switches that either allow or block the manufacture of the cognate message.
And how is that message made? The enzyme complex that creates the message is called “RNA polymerase II.” Not all genes are transcriptionally active at the same time, and some never become activated at all (eg, neurons do not do the same job as, say, skeletal muscles, and have very different activation profiles). Understanding how the RNA polymerase II complex knows which gene to turn on in a complex cellular environment has been a focus of intense investigation for decades.