Fishing Expeditions and Autism: A Big Catch for Genetic Research?

I am a fan of the television show Deadliest Catch—a documentary series that follows the travails of deep-sea fishermen in the Bering Sea. (Actually, it is mostly about deep crab fishing.) Living in Seattle, I have actually seen some of the boats filmed on the show.

The variety of equipment the fishermen use to capture sea life is extraordinary. Trawlers and purse seiners—boats that use long-line nets and gill nets—make it possible to catch thousands of fish at a time. I am constantly struck by the comparison between these large, industrial efforts and the “weekend” fishermen that Seattle also has by the thousands. The amateurs use simple fishing poles to catch one fish at a time. Where the Deadliest Catch boats are based, you can often see both styles side by side. I mention these 2 contrasting styles of fish harvesting because there is a comparison that I would like to make in this month’s column and in the next.

It is not much of a stretch to say that isolating the genes responsible for complex behavioral disorders can seem like fishing expeditions (complete with analogous net comparisons). There are giant efforts that deploy the molecular equivalent of purse seiners designed to snag large groups of genes that share a potential involvement in whichever presenting behavior is under study. These efforts can be contrasted with technologies that use the equivalent of small fishing poles, the goal of which is not to catch large, glittering groups of nucleotides but single genes, one at a time.

In this column and the next, we will tackle one of the most slippery issues in the behavioral sciences: the genetic basis of autism. We will closely examine 2 sets of genetic “fishing” techniques that each attempt to isolate sequences associated with the disorder. This month’s column will describe the success of the genetic equivalent of Deadliest Catch nets—large genetic screens that are capable of isolating many genes at one time. Next month, I will focus on research that is more reminiscent of our weekend fishermen with fishing pole–like techniques that can isolate single sequences.

My description of one of these larger fishing techniques for genes will begin with some comments on the diagnostic categories of autism. I will show just how hard it is to come up with behavioral profiles that are sufficiently robust to withstand the cold mathematical scrutiny of the behavioral genetics laboratory. I will then briefly describe some of the details of a technique called homozygous mapping and some of the surprising recent success using the technique with Eurasian and Middle Eastern families.

Diagnostic difficulties
One of the biggest difficulties in characterizing autism at the molecular level is its complexity: autism is impossible to characterize in monolithic, overarching diagnostic terms. Symptoms can include social deficits, communication problems, and obsessive-compulsive and repetitive behaviors. Many patients with autism cannot detect changes in the affective state of another person or predict a person’s interior motivational states based on specific visual cues (canonical Theory of Mind tests). And many of these behavioral symptoms are accompanied by GI complaints, seizures, epilepsy, and sleep disorders. Do these variations in symptoms describe specific disease states, each with their own unique genetic etiologies?