12 PSYCHIATRIC TIMES www.psychiatrictimes.com
MOLECULES OF THE MIND
Fishing Expeditions and Autism: A Big Catch for Genetic Research?
I The variety of equipment the fish- ermen use to capture sea life is ex- traordinary. Trawlers and purse sein- ers—boats that use long-line nets and gill nets—make it possible to catch thousands of fish at a time. I am con- stantly struck by the comparison be- tween 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. 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 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 at- tempt to isolate sequences associated with the disorder. This month’s col- umn 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. It is not much of a stretch to say that isolating the genes responsible for complex behavioral disorders can seem like fishing expeditions (com- plete with analogous net compar- isons). 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. am a fan of the television show Deadliest Catch—a doc- umentary series that follows the travails of deep-sea fish- ermen 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. up with behavioral profiles that are sufficiently robust to withstand the cold mathematical scrutiny of the be- havioral genetics laboratory. I will then briefly describe some of the details of a technique called homo- zygous 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 char- acterizing autism at the molecular level is its complexity: autism is impossible to characterize in mono- lithic, overarching diagnostic terms. Symptoms can include social deficits, communication problems, and obses- sive-compulsive and repetitive be- haviors. 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 (canon- ical Theory of Mind tests).And many of these behavioral symptoms are accompanied by GI complaints, seizures, epilepsy, and sleep disor- ders. Do these variations in symp- toms describe specific disease states, each with their own unique genetic etiologies? We do not currently know.Autism is usually classified as a severe form of 1 of the 5 so-called pervasive de- velopmental disorders (PDDs). Chil- dren who display milder symptoms may have an autism spectrum dis- order (ASD). Asperger syndrome is often separated from classic autism because there is usually no delay in language development. These terms are frequently used interchangeably, unfortunately, which reflects the flu- id nature of the diagnostic observa- tions. One of my favorite categories decries a form of diagnostic surren- der: PDD, not otherwise specified. (Just so you know, terms like these drive behavioral geneticists nuts!) But there are genes All this has not stopped us from researching the phenomenon, of Part 1 Initial studies that confirmed a ge- netic role came from the traditional family and twin heritability studies, some of which are now decades old. Some of the best recent work comes from assessing sibling recurrence It is now clear that multiple genes expressed in specific combinations are involved differently in creating specific autistic behavioral profiles. It is also clear that wide nucleotide vari- ations within these candidate genes exist that are undoubtedly more capa- ble of predicting discrete autistic be- haviors than others. risk. Usually described as a percentage, sibling recurrence risk is the formal probability that a younger sibling of a child with autism will also have the disorder. When autism is defined nar- rowly, the normal rate in unrelated populations is about 1 affected child per 500 (0.002%). When you look at sibling recurrence risk, the rate rises to about 1 in 6 (15%). Thus, there is ample reason to pursue genetic re- search in this area. But that is where the easy stuff ends. Although many genes over the years have been nominated as the source of the behavioral anomalies, few studies have been successfully replicated. Specific chromosomal in- versions, large deletions, chromo- somal translocations, and changes in copy number of individual genes (Figure) have been observed as risk factors for autism. In fact, you can practically name any type of mutation and find that it has been associated in the past decade, at least to some extent, with some part of the autism spectrum. Looking at first cousins Given the large number of potential genes in autism, one might expect that the research method of choice would include the deployment of large, Deadliest Catch–like gene fish- ing protocols. Recent progress has in- deed been made using one of these larger screening technologies, a tech- nique called homozygous mapping. What follows is a brief description of the technique. course. And the results after years of looking are clear: there is a tantaliz- ing and substantial genetic compo- nent to the disorder regardless of how it is classified. Human genetic disorders that have
by John J. Medina, PhD
complex, multi- gene origins have 2 overall causes. The first arises from the random roll of the meiotic dice—presenting cases that show no pattern of previ- ous inheritance. In rare cases, herita- ble forms of what appears to be the same disease also exist. Mutations in these patients clearly show a pattern that can be transferred from one gen- eration to the next.
Homozygous mapping is capable of identifying these rare, heritable (in- variably recessive) disease forms. The technology takes advantage of the presence of consanguineous fam- ilies . . . which should probably be ex- plained before we go further.
For decades, molecular biologists have known about the great power of studying persons whose parental lin- eages share a close, common ances- tor. The probability of their offspring exhibiting an autosomal recessive trait is much greater than in the gen- eral population. (Recall that autoso- mal recessive conditions are traits that are expressed when the subject has 2 identical copies of a particular gene in a nonsex chromosomal background. Homozygous mapping employs such populations and can be divided into 2 steps:
Subjects who carry a specific, well-defined disorder are identi- fied.Accomplishing this first step, which requires the researchers to decide on a specific set of diag- nostic criteria, is one of the hardest parts of the entire procedure.
Once identified, subjects are screened for nucleotide sequences that they share in common and are homozygous for both chromo- somes. The assumption is that these regions are donated from both paternal and maternal lineag- es who themselves shared a recent common ancestor. That is a rea- sonable supposition if you are studying closely related persons, such as first cousins. Although admittedly a tough tech-
nique to execute properly, homozy- gous mapping has proved to be suc- cessful in isolating gene sequences that mediate rare diseases related to neural development. Until very re- cently, however, it had not been tried
(Please see Fishing and Autism, page 17)