Hoxa1 is what geneticists call a "highly conserved" gene, meaning that the sequence of nucleohdes that make up its DNA has changed little over the course of evolution. We assume that this is a characteristic of genes that are critical to survival: they suffer mutations as other genes do, but most changes are likely to be fatal, so they are rarely passed on to subsequent generations. Although many other genes appear in several forms -- for example, the genes that encode eye color or blood type -- highly conserved genes are not commonly found in multiple versions (also known as polymorphic alleles, or allelic varIants). The fact that no one had ever discovered a variant of Hoxa1 in any mammalian species suggested that my colleagues and I might have trouble finding one in cases of autism. On the other hand, it seemed likely that if a variant allele could be found, it might well be one of the triggers for the development of the disorder.
The human version of the gene, labeled as HOXA1, resides on chromosome 7 and is relatively small. It contains just two protein-coding regions, or exons, along with regions that regulate the level of protein production or do nothing at all. Deviations from the normal sequence in any part of a gene can affect its performance, but the vast majority of disease-causing variations are in the protein-coding regions. Thus, we began the search for variant alleles by focusing on the exons of HOXA1. Using blood samples from people with autism and from subjects in a control group, we extracted the DNA and looked for deviations from the normal sequence of nucleotides.
The good news is that we have identified two variant alleles of HOXA1. One has a minor deviation in the sequence of one of the gene's exons, meaning that the protein encoded by the variant gene is slightly different from the protein encoded by the normal gene. We have studied this newly discovered allele in detail, measuring its prevalence among various groups of people to determine if it plays a role in causing autism. (The other variant allele is more difficult to investigate because it involves a change in the physical structure of the gene's DNA.)
We found that the rate of the variant allele among people with autism was significantly higher than the rate among their family members who do not have the disorder and the rate among unrelated individuals without the disorder. The differences were much greater than would be expected by chance.
The bad news is that, just as the family studies had predicted, HOXA1 is only one of many genes involved in the spectrum of autism disorders. Furthermore, the allele that we have studied in detail is variably expressed -- its presence does not guarantee that autism will arise. Preliminary data indicate that the variant allele occurs in about 20 percent of the people who do not have autism and in about 40 percent of those who do. The allele approximately doubles the risk of developing the condition. But in about 60 percent of people with autism, the allele is not present, meaning that other genetic factors must be contributing to the disorder.
To pin down those factors, we must continue searching for other variants in HOXA1, because most genetic disorders result from many different deviant alleles of the same gene. Variations in other genes involved in early development may also predispose their carriers to autism. We have already discovered a variant allele of HOXB1, a gene on chromosome 17 that is derived from the same ancestral source as HOXA1 and has similar functions in the development of the brain stem, but its effect in autism appears to be minor. Other investigators are scrutinizing candidate regions on chromosome 15 and on another part of chromosome 7. Although researchers are focusing on alleles that increase the risk of autism, other alleles may decrease the risk. These could help explain the variable expression of the spectrum of autism- related disorders.View Next Page