For decades, molecular biologists have known about the great power of studying persons whose parental lineages share a close, common ancestor. The probability of their offspring exhibiting an autosomal recessive trait is much greater than in the general population. (Recall that autosomal 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:
1. Subjects who carry a specific, well-defined disorder are identified. Accomplishing this first step, which requires the researchers to decide on a specific set of diagnostic criteria, is one of the hardest parts of the entire procedure.
2. Once identified, subjects are screened for nucleotide sequences that they share in common and are homozygous for both chromosomes. The assumption is that these regions are donated from both paternal and maternal lineages who themselves shared a recent common ancestor. That is a reasonable supposition if you are studying closely related persons, such as first cousins.
Although admittedly a tough technique to execute properly, homozygous mapping has proved to be successful in isolating gene sequences that mediate rare diseases related to neural development. Until very recently, however, it had not been tried on such complex challenges as autism. When it was, it proved to be invaluable in the autism-screening procedures.
Researchers first had to find consanguineous families with autistic children. They established a collaborative network called the Homozygosity Mapping Collaborative for Autism (HMCA) in the Middle East and throughout Eurasia.1 The reason for this geographic localization has to do with statistical access. It is quite common in the Middle East for cousins to marry each other. Since the families tend to be large, the researchers reasoned they would most likely find persons that met both their genetic and behavioral criteria. They hit pay dirt. The researchers were able to find 88 consanguineous families with autistic children.
The investigators next scanned the genomes of all participants at high resolution. They were looking for a wide variety of chromosomal aberrations, such as inversions, deletions, duplications, and something called copy-number variations.
After exhaustive screening, the researchers found that 6 chromosomal regions in the HMCA sample had inherited, homozygous deletions. These deletions varied in size from a low of 18 kilobases to more than 880 kilobases.
Exactly what genes were on these important chromosomal regions, and how might their characterization increase our understanding of autism? To discover what happened next, we need to switch fishing protocols. We are going to tie up our large fishing trawlers, which is what homozygous mapping is, and inspect the catch. Once inspected, the next steps will then involve breaking out our much smaller fishing poles, putting some bait on the end, and casting our lines back into the genomic waters.
As you see in the Figure, a large number of genes were netted in this experiment. I will describe exactly what was in the catch and how this increases our understanding of autism next month.