DNA discovery may help explain disorders such as autism

Researchers have made a discovery that may in future help to explain many aspects of human social behavior and disorders such as autism.

The researchers, Drs. Larry Young and Elizabeth Hammock, of Emory University, using the native vole, traced social behavior traits, such as monogamy, to seeming glitches in DNA that determines when and where a gene turns on.

The length of these repeating sequences , at one time dismissed as mere junk DNA, in the gene that codes for a key hormone receptor determined male-female relations and parenting behaviors in a species of voles.

This is the latest discovery in a two decades-old scientific quest for the neural basis of familial behavior begun at the National Institute of Mental Health (NIMH) Intramural Research Program in the mid l980s by NIMH director Thomas Insel, M.D. By l993. His team had discovered that the distribution of brain receptors that bind to the hormone vasopressin differed dramatically between monogamous and polygamous vole species and accounted for their divergent lifestyles. How such behavioral differences could have evolved in animals that otherwise appear almost identical remained a mystery.

Insel says that the research appears to have found one of those hotspots in the genome where small differences can have a large functional impact, and individual differences are not in a protein-coding region, but in an area that determines a gene’s expression in the brain. He says this is an extraordinary example of research linking gene variation to brain receptors to behavior.

Hammock and Young were particularly intrigued with microsatellites, repeating sequences of letters in the genetic code peppered throughout these regulatory areas of the vasopressin receptor gene.

Apparently each animal species has its own signature microsatellites; for example, the repeating letter sequences are much longer in monogamous than in polygamous vole species, and even within a species, there are differences in the number of letters in the sequence among individuals.

The researchers first demonstrated in cell cultures that the vole vasopressin receptor microsatellites could modify gene expression.

Then they bred two strains of a monogamous species, the prairie vole, one with a long version of the microsatellites and the other with a short version.

Adult male offspring with the long version had more vasopressin receptors in brain areas involved in social behavior and parenting and they also checked out female odors and greeted strangers more readily and were more apt to form pair bonds and nurture their young.

Hammock says it helps if brain circuits are thought of as as locked rooms, and the vasopressin receptor as a lock on the door, and vasopressin as the key that fits it, so only those circuits that have the receptors can be 'opened' or influenced by the hormone.

He says an animal's response to vasopressin depends upon which rooms have the locks and the research shows that the distribution of the receptors is determined by the length of the microsatellites.

Prairie voles with the long version have more receptors in circuits for social recognition, so release of vasopressin during social encounters facilitates social behavior. If such familial traits are adaptive in a given environment, they are passed along to future generations through natural selection.

The researchers suggest that variability in vasopressin receptor microsatellite length could help account for differences in normal human personality traits, such as shyness, and perhaps influence disorders of sociability like autism and social anxiety disorders.

The Emory researchers have found that the bonobo, an ape noted for its empathic traits, unlike its relative the chimpanzee, has a microsatellite with a sequence similar to that of humans. Two studies have found modest associations between alterations in this microsatellite and autism in some families. As subgroups of autism spectrum disorders are characterized, a stronger connection may emerge.

According to Young, far from being junk, the repetitive DNA sequences, which are highly prone to mutate rapidly, may ultimately exert their influence through complex interactions with other genes to produce individual differences and social diversity.

The research was funded, in part, by the National Institute’s of Health’s (NIH) National Institute of Mental Health (NIMH) and National Center for Research Resources (NCRR). The research was also supported by the National Science Foundation.

The study is published in the June 10, 2005 Science.