A discovery that may someday help to explain human social behavior and disorders such as autism has been made in a species of pudgy rodents by researchers funded, in part, by the National Institutes of Health’s (NIH) National Institute of Mental Health (NIMH) and National Center for Research Resources (NCRR).

The researchers 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 — once 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. Drs. Larry Young and Elizabeth Hammock, Emory University, report on their findings in the mouse-like animals native to the American Midwest in the June 10, 2005 Science.

The discovery is the latest in a two decades-old scientific quest for the neural basis of familial behavior begun at the NIMH Intramural Research Program in the mid l980s by now 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. Yet, how such behavioral differences could have evolved in animals that otherwise appear almost identical remained a mystery.

“This research appears to have found one of those hotspots in the genome where small differences can have large functional impact,” explained Insel. “The Emory researchers found individual differences not in a protein-coding region, but in an area that determines a gene’s expression in the brain. 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.

“It was considered junk DNA because it didn’t seem to have any function,” noted Hammock.

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

The researchers first showed in cell cultures that the vole vasopressin receptor microsatellites could modify gene expression. Next, 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 (olfactory bulb and lateral septum). They also checked out female odors and greeted strangers more readily and were more apt to form pair bonds and nurture their young.

“If you think of brain circuits as locked rooms, the vasopressin receptor as a lock on the door, and vasopressin as the key that fits it, only those circuits that have the receptors can be ‘opened’ or influenced by the hormone,” added Hammock. “An animal’s response to vasopressin thus depends upon which rooms have the locks and our 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.

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, suggest the researchers. 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.

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, according to Young.

In addition to NIH, the research was also supported by the National Science Foundation.

NIMH and NCRR are part of the National Institutes of Health (NIH), the Federal Government's primary agency for biomedical and behavioral research. NIH is a component of the U.S. Department of Health and Human Services.