Mood Genes

From Mood Genes: Hunting For Origins of Mania and Depression

by Samuel H. Barondes

© 1998 by Samuel H. Barondes. All rights reserved.
Used with permission of W.H. Freeman and Company.

(Posted October 16, 1998 · Issue 40)

Editor's note: Samuel H. Barondes and his colleagues are engaged in what may be the most challenging and complex type of genetic research: the hunt for genes that affect not obvious physical features, or even relatively straightforward physical diseases, but the most elusive and fluid of human characteristics - our thoughts and emotions, specifically as manifested in mental illness. Barondes' work focuses on manic-depressive illness (or bipolar disorder), which is characterized by violent mood swings. About one in a hundred people are afflicted with the disorder in its most extreme form; several times that number suffer from a milder version. The malady runs in families, which makes it a good candidate for genetic research. Among the factors that complicate the search are the environmental influences that can contribute to a mood disorder, and the fact that multiple genes may be involved in manic-depressive illness. Mood Genes is a groundbreaking work that thoroughly explores the psychiatric and genetic research that seeks to alleviate the suffering of those trapped on an emotional roller coaster.

Here Barondes guides us through the intricacies of chromosome mapping, and describes the chromosome-screening studies done with several extended Costa Rican families (identified by numbers), among whom was found a high incidence of manic-depressive illness. Researchers were led to this population by one family member, Ana, who had seen many of her relatives, including her sixteen-year-old son, wracked by manic-depressive illness. The work with Ana's family would yield some momentous results.

Whenever you can, count. - Francis Galton

While the members of Ana's extended family were being evaluated clinically, great strides were being made in mapping human chromosomes. The starting material for this work was a set of standard DNA samples from several dozen families that had been collected in the 1980s at the Centre d'Etude du Polymorphisme Humain (CEPH) in Paris and distributed to geneticists around the world. Using the CEPH samples facilitated the relative positioning of newly discovered markers - mostly short tandem repeat polymorphisms (stirps) - on the emerging chromosome maps. These maps are continually updated through an international cooperative effort, as part of the Human Genome Project.

Much of the mapping is being done in France at a foundation called Généthon (the name - derived from gene telethon - reflects its support by the French equivalent of the Jerry Lewis telethons that helped fund the discovery of the gene responsible for muscular dystrophy). Another major mapper of stirps is a consortium of American scientists, many of whom are organized as the Cooperative Human Linkage Center. By mid-1994, when the genome screening of Ana's family was in full swing, these French and American collaborators had localized about six thousand markers on the map, so the average distance between known markers was less than 1 centimorgan (roughly a million base pairs).

 

A typical chromosome map includes a drawing of its physical features, the locations of some named markers, and measurements of the distances between them. Figure 1, for example, is a map of human chromosome 18 published in Science in 1994.

A critical physical feature of each chromosome is the location of a natural point of constriction, the centromere, which separates it into two segments called arms - a short one called p (for the French, petit) and a long one called q. Other features are brought out when the chromosome is stained with a dye that adheres to certain regions, giving rise to a distinctive pattern of bands (shown in alternating gray and white in the diagram). These bands have been assigned numbers relative to the centromere that serve as zip codes for markers and genes. Lined up next to the chromosome in the drawing are the positions of some stirp markers, which serve as more precise addresses. These markers may appear to be closely packed, but there are actually considerable intervals between them, indicated at the far left of the diagram. Though chromosome 18 is one of the smaller human chromosomes, it is still huge in molecular terms: it contains a double strand of DNA that is about 150,000,000 base pairs long and spans about 150 centimorgans, with about 25 genes in each centimorgan.

Similar maps are available for all the other chromosomes. There are also many additional markers that can be employed to explore a particular chromosome region in more detail. Both the basic maps and the continuous development of supplementary markers have proved to be indispensable tools in the hunt for mood genes in Ana's extended family.

That hunt began toward the end of 1993 with a screen of all the chromosomes of each person with narrowly defined manic-depressive illness - that is, bipolar disorder, type I - in Costa Rican Families 1 and 4, using 307 markers based on stirps. What this meant in practice is that a group of researchers, including Alison McInnes, Michael Escamilla, Nelson Freimer, and their staff in San Francisco, and Pedro Léon and his staff in San José, began the tedious job of examining the DNA samples from more than two dozen manic-depressive people, as well as other relatives, with 307 pairs of custom-made bits of DNA - the primers - each designed to assess a particular polymorphism. The task comprised many thousands of laborious examinations, each carefully checked for accuracy.

Though measurements of stirps have now been automated, in 1993 they were done by hand - by going through a set of steps that began with the mixing of each DNA sample with each set of primers and ended with the careful measurement of the lengths of the stirps. And the sole immediate reward for all this work was the knowledge that every measurement was being done accurately. Only after the stirp lengths in each sample for every one of the 307 markers had been determined, transmitted to Lodewijk Sadkuijl in Holland, and analyzed by a complex computer program - an overall process that would take more than a year - would this large team of researchers learn if they had succeeded in finding any evidence of linkage. Unless they did, all their labors would have been for naught.

Fortunately, the initial screen identified promising regions on several chromosomes. These were then scrutinized further with an additional 166 markers (more thousands of elaborate measurements), each known to cover a region adjacent to one that showed promise in the initial screen. Were a promising marker truly close to a mood gene, nearby markers should also give evidence of linkage. If they didn't, that would argue against the possibility that this chromosome region contained a mood gene.

Of the 473 markers used in the two-stage procedure, 23 met the screening criteria for possible linkage to a mood gene in either Family 1 or Family 4, and 6 met the screening criteria for the combined data set from both families. They are indicated in figure 2 by circles (Family 1), diamonds (Family 4), or stars (combined families) - with all the chromosomes depicted as the same size rather than drawn to scale.

Of the regions identified, the most likely site of a mood gene appears to be the cluster of three stars in the lower part of chromosome 18, the area with the broad zip code of 18q22-23; this cluster of identical marker alleles is shared by 23 of the 26 people with manic-depressive illness. What this clustering implies is that this chunk of chromosome 18 - and the mood-gene allele it presumably contains - came from a common ancestor with manic-depression. And even though it was still possible that the apparent sharing of this chunk of chromosome 18 in relatives with the mood disorder was just a coincidence, statistical analyses of the results (using several methods) indicated that this was unlikely. Five years of driving over the potholed roads of Costa Rica and of meticulous psychiatric and genetic testing had finally produced an encouraging result: 18q22-23 appears to contain a mood gene.

Had this Costa Rican study been the first to report a likely location of a mood gene, it would have been greeted with considerable enthusiasm by the scientific community. But because of the widely heralded Amish and Israeli studies that had turned out to be disappointments, the reception of this new study was respectful but restrained.

Samuel H. Barondes is the Jeanne and Sanford Robertson Professor and director of the Center for Neurobiology and Psychiatry at the University of California, San Francisco. He is the author of Scientific American Library's Molecules and Mental Illness (1993)

 

Endlinks

El Mal and G8 - for more on gene hunting, see these HMS Beagle Featured Essays from Alice Wexler's book Mapping Fate, which explores the Wexler family's personal experience with Huntington's disease, and their participation in the search for its genetic roots.

National Alliance for the Mentally Ill - outlines recent research concerning genetics and mental disorders.

Electronic Genetics Newsletter: Three Studies Link Genes to Manic Depression - a brief outline of recent studies exploring the genetic basis of depression.

Genomic and Genetic Resources on the World Wide Web - a collection of genetic resources including databases, genome centers, and chromosome maps.

Plain Talk About Depression - provides background information about depression.