Posted by Adam on January 31, 2000, at 17:36:01
In reply to The Human Genome Project, posted by Sam on January 31, 2000, at 2:43:01
> Does anyone know if they have made any progress towards identifying genes or defective genes correlating to manic depression and schizophrenia etc.?
Well, there's this...
Am J Hum Genet 2000 Jan;66(1):205-215
Full-Genome Scan for Linkage in 50 Families Segregating the Bipolar Affective Disease Phenotype.
Friddle C, Koskela R, Ranade K, Hebert J, Cargill M, Clark CD, McInnis M, Simpson S, McMahon F, Stine OC, Meyers D, Xu J, MacKinnon D, Swift-Scanlan T, Jamison K, Folstein S, Daly M, Kruglyak L, Marr T, DePaulo JR, Botstein DDepartment of Genetics, Stanford University, Stanford, CA, USA.
[Record supplied by publisher]A genome scan of approximately 12-cM initial resolution was done on 50 of a set of 51 carefully ascertained unilineal multiplex families segregating the bipolar affective disorder phenotype. In addition to standard multipoint linkage analysis methods, a simultaneous-search algorithm was applied in an attempt to surmount the problem of genetic heterogeneity. The results revealed no linkage across the genome. The results exclude monogenic models and make it unlikely that two genes account for the disease in this sample. These results support the conclusion that at least several hundred kindreds will be required in order to establish linkage of susceptibility loci to bipolar disorder in heterogeneous populations.
Not very satisfying, is it? That's why I think I got so worked up about the 5-HT2A/suicide link (which still needs to be proven). It seems to be awfully rare to find such strong correlations in the realm of mental illness. But people have been saying for years that there's a genetic component to bipolar illness, and the various pedigrees that have been done in the past clearly support this. Exogenous factors like, say, a viral infection can hugely complicate the issue, especially if the infection is temporary and the virus is of a type that leaves no genetic trace of its presence (i.e., it doesn't incorporate its genome into that of the host, such as a virus with a lytic and lysogenic cycle that can remain dormant for years or forever). However, the fact remains that bipolar illness has shown a strong familial link. Knowing the genetically predisposing factors can only help.
I think things will start to take off when the relationship between gene regulation and pathology starts to get worked out. That's one of the next big steps. Once the human genome has been sequenced and mapped completely (we're maybe two or three years away from that), of course people will look for mutations in the coding sequences of genes, and the enormous work of structure-function analysis of the protein products will assuredly illuminate the role of mutations, as well as the rational design of new drugs. But there's also the question of differential expression, which is an important factor that can confound standard genetic analysis. Gene regulation (signal transduction cascades, the importance of regulatory elements such as promotors or enhancers, sequences that affect mRNA stability, etc., etc.) present us with so many possible permutations that it's nearly impossible sometimes to tease out what the source of the difference is (a mutation someplace, most likely, maybe in a sequence not clearly associated with the "gene"). But you can at least identify resultant differences, and that will also allow one to build strategies for counteracting the effects of, say, the excessive production of an enzyme or the insufficient expression of a receptor. Massively parallel differential expression screening techniques have been developed and are being perfected. Once we have a good database of differential display and SAGE libraries, for instance, the nature of disease will be greatly elucidated.
poster:Adam
thread:20163
URL: http://www.dr-bob.org/babble/20000128/msgs/20228.html