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Genetic associations with disease may result from alleles that increase protection from one pathogen but increase vulnerability to another.

The genetic variation responsible for these associations may persist indefinitely, because the success of a variant is negatively related to its frequency.

As a pathogen variant increases, it favors increased frequency of a host variant that controls it; as this host variant becomes more prevalent, it increasingly disfavors the pathogen variant. “Dynamical polymorphisms” of resistance genes may thus persist by this process of nonprogressive seething.
If underlying infectious causes are not recognized, the reduced success of some host variants (due to the inherent costs of the particular genetic defense or to the increased vulnerability to the existing mix of pathogens) could be misconstrued as a genetic disease.

Variations in human leukocyte antigens (HLA) appear to be a particularly important example of this process, because different HLA alleles are associated with differences in recognition and presentation of foreign antigens, or with differences in vulnerability to autoimmune disease as a consequence of cross reactivity between pathogen and host antigens.

HLA variants are associated with vulnerability to infectious diseases such as malaria and tuberculosis, and infection has been causally linked to HLAassociated autoimmune diseases such as herpes stromal keratitis and Reiter’s syndrome. The high degree of polymorphism of such alleles implicates a role for infection in many diseases that exhibit moderate heritibilities.

HLA variants are associated with many chronic diseases, such as juvenile diabetes, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Crohn’s disease, myasthenia gravis, Hodgkin’s disease, multiple sclerosis, Grave’s disease, narcolepsy, and pernicious anemia.

Individuals with HLA B-27, for example, comprise about 5 percent of the population and are about 80 times more likely to have ankylosing spondylitis, which is often manifested by severe arthritis-like conditions. The monozygotic twin concordance for most of these HLA-associated diseases is less than 50 percent—something other than host genetics is therefore making a major contribution. Infectious causation has not been investigated for some of these HLA associations; for others there is suggestive evidence.

Juvenile diabetes, for example, is due to the gradual disappearance of insulin production. Its temporal association with infection, the similarity of viral antigens with autoimmune-associated HLA antigens, and regional and seasonal patterns, implicate infectious causation. Coxsackie virus is a
leading suspect.

The reasons for the presence and maintenance of trinucleotide repeatdiseases such as fragile X and myotonic dystrophy are largely unknown.
These diseases occur after a small, “subclinical” length of trinucleotide repeats lengthens rapidly over several generations as a result of errors associated with a hairpin transcriptional structure. The lineages of these people then tends to dwindle to extinction. Individuals with subclinical repeat
lengths are virtually absent in some regions and too widespread in other regions to be attributed solely to founder effects. The low frequency of new haplotypes among such individuals suggests that the low repeat numbers are generated too rarely by new mutations to be maintained solely by mutation.
This set of characteristics is consistent with the subclinical repeats being a defense against infectious agents and are difficult to explain without invoking such a benefit; we therefore suggest that the possibility of a defensive function of subclinical repeat lengths warrants investigation.

Psychological Phenomena

The fitness load approach also applies to psychological phenomena.

Psychological and behavioral alterations among infected individuals may represent manipulations of hosts for the spread of pathogens, defenses against the pathogen, or side effects of infection that benefit neither host nor pathogen. Rabies is a dramatic example of a manipulation: the pathological rage induced by the virus increases the chance of biting and hence transmission of the virus in the saliva. Syphilitic insanity appears to be an example of a side effect. These examples could be dismissed because they are so extreme, but it is the extreme examples that are the most conspicuous
and that therefore will tend to be discovered without a concerted research effort.

Just as it was inappropriate to reject infectious causation of human cancers on the basis of the conspicuous progression of Rous’s sarcoma in chickens, it would be inappropriate to reject the idea that pathogens could cause subtle changes in human behavior on the basis of
the conspicuous psychological effects of rabies and syphilis.

Had Treponema pallidum been a less conspicuous organism, causing less conspicuous mental illness, and less conspicuous links between early symptomatic infection and mental illness we might not recognize even today that this spirochaete can cause mental illness.
The intricacies of neuronal circuitry suggest that behavioral changes may result from slight changes in brain structure; and such slight changes may be more difficult to link to infectious organisms than the gross pathological changes found in other less intricate tissues, such as the changes in
the lungs caused by M. tuberculosis.

Moreover, generating appropriate animal models for testing of infectious causation often may be very difficult or even impossible because of the intellectual complexity of human behavior, the subtleties of variations in human behavior, and the difficulties of understanding the thought processes of nonhuman subjects.

Considering these problems, we cannot use the absence of conspicuous evidence of infection-induced behavioral alterations as evidence of the absence of such alterations.
In spite of these limitations, a combination of comparative study and animal experimentation are already proving useful for investigations of some psychiatric disorders. Borna disease virus, for example, has a tropism for the limbic system and is known to cause mood disorders in sheep, horses,
and rats. It has been isolated from human brain tissue, and infections in humans are significantly associated with schizophrenia and clinical depression (i.e. bipolar disorder).
Evidence also implicates infectious causation of some obsessive compulsive disorders by
streptococcal infections.


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