Tuesday, June 16, 2009

Genetics in clinical practice--the tail end of the spectrum?

One of the more interesting talks at the Bristol meeting, perhaps because it's an area we don't know much about, had to do with clinical applications of genetics. The question concerned when, where, and how genetic information can be useful in the clinic. But the issues go much deeper than that, and relate to main points in our 'Mermaid' book.

The idea presented was that genetic information can be useful, not so much for disease risk prediction, because genotypes have poor predictive power for 'complex' traits (that is, and somewhat circularly, those that are not due to a single, and hence predictive, gene!). Instead, the argument was that genotyping can help determine therapy in the diagnostic sense of determining which of many causes may apply to, and hence guide therapy for, individual cases of a given disease.

An example given was MODY, or 'maturity onset diabetes of the young. MODY runs in families and can mimic both type 1 and type 2 diabetes, though most often it is a mild form of T1D, but with patients continuing to make some insulin (T1D, or juvenile diabetes is due to a failure to make insulin; T2D, or adult diabetes, is failure of cells to respond to insulin). The speaker, Dr Andrew Hattersley, described one family in which each affected member was being treated differently, but once the causal gene was known, each member was treated more appropriately, and the disease then better controlled. This was very good to hear because all too often even knowing the causal gene can't inform treatment--Huntingdon's disease comes to mind.

Hattersley also discussed a gene that causes three forms of achondroplasia, or dwarfism, but the particular mutation in that gene determines whether an individual will be somewhat shorter than normal, or will be much more severely affected, and knowing the mutation during pregnancy helps to prepare the family and clinician.

He primarily discussed single gene disorders, although these are often disorders that can be caused by a number of different mutations or even different genes, but in the instances described, knowing the specific mutation can make the difference between useful medical intervention and none. The idea is essentially that the 'same' disease is not really the same in different individuals if enough specificity is known, and that when a gene's effects are understood, knowing the causal gene is clinically relevant.

By contrast, all too often in human genetics identifying genes whose variation is statistically associated in at least some studies with the occurrence of disease contributes nothing toward treatment, because the statistical connection is too weak to be useful. That is the problem that is now widely recognized in regard to GWAS (see our many earlier posts) for complex diseases, so we were heartened to learn that this is not always the case. In some cases, knowing the physiological pathway is very useful.

The much broader relevance of these points is that they relate to genetic determinism: the degree and specificity to which genes determine phenotypes (the same applies to environmental factors). Only to the extent that genes determine traits in organisms can knowing the genotype be used to predict the trait. That has everything to do with views, accurate or hyped, about the usefulness of huge genotyping studies to health. It has to do with the use of genetics in social behavioral and other societal contexts. And it has to do with the origins of traits and with evolution itself.

To the degree that natural selection molds and creates (produces) the traits we see in organisms--and that it does so is at the heart of Darwinian theory--genes must determine traits. That's because if genotypes do not determine the trait, selection for or against variation in the trait won't affect the frequency of genetic variation, and hence won't guide genetic evolution. Yet the modern Darwinian evolutionary theory is entirely based on genetic determinism.

With selection on phenotypes, not genotypes, if the connection between genotype and phenotype is weak, selection only weakly affects the relative success ('fitness') of genotypes, and their frequency changes over the generations will largely be the result of chance, not selection.

When a mutation strongly affects a trait, and the trait is important to organisms' success, then Darwinian theory works just fine as advertized. But this is not so if traits are so genotypically complex that selection hardly affects an individual gene.

There is a middle ground. If a trait, like a disease, is a strong reflection of a specific genotype, but many different genotypes can generate similar traits, then prediction can be weak but once the trait has arisen it can be useful to determine which of those causes is responsible. From an evolutionary point of view, if each instance of a trait is due only to variation in a single gene, then selection can affect the frequency of that variation.

The key difference is that for complex traits the phenotype is thought to be the simultaneous result of variation at many different genes. There are so many combinations of genotypes that can generate similar phenotypes, that one can't usefully predict the latter from the former--or, perhaps, not even go back the other way, unless variation at only one or a few genes is responsible in a given instance.

Thus, prediction in development, medicine, or evolution all depend centrally on the degree to which genes individually, or in aggregate, determine the traits you bear in life. In the 'tail' end of the causal spectrum, where specific variants exert strong effects, things work out nicely.

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