Re: What is the evolutionary background of Alagille Syndrome?

Good question Alaina! Lets see what is known about Alagille syndrome, and then see if we can make sense of its genetics from an evolutionary perspective.

Alagille Syndrome is an inherited genetic disorder characterized by a reduced number of small bile ducts within the liver, which can result in various forms of liver disease, as well as abnormalities in at least two other organs including the heart, eyes, spine, pancreas and kidneys. However, many people who have this disease have very mild symptoms and can often appear to be perfectly healthy. In addition, the disease can be difficult to diagnose in some cases because the findings in other organs can be mild or variable, even in family members of a known patient. Family members can also be affected very differently; one family member might have severe heart disease, another severe kidney disease, and a third severe liver disease. Despite these obstacles to diagnosing the disease, Alagille Syndrome seems to be inherited as a dominant trait. So that if one of your parents has it, you have about a 50% chance of developing the disease, but if neither of your parents do, your chances are almost zero (assuming you can diagnose the disease properly).

These observations already tell us a few things about the genetics of this disease. First of all, it has what is called incomplete penetrance, so that even people who have the identical genetic makeup (as far as the root cause of the disease is concerned), can have different forms of the disease. This will be important for understanding how the disease could have spread through the population. In addition, the fact that it is a dominant trait means that you only have to inherit one copy of the responsible gene, instead of two, in order to contract Alagille Syndrome.

The actual genetic defect that is responsible for this syndrome is found on Chromosome 20, and is believed to be a gene called Jagged1. Mutated versions of this gene are observed in about 70% of patients suffering from Alagille Syndrome. The Jagged1 gene produces a cell-surface protein that interacts with a protein produced from a gene called Notch1. The interaction of these cell surface proteins results in the differentiation of cells during the course of development. Disruptions of these interactions will result in mistakes during development, such as those seen in Alagille Syndrome.

Scientists have examined the Jagged1 genes in a large number of individuals suffering from Alagille Syndrome, as well as their families, and as a result we know what sorts of mutations in this gene are responsible for the disease. These mutations include deletions (where DNA is removed), insertions (where DNA is added), mis-sense mutations (where a different amino acid is specified), non-sense mutations (where a prematurely short protein is specified), and splice site mutations (where the protein is assembled with large pieces missing or with large unwanted pieces added). Some of these mutations are found in areas of the Jagged1 gene that seem to be important for its function, but many are not. In addition, some people with the disease have had the entire region of chromosome 20 containing the Jagged1 gene deleted. However, none of these different mutations, or the deletion of the entire Jagged1 gene can be correlated with the various degrees of penetrance observed for the syndrome.

The fact that any of these mutations can result in the most severe version of the disease tells us that the disease itself is due to the loss of one functional copy of the Jagged1 gene. It doesn't matter if the function is lost because one copy was deleted, or because one copy suffered a single base insertion (as long as that insertion disrupts the function of the gene). This tells us that two functional copies of the Jagged1 gene are necessary for normal development. Because of this, Alagille Syndrome is an example of a disease caused by haploinsufficiency, the situation that you have when the haploid number (n) of genes is insufficient for normal function.

Knowing that haploinsufficiency of Jagged1 is all that is needed to develop Alagille Syndrome, we can start to draw some conclusions about its evolution. First off, we can conclude that most of the various families in which this disease is found are unrelated to each other. In most families, the mutation which causes the loss of function of the Jagged1 gene occurred spontaneously and independently from the others. For example, in one study of 19 families affected by Alagille Syndrome, twelve different mutations in the Jagged1 gene were observed, and seven of these were so-called novel mutations -- these mutations have not been observed in any other families. In another recent study of 54 Alagille Syndrome patients, thirty-five different Jagged1 mutations were observed, thirty-one of which were novel. So, it seems likely most cases of Alagille Syndome in unrelated individuals developed independently from one another.

In contrast, other disease causing mutations which can be traced individual founding ancestors (e.g. Breast Cancer in Scotland, and Huntingtons Chorea in Japan). In addition, there is at least one example of a genetic mutation that seems to offer protection against HIV infection which can be traced to a common ancestor in northern Europe.

The fact that there are so many independently generated mutant versions of the Jagged1 gene suggests two scenarios for the evolutionary history of this disease. Either (1) many of these mutations are very old, and have persisted in the population for a long time, or (2) the mutation rate for this gene is high, because it is easy to maintain mutant versions of the Jagged1 gene in the population. Although the studies of Jagged1 gene mutations are still preliminary at best, I think that if (1) were the case, we would see a different global pattern of mutations, where you have unrelated families who have inherited the same mutant gene. Instead, it looks like novel mutations occur in the Jagged1 gene at random all over the world, resulting in new instances of the Syndrome.

Now, the next logial question is, "why are these mutations not immediately removed from the population by the process of natural selection? " The answer lies in the observations that were noted in the beginning of this answer. Remember that this disease demonstrates incomplete penetrance, and that the various mutants and deletions of Jagged1 do not affect the degree to which the disease manifests itself. This means that there are other factors (some genetic and some environmental) which determine the severity of the disease. So, it is possible for someone to be missing one copy of the Jagged1 gene and have a very mild case of the disease. This means that they can survive to adulthood and reproduce, and pass on their defective copy of the Jagged1 gene or even the partially deleted chromosome 20 onto the next generation.

So, to address your question, it is not genetic drift that has spread this disease through the human population. It is the process of mutation, which continually generates new mutant versions of the Jagged1 gene from the functional version. In the case of many other genes where this occurs, the mutant versions turn out to be lethal or extremely deleterious, and are removed from the population by natural selection. However, in the case of Alagille Syndrome, the mutant versions of Jagged1 result in a disease which is sometimes lethal and sometimes mild. Therefore, in some cases, the mutants can be passed on to the next generation. Of course two defective copies of Jagged1 will be lethal. We can tell this because no one suffering from Alagille Syndrome has been observed with two mutant versions of the gene.

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