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Many of the articles that we have written in the past few months have focused on deletions of genes on chromosome 18. Following the publications of these articles, we often field questions from families about what this all means for people with tetrasomy 18p. Understandably, they wonder whether having extra copies of these genes will have the same effect as having missing copies. In the grand majority of cases, we have to say that we simply don't know yet. The genes responsible for the health and developmental concerns in someone with 18p- might not be the same genes responsible for concerns in someone with tetrasomy 18p. Researching tetrasomy 18p presents some unique challenges that require innovative approaches.
One challenge in studying tetrasomy 18p is the uniformity of the genetic change. As many of our readers may know, there is a great deal of variation in the breakpoints of people with 18p- and 18q-. Scientists have taken advantage of this variety by comparing people with different breakpoints to link up genes with specific findings. In contrast, everyone with tetrasomy 18p has the exact same genetic change. Therefore, one of the tools we use with 18p- and 18q-, breakpoint variation, is not an option in tetrasomy 18p.
Another challenge is that one of the tools we use in study 18p- and 18q-, mouse models, are not available for tetrasomy 18p. Labs around the world have created mice with deletions of single genes for nearly all the genes in the mouse genome. We can use the information about these mice to make guesses about how deletions of these same genes will affect humans. This has helped to shed light on 18p- and 18q-. However, a mouse model with two extra copies of the genes on 18p has not been developed. This adds an additional challenge to studying tetrasomy 18p.
Lastly, we rely on population databases to give us some hints about the effects of a change in the number of copies of a gene. These databases include individuals with small duplications and deletions that are reported to be in good health with no major medical or developmental problems. These "copy number variants" in "normal" people suggests that the genes contained within them are not associated with any problems. In the case of duplications, though, we have to consider the way that the genes are regulated. Gene regulation refers to the way that a gene is switched on and off. There are regions within the genome that are responsible for regulating specific genes. Those regions are often, but not always, close to the gene itself. Therefore, it is impossible to know whether the small duplications in those populations behave like duplications in someone with multiple copies of an entire chromosome arm. Thus, the use of population databases is another tool that we cannot use as effectively to study tetrasomy 18p.
Due to these challenges, we have to develop a new approach to understanding Tetrasomy 18p. One potential approach is to look at gene expression. Although the genes are the same in every cell of the body, they might not necessarily by turned on in all of those cells. In other words, they might not be expressed in the same way in all the cells of the body. We believe that, in many cases, the body can compensate for an extra copy of a gene by altering the expression of that gene. Those cases where the number of copies of the gene do in fact change the expression of the gene suggest that they are the cause of the medical and developmental issues faced by people with Tetrasomy 18p. Those are the genes that we are hoping to identify.
Based on the results from an experiment we did several years ago, we learned that there is a great deal of variability in how different genes on chromosome 18 are expressed, even between individuals with the exact same genetic change (tetrasomy 18p). There is simply too much natural variation between different people's gene expression, regardless of the presence or absence of an underlying chromosome abnormality. This makes it difficult to make meaningful comparisons among individuals.
One possible approach to solving this problem is to compare the gene expression from someone with Tetrasomy 18p to the gene expression from the exact same person without Tetrasomy 18p. This is not as impossible as it sounds. There are several people who are mosaic for Tetrasomy 18p. This means that some of their cells have the normal number of chromosomes and some have the extra tetrasomy chromosome. If we begin with skin cells from these people, we can separate the two types of cells and compare their gene expression. Because the only difference between these two types of cells is the presence of the extra chromosome, we know that this chromosome is responsible for changes in gene expression, and is therefore a good candidate to be a key gene.
Although this article has focused on tetrasomy 18p, it is important to note that many of these challenges and possible strategies may also apply to individuals with trisomy 18.
In many ways, it is easier to study 18p- and 18q- than tetrasomy 18p and trisomy 18, simply because there are more research tools at our disposal. However, the scientists at the Chromosome 18 Clinical Research Center are no strangers to challenges, and we look forward to tackling these issues as we continue to work towards a more complete understanding of the chromosome 18 conditions.
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