Download New Ideas About Far Reaching Effects of an Extra Chromosome 21

New Ideas About Far Reaching Effects of an Extra Chromosome 21 Campbell K Brasington, MS, CGC Levine Children’s Hospital, Carolinas Medical Center, Charlotte, NC Recently, a paper was published in the journal Nature by Letourneau and colleagues (2014) from the University of Geneva that raised a lot of discussion on social media, particularly on our local DSAGC Facebook page. I am a genetic counselor and not a basic genetics researcher by any means. Some of the technical detail in this study is even over my head, but thought I would try to explain in basic terms what the results of this study mean to me as a clinical genetics provider (someone who sees individuals with Ds in the clinic) and how this might translate into current and future research directions. So in this study, the authors looked at a set of identical twins where one had trisomy 21 and the other did not. How can this be, don’t identical twins share 100% of their DNA? You are technically correct, however rarely, an embryo can start out with trisomy 21 and then in the early stages of cell division, the extra chromosome is lost and the embryo reverts back to two chromosome 21s (this is called “trisomy rescue”). If there is additionally a twinning event right around the time the trisomy rescue occurs, then you would end up with basically identical twins where one has trisomy 21 and the other does not. Or an embryo can start out disomic (two chromosome 21s), and then a misdivision of chromosomes occurs in those early cell divisions causing all cells in that new cell line to have trisomy 21 (basically, the way mosaic Down syndrome occurs). Again, if a twinning event occurs around this same time, you can also have one twin with trisomy 21 and the other without. (Interestingly, the discordance in the twins from the Nature study was not from either explanation but from a much more rare sequence of events that required more than just two random changes to cause the differences in their chromosome make up [Dahoun et al, 2008].) Studies on identical twins are used in genetics research a lot to help tease apart what might be a genetic influence on a specific disease process vs. what may be environmental influences. By controlling for genetic makeup or for environmental exposures, researchers can be more confident that a condition is most likely to be influenced more by genetic factors or by environmental factors. The use of the discordant twins in the Nature study allowed the researchers to look at the effects of the extra chromosome 21 without any other environmental influences. It has long been assumed that the features associated with Down syndrome are mainly caused by the overexpression of the 200‐300 or so genes along chromosome 21. It has also been known for some time that genes on one chromosome can be influenced or regulated by genes on other chromosomes. The Nature study is one of the first studies to be able to look at the effects of trisomy 21 on other genes in the genome and is a beautifully done study. [There was a FB comment chuckling at Dr. Harpold’s use of the word ‘elegant’ to describe this study. While seemingly out of place, this is a common term researchers use to describe a very well‐
designed and executed study. ] The study authors found that: 1) Gene expression between the twins was organized and regulated in domains along ALL their chromosomes, not just chromosome 21. 2) These regulatory domains were also found to be conserved in the trisomy 21 mouse (Ts65Dn), so were confirmed in another genomic model. 3) In most of the chromosomes, large regions of upregulated genes alternate with large regions of downregulated genes (this effect appears to be usually masked in typical, non‐related individuals because of their innate genetic variation) 4) In the twin with trisomy 21, the opposite occurred where the areas of upregulated genes appeared to be downregulated instead, and the areas of downregulated genes were instead upregulated, causing a “flatter” gene expression overall. It is speculated that these gene domains along all of the chromosomes may help provide cells with access to important or necessary genetic information at the time and location it is needed for normal cellular processes. The results of the study suggest that this diminished difference in gene expression (both up and down) among individuals with trisomy 21 might interfere with the usual functions of the cell and may be another mechanism for the features associated with the syndrome. It also shows that the effects of trisomy 21 may be more far reaching than just the overexpression of those genes found on chromosome 21. Obviously, this study raises many more questions than it answers but that is not new to anyone who has been following genetics over the past few decades! Certainly the development of new genetic technologies has outpaced our understanding of how many of these new findings are used and interpreted for our patients we see in our clinic and how they can be applied to clinical care. This study’s findings do open many new doors for other ways to look at Down syndrome and how we might develop effective treatments that will improve overall health, cognition and quality of life for children and adults with Down syndrome. This will build upon and enhance research already ongoing and may also help in understanding the effects of other trisomies, such as trisomy 18 and trisomy 13. Personally, I am excited by this study because it shows that researchers are continuing to think about Down syndrome in new and innovative ways and how it affects the people we know and love who have Down syndrome so that future generations will benefit. References: Dahoun S et al. (2008). Monozygotic twins discordant for trisomy 21 and maternal 21q inheritance. Am J Med Genet, 146A, 2086‐2093. Latourneau A et al. (2014). Domains of genome‐wide gene expression dysregulation in Down’s syndrome. Nature, 508, 345‐350. Pope B and D Gilbert. (2014). Up and down in Down’s syndrome. Nature, 508, 323‐324.