genetics, human conditions, technology

Genome-Wide Effects of Down’s Syndrome

Normally, a person has 46 chromosomes total, or 23 pairs of chromosomes. If a person has three copies of one of the chromosomes (instead of two copies), it can lead to serious developmental complications. One possibility is trisomy 21, or three copies of chromosome 21, which causes Down’s syndrome. (Most trisomies are lethal during development, resulting in an early-stage miscarriage, but trisomy 21 is an exception.) However, it turns out that having Down’s syndrome is not as simple as just having one extra, little chromosome — based on a study published earlier this month, the presence of the extra chromosome 21 actually effects every other chromosome — the entire genome — in the affected individual.

trisomy 21 Down syndrome
Down’s syndrome is caused by trisomy 21, or having an extra chromosome 21. (Image credit: National Human Genome Research Institute)

In the recent study, researchers looked at a pair of monozygotic (identical) twins where one of the twins had Down’s syndrome but the other did not — a very rare occurrence. Specifically, the researchers analyzed which genes were being activated, or expressed, and which were not, in each of the twins. (They did this by looking at messenger RNA [mRNA] levels in skin samples from each twin.) They found that the twin with Down’s syndrome had relatively under-expressed (or inactive) genes in several areas on different chromosomes, and overly-expressed (or overly-active) genes in other chromosome areas (compared to the twin, and other people, without Down’s syndrome). Overall, significant gene expression level changes were seen for 182 genes, which make up about 1% of the genome. Changes were seen on every chromosome.

How can one extra chromosome clearly change the expression of 182 genes in the genome? Many genes play crucial roles in controlling the expression of other genes. So when an extra chromosome 21 is present, genes on the chromosome that are important for regulating genes on other chromosomes might not work correctly, resulting in the disruption of gene expression across the genome. Specifically, some of the genes on the extra chromosome 21 are suspected to play important roles in regulating the expression of genes on other chromosomes through epigenetic modifications. (The authors did not find differences in epigenetic modifications via methylation, but instead suspect that histone modification may be affected — for example, HLCS is a gene located on chromosome 21 that is important for getting biotin to attach to histones, which is an essential part of how all genes are regulated.) Next, the researchers want to look into the involvement of specific genes in causing Down’s syndrome.

It is worth noting that the differences in gene expression levels between a person with Down’s syndrome and a person without it could vary greatly depending on the specific Down’s syndrome case, such as a person with trisomy 21 in every cell of their body compared to somebody with mosaic trisomy 21.

While this paper gives us a better understanding of how Down’s syndrome manifests, it is still unclear whether the gene expression effects are due to the over-expression of specific genes on chromosome 21, or to the extra DNA material in general.

So while having an extra chromosome may, on first glance, appear to be a straight-forward problem — there’s simply one more chromosome than normal — the more we learn about genetics and how our cells function, the clearer it becomes that nothing about them is simple, nor do problems occur in isolation. Our bodies are full of complex, interactive pathways that constantly respond and regulate each other, and so when some key components fail, the results can be quite deleterious.

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