Trisomy 21 – A Deeper Look

Trisomy 21 – A Deeper Look

Most of us know that Trisomy 21 means there are three chromosomes on the 21st chromosome instead of 2. While this discovery was only made in 1959 (1) we are still trying to understand what this extra chromosome actually means. As a parent I want to know because if we understand it then maybe we can help to support our children develop to the best of their abilities. It always strikes me as important to note that generally in DS, IQ declines during childhood and continues decreasing in adolescence and adulthood (2). Therefore the affects of this extra chromosome are progressive – they worsen with age and while I know you can’t cure DS, maybe we can at least slow down cognitive deterioration. In order to begin understanding this lets begin with the chromosomes.

Trisomy 21 – A Deeper Look

A good way to get an understanding of chromosomes is to watch these two you tube videos.

A chromosome is a storehouse for our DNA and genes. Having an extra 21st chromosome means having a whole extra set of genes and DNA. The problem with this is that some of these genes are constantly expressing (over expression), meaning there is too much of some proteins being produced in the body and these proteins can cause damage (3, 4).

What are the proteins?

Proteins are large, complex molecules made up of amino acids. Within the body they have many critical roles. They do most of the work in cells and are required for the structure, function, and regulation of the body’s tissues and organs.

Examples of proteins are;

  • Antibodies – Antibodies bind to specific foreign particles, such as viruses and bacteria, to help protect the body. Immunoglobulin E – IgE
  • Enzyme – Enzymes carry out almost all of the thousands of chemical reactions that take place in cells. They also assist with the formation of new molecules by reading the genetic information stored in DNA. E.g. Phenylalanine hydroxylase
  • Messengers – Messenger proteins, such as hormones, transmit signals to coordinate biological processes between different cells, tissues, and organs. E.g. Growth Hormone
  • Structural components – These proteins provide structure and support for cells. On a larger scale, they also allow the body to move. E.g. Actin – Important part of muscle
  • Transport/storage – These proteins bind and carry atoms and small molecules within cells and throughout the body.e.g. Ferritin – carry’s iron

So what Proteins does the 21st Chromosome Make?

Humans typically have 46 chromosomes in each cell, divided into 23 pairs. This includes two copies of chromosome 21, one copy inherited from each parent. Chromosome 21 is the smallest human chromosome representing 1.5 to 2 percent of the total DNA in cells, consisting of 225 genes (5) of which approximately 170 code for proteins (6). These proteins perform a variety of different functions in the body.

Over expression of the trisomic genes and their resultant proteins is not straight forward. A study by Lyle 2004 (4) examined the tissues of brain, heart, kidney, liver, lung, and muscles at two different ages in DS mouse models and found;

  • Only approximately a third of the genes (37%) were expressed at 1.5-fold.
  • On average, 45% of the genes were expressed at significantly lower than 1.5-fold, and
  • 9% were not significantly different from 1.0.
  • 18% of the genes were expressed at levels significantly greater than 1.5-fold.

Another study (10) examined the gene expression within the tissues, there averages varied

  • The cortex was 1.63
  • Heart 1.73
  • Kidneys 1.23
  • Muscle 1.16

A different study (9) examining gene activity across all chromosomes within cells from the cerebral cortex and cerebellum found an increase in expression of only 25 genes on the 21st chromosome. These increases varied between individuals, with some showing no increases on the same genes. They also found differences in expression levels of genes on other chromosomes – about 85 genes whose expression increased and 100 whose expression decreased. Gene expression increases and decreases on other non 21st chromosome genes were also found by Amano et al (8).

Why so complicated?

There are a few theories for the differences in the genetic expression of the extra chromosome. These include;

  • Allelles
  • Different points of development – so a gene may over express more when it is being very active
  • Genetic variation
  • Environmental factors

It is worth noting that in the DS mouse models there is no allelle difference, for the Ts1Cje mouse model there is also no genetic variance, and very minimal genetic variation for the Ts65Dn model. Which suggests other factors are at play.

So as with most things in life it is complicated. There is a lot of individual variance but there are also some critical genes which are commonly over expressed – genes affecting brain function and development such as DYRK1A and RCAN1 and proteins that cause a lot of oxidative stress and damage in the body such as SOD2. Slowing over active genetic expression and protein production is really important. Unfortunately identifying exactly what genes are over expressed, by how much and when in individuals is not generally possible. So supplementing and focusing on key genes such as with the Targeted Nutritional Intervention (TNI) protocol and EGCG,  from green tea, increasing anti-oxidant intake  is a good place to start. Whilst doing this it’s important to also look at functional aspects – what nutrients are depleted, what functional processes are being hindered. Testing such as organic acids testing is useful for this. It’s also essential to keep the body healthy and this revolves around digestive system, diet, exercise and minimising exposure to environmental toxins. When looking at genes we want to focus on the genes that have a particularly powerful effect on cognitive health and development, speech and oxidation.  As well as genes with important functions that consistently prove to be over or under expressed in studies.


  • Jacobs P., Baikie A., Court-Brown W., Strong J. The somatic chromosomes in mongolism, Lancet, 1959, vol. i (pg. 710 – 711)
  • Carr J.. Annotation: long term outcome for people with Down’s syndrome, J. Child Psychiatr., 1994, vol. 35 (pg. 425 -439)
  • Kahlem P, Sultan M, Herwig R, Steinfath M, Balzereit D, et al. Transcript level alterations reflect gene dosage effects across multiple tissues in a mouse model of down syndrome. Genome Res. 2004;14:1258–1267. [PMC free article] [PubMed]
  • Lyle R, Gehrig C, Neergaard-Henrichsen C, Deutsch S, Antonarakis SE. Gene expression from the aneuploid chromosome in a trisomy mouse model of down syndrome. Genome Res. 2004;14:1268–1274. [PMC free article] [PubMed]
  • Hattori M, Fujiyama A, Taylor TD, Watanabe H, Yada T, Park H-S, Toyoda A, Ishii K, Totoki Y, Choi DK, et al. The DNA sequence of human chromosome 21. Nature. 2000;405:311–319. doi: 10.1038/35012518. [PubMed] [Cross Ref]
  • Gardiner K, Costa ACS. The Proteins of Human Chromosome 21. American Journal of Medical Genetics Part C, Seminars in Medical Genetics. 2006;142C(3):196-205.
  • Gardiner K, Fortna A, Bechtel L, Davisson MT. Mouse models of Down syndrome: how useful can they be? Comparison of the gene content of human chromosome 21 with orthologous mouse genomic regions. Gene. 2003;318:137–147. [PubMed]
  • Amano K, Sago H, Uchikawa C, Suzuki T, Kotliarova SE, Nukina N, Epstein CJ, Yamakawa K. Dosage-dependent over-expression of genes in the trisomic region of Ts1Cje mouse model for Down syndrome. Hum Mol Genet. 2004;13:1333–1340. doi: 10.1093/hmg/ddh154. [PubMed] [Cross Ref]
  • Kahlem P, Sultan M, Herwig R, Steinfath M, Balzereit D, Eppens B, Saran NG, Pletcher MT, South ST, Stetten G, et al. Transcript level alterations reflect gene dosage effects across multiple tissues in a mouse model of Down syndrome. Genome Res. 2004;14:1258–1267. doi: 10.1101/gr.1951304.[PMC free article] [PubMed] [Cross Ref]