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Thursday, May 23, 2013

Genetic mosaicism may affect genome studies

There are so many things I love about this story, not the least of which is that the senior author on the paper is named Hudson Freeze. Kudos to his parents. More importantly, this study exposes a hitherto unsuspected problem with genomic studies. Not all the cells within a person contain the same genes.

To be clear, it’s not the phenomenon of having cells of different genotype that’s novel. Scientists have known about the existence of genetic ‘mosaics’ for over eighty years. Occasionally when cells divide, DNA replication or chromosome division goes slightly awry and you end up with two daughter cells that are not genetically identical.

The drawing below illustrates mosaicism (don’t worry about the name of the specific gene or syndrome in the captions, they’re from a different article). 

What is new is the realization that mosaicism may have to be taken into account when doing genomic studies. Case in point, three young children with glycoyslation disorders. Briefly, these kids have mutations that prevent their cells from attaching the right sugars in the right places to their proteins. Sugar placement is surprisingly critical for a whole host of functions, including cognitive ability.

Here’s the interesting part: only some of these kids’ cells contained the relevant mutation. This made it difficult to accurately diagnose them, because genetic studies came up negative or inconclusive. The scientists realized that they were dealing with mosaicism. That is, only a subset of the kids’ cells were defective.

Going forward, Freeze and his colleagues suggest that researchers be cautious about how much credence they pay to whole genome studies. Those studies obviously involve only a tiny fraction of a person’s cells and could possibly be misleading.

By the way, this study dealt with ‘somatic mosaicism’. The children with this condition had originated from a single fertilized egg and some of their cells had subsequently mutated. This is a common enough occurrence that some researchers believe we may all be somatic mosaics. Under rare circumstances, two fertilized eggs will fuse into one embryo (the reverse of identical twinning) and the resulting baby will have some cells that are derived from each of those eggs.


Ng, B., Buckingham, K., Raymond, K., Kircher, M., Turner, E., He, M., Smith, J., Eroshkin, A., Szybowska, M., Losfeld, M., Chong, J., Kozenko, M., Li, C., Patterson, M., Gilbert, R., Nickerson, D., Shendure, J., Bamshad, M., & Freeze, H. (2013). Mosaicism of the UDP-Galactose Transporter SLC35A2 Causes a Congenital Disorder of Glycosylation The American Journal of Human Genetics, 92 (4), 632-636 DOI: 10.1016/j.ajhg.2013.03.012.