The Genetics of Mosaics and Chimeras.

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Hello today I will write about a very interesting aspect of genetics.

In genetics there is a term called “genetic mosaic”. This is an organism that has cells with two or more genotypes. How do Genetic mosaics arise? Well, scientist can create genetic mosaics in the lab using a variety of techniques (I’ll describe these in future posts) but it can happen naturally when chromosomes do not segregate properly during cell division (a process called non-disjunction). This can lead to trisomies and monsomies where some cells have three sets or 1 set of chromosomes respectively, instead of the typical 2 sets of chromosomes. Genetic mosaics can also arise when one cell, early in development, acquires a spontaneous mutation and all future cell divisions will carry this mutation. Thus, you end up with an organism with wild-type (normal) and mutant cells.

One type of genetic mosaic is called a Chimera. There has been some confusion with the terms Mosaic and Chimera and sometimes these terms are used interchangeably. In general, a genetic Mosaic is used to describe an organism with more than one genotype that is derived from a single organism. In contrast, a genetic chimera is an organism that has cells that have different genotypes because of the fusion of at least two different organisms.

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The term Chimera comes from the mythological Greek creature that is a composition of 3 different animals: a lion in the front, a goat’s head in the middle and a snake as its tail.

Did you know if you are a recipient of an organ or blood transfusion you are a chimera? This is because you are now composed of two genotypes, your original genotype and the genotype of your donor.

Chimeras can occur in birds such as this half blue and half green budgie:

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and the famous two faced cat called Venus who has her own Facebook page:

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Venus has been described as a chimera because of her two different colours faces and different colour eyes (fusion of two individuals). But some geneticists believe she is not a chimera but a mosaic (a single embryo). Further, some geneticist argue that technically she is not even mosaic as the genotype of all her cells are the same, but it is how the genes expressed from the X chromosomes are different. Most Calico cats are female and the colour patches are due to X inactivation (females have two X chromosomes males have one X and one Y). In females both X chromosomes aren’t active and in each cell, one of the two X chromosomes is inactivated or turned off. The coat colour genes are found on the X chromosome. This inactivation is need to compensate for the effect of the X chromosomes in males and females, since females have twice as many. Venus may be just a rare chance event of X inactivation on one side of her face. Sequencing cells from different patches should resolve this mysterious cat.

Chimeras can occur in invertebrates such as this lobster:

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The colour of the lobster’s shell is a mix of yellow, red, and blue pigments that result in the normal brownish-green colour of most lobsters. A mutant lobster that lacks blue and yellow pigments causes a red pigment, and this mutant lobster may have fused with the normal lobster to form a chimera early in development.

Chimeras are not exclusive to animals and even plants and fruits such as this chimeric apple:

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A really interesting type of chimera is called a gynandromorph. These chimeras are composed of male and female organisms. A striking type of gynandromorph are the ones with bilateral asymmetry meaning they show female on one side and male on the other side. This is thought to occur early in development when two zygotes (male and female) fuse to form one organism and hence you have both male and female cells developing as one organism. Here is an example of a zebra finch that is half male and half female:

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Interestingly, the neural song circuit on the right had a more masculine phenotype than that on the left. This finch shows that the genetic sex of brain cells contributes to the process of sexual differentiation (Agate et al. 2003).

It can also occur in insects such as the butterfly:

PHOTOGRAPH BY JAMES K. ADAMS
This tiger swallowtail Papilio glaucus is either all dark or all yellow, but this gynandromorph shows a yellow left side that is male and right dark side that is female.

As I mentioned earlier if you are an organ recipient you are also a chimera but it is otherwise known to happen naturally in humans as seen in the skin pigmentation of this person:

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One famous human chimera is the the model and musician Taylor Muhl

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and I encourage you to read this article which explains that chimeras can happen naturally in humans if a developing fetus absorbs its fraternal twin and becomes part of a single fetus.

Another famous example of a human chimera is woman named Karen Keegan, who needed a kidney transplant. But she is not a chimera because of her kidney transplant. During the test to find a suitable donor the doctors discovered Karen Keegan was a genetic chimera and published their results in the New England Journal of Medicine (Yu et al. 2002).

It was Karen Keegan’s documented chimerism that saved Lydia Fairchild from fraud charges. In 2002 Lydia Fairchild was charged for fraud in applying for child welfare support, as DNA testing showed that her children were not hers. Her lawyer was able to provide evidence based on Karen Keegan’s chimerism and showed that indeed Lydia Fairchild was also a genetic chimera with two sets of DNA and that one of her sets of DNA could be the mother of her children.

You might think human chimeras are extremely rare, but in fact it is more common than you think and we all might have a form of microchimerism. If you are a mother who has given birth, some of your developing child’s cells pass through the placenta and are incorporated into your body. So, if you had a boy you may have microchimerism and carry cells with a Y chromosome in some of your tissues Rao et al. (2008). It can also work in the other direction in that your mother cells can be incorporated in your body. So we may all carry some of our mothers cells!

The potential health consequences of microchimerism is unknown but some researchers propose this could be the cause of some autoimmune reactions and is consistent with autoimmune diseases in in middle-aged women, Nelson (1996) and some people who retain a high proportion of their mother’s cells also have higher rates of autoimmune diseases. This is presumably because the immune system recognizes the cells as foreign.

Finally, I will end with interspecies chimeras in particular human animal chimeras. This may seem like science fiction but in 2017 a human pig chimera was published in the journal Cell and reported to have 0.001% human cells, with the rest being pig, Wu et al. (2017). Why would scientist do this you may ask? This kind of research allows insights into species evolution, embryogenesis, and human disease. In addition, the pig has organs very similar to those of human organs and may someday provide donor organs for humans. Sheep are also good candidates for organ donors and as I write this article on genetic mosaics and chimeras, today (Feb. 19th 2018) a sheep-human chimera has been reported at the annual meeting of the American Association for the Advancement of Science.

I hope I have stimulated your interested in genetic mosaics and chimeras. If you are still interested, there are plenty of articles on the internet but I hope I have brought you a good introduction to this fascinating aspect of genetics.

References:

Agate et al. (2003). Neural, not gonadal, origin of brain sex differences in a gynandromorphic finch. PNAS 2003 April, 100 (8) 4873-4878. DOI: https://doi.org/10.1073/pnas.0636925100

Nelson (1996). Maternal-fetal immunology and autoimmune disease: is some autoimmune disease auto-alloimmune or allo-autoimmune? Arthritis Rheum. 1996 Feb;39(2):191-4.

Rao et al. (2008). Short communication: Y chromosome microchimerism in female peripheral blood. Reprod Biomed Online. 2008 Oct;17(4):575-8.

Wu et al. (2017). Interspecies Chimerism with Mammalian Pluripotent Stem Cells. Cell Volume 168, Issue 3, p473–486.e15, 26. DOI: https://doi.org/10.1016/j.cell.2016.12.036

Yu et al. (2002). Disputed Maternity Leading to Identification of Tetragametic Chimerism. N Engl J Med 2002; 346:1545-1552 DOI: 10.1056/NEJMoa013452