Genetics Index Glossary
Mosaicism and Chimerism
Mosaics and chimeras are animals that have more than one genetically-distinct population of cells. The distinction between these two forms is quite clearly defined, although at times ignored or misused. In mosaics, the genetically different cell types all arise from a single zygote, whereas chimeras originate from more than one zygote.
Mosaics are not uncommon; in fact, roughly half of the mammals on earth are a type of mosaic. A chimera, on the other hand, is not something you're likely to come across unless you are an experimental embryologist or raise cattle.
The term mosaic is usually applied to an animal that has more than one cytogenetically-distinct population of cells. For example, in a human mosaic, some of the cells might be 46, XX and some 47, XXX. The fraction of cells having each genotype is quite variable, reflecting how early during embryogenesis the mosaicism originated. In most but not all cases, the mosaicism can be detected in cells from all tissues.
What is the clinical significance of mosaicism? If the proportion of cytogenetically abnormal cells in a mosaic is sufficiently large, that individual will manifest disease. Conversely, if the abnormal cells are proportionally small in comparison to cytogenetically normal cells, the normal cells may be sufficient to prevent disease or reduce its severity. For example, a large majority of humans having Turner's syndrome (X chromosome monosomy) die prior to birth. Many of the Turner's individuals that do survive are found to be mosaics with a substantial fraction of normal cells (e.g. 46 XX/45 XO mosaics).
X chromosome Mosaicism
Early in embryogenesis in mammals, all but one X chromosome are functionally inactivated through a process called X chromosome inactivation. Because this inactivation occurs randomly, all normal females have roughly equal populations of two genetically different cell types and are therefore a type of mosaic. In roughly half of their cells, the paternal X chromosome has been inactivated, and in the other half the maternal X chromosome is inactive. This has a number of important biological and medical implications, particularly with regard to X-linked genetic diseases.
Cats provide a unique opportunity to observe X chromosome inactivation and help visualize how it affects all females. Tortiseshell cats, as seen below, have a coat that is a mixture of black and orange hair. Calico cats are similar, but also have patches of white, which is encoded by another gene.
The gene encoding orange coat color is X-linked (that is, on the X chromosome). Black color is encoded by either a co-dominant allele on the X chromosome or, more likely, an autosomal gene that is masked by the orange gene. For explanatory purposes, we will consider the orange gene (O) and its non-orange allele (o), to both be X-linked. Normal male cats have a single X chromosome and can carry either the O or o gene, leading them to have an orange or black coat, respectively.
Female cats, with two X chromosomes, can have any of three genotypes relative to the orange gene: OO (orange coat), oo (black coat) or Oo (tortiseshell or calico). The tortiseshell pattern of fine patches of black and orange reflects the pattern of X chromosome inactivation in the hair follicles.
In black patches, the X chromosome bearing the orange allele has been inactivated and the X chromosome bearing the non-orange allele is active. Precisely the converse is present in patches of orange fur. The random nature of X chromosome inactivation is evident - there are relatively large patches of both black and orange (similar to getting 5 heads in a row when flipping coins), but most of the coat is a fine mixture of orange and black (heads, tails, tails, heads, tails ...).
So what if you're not interested in cat coat colors? Maybe you don't even like cats. Is understanding this information still important? Yes! The pattern of X chromosome inactivation seen as black and orange fur in the coat of a tortiseshell cat is present in all tissues of all female mammals. That pattern is just not usually visible because, for example, human skin colors are not encoded by X-linked genes. However, understanding X chromosome inactivation and mosaicism is of great importance in all species for understanding the pathophysiology of X-linked genetic diseases.
In mythology, a chimera is a fire-breathing monster composed with a lion's head, a goat's body and a serpent's tail. In medical science, a chimera is an individual having more than one genetically-distinct population of cells that originated from more than one zygote. How is this possible, and just how fast should you run if you see one?
Chimeric cattle are not at all rare. When a cow has twins, it is almost inevitable that anastomoses (areas of joining) develop between the fetal circulatory systems early in gestation. This leads to exchange of blood between the two fetuses. Fetal blood contains hematopoietic stem cells, and each fetus is permanently "seeded" with stem cells from its twin. The result is that both animals are hematopoietic chimeras. A variable fraction of all their cells that are derived from hematopoietic stem cells (peripheral blood cells, Kupffer cells in the liver, lymphocytes and macrophages in lymph nodes and spleen, etc) are from the twin.
Major clinical signifcance is seen when one fetus is a female and one a male. In such cases, the female fetus is exposed to hormones from the male and is masculinized. Such female cattle are called freemartins. The external genital tract of a freemartin looks like a female, although usually infantile. The degree to which the internal genital tract is masculinized varies, but typically, the vagina is very short and uterine horns are rudimentary. Pretty obviously, these animals are sterile. Freemartins are seen occasionally in other species, although much less commonly than in cattle, probably because those animals do not have the propensity seen in cattle to form vascular anastomoses among fetuses early in gestation.
There are reports of naturally-occurring chimerism in a variety of species. Such individuals undoubtedly do occur, although they are quite rare. The most likely pathogenesis in such cases is fusion of two early embryos into one. This is suspected because chimeras are also produced experimentally, and have been a valuable research tool in several biomedical disciplines. The basic technique is to combine two very early embryos such that their cells intermix and the resulting conceptus has cells from both original embryos. This technique has been widely applied with mice and has also been applied to ruminants.
The chimeric animal shown below is a baby "geep", made by combining a goat and sheep embryo. Notice the chimerism evident in the skin - big patches of skin on front and rear legs are covered with wool, representing the sheep contribution of the animal, while a majority of the remainder of the body is covered with hair, being derived from goat cells.
Courtesy of Dr. Gary Anderson, University of Califonia at Davis
Chimeric mice and sheep-goat chimeras have been most useful in answering fundamental questions about developmental biology and pathology. There is also some potential that this technique can be applied to problems such as rescue of endangered species. It is possible, for example to construct a goat-sheep chimera such that a goat fetus is "encased" in a sheep placenta. This enables a sheep to carry a goat to term, which will not occur if you simply transfer goat embryos into sheep (the sheep will immunologically reject the goat placenta and fetus). It may be possible to extend this procedure to allow embryos from severely endangered species to be carried by recipient mothers from another species.
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Next Topic for Cytogenetics: Chromosomal Diseases: An Overview
Last updated on February 5, 2017
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