Chimera (genetics)

A chimeric mouse with its offspring

Typically seen in non-human zoology (but also discovered to a rare extent in humans), a chimera is an animal that has two or more different populations of genetically distinct cells that originated in different zygotes; if the different cells emerged from the same zygote, it is called a mosaicism.

Chimeras are formed from four parent cells (two fertilized eggs or early embryos fused together) or from three parent cells (a fertilized egg is fused with an unfertilized egg or a fertilized egg is fused with an extra sperm). Each population of cells keeps its own character and the resulting animal is a mixture of tissues.

This condition is either inherited, or it is acquired through the infusion of allogeneic hematopoietic cells during transplantation or transfusion. In nonidentical twins, chimerism occurs by means of blood-vessel anastomoses. The likelihood of offspring being a chimera is increased if it is created via in vitro fertilization. Chimeras can often breed, but the fertility and type of offspring depends on which cell line gave rise to the ovaries or testes; varying degrees of intersexuality may result if one set of cells is genetically female and another genetically male.

Tetragametic chimerism

Tetragametic chimerism is a less common cause of congenital chimerism. It occurs through the fertilization of two ova by two sperm, followed by the fusion of the zygotes and the development of an organism with intermingled cell lines. This happens at a very early stage of development, such as that of the blastocyst. Such an organism is called a tetragametic chimera as it is formed from four gametes — two eggs and two sperm. Put another way, the chimera is formed from the merging of two nonidentical twins in a very early (zygote or blastocyst) phase. As such, they can be male, female, or hermaphroditic.

As the organism develops, the resulting chimera can come to possess organs that have different sets of chromosomes. For example, the chimera may have a liver composed of cells with one set of chromosomes and have a kidney composed of cells with a second set of chromosomes. This has occurred in humans, and at one time was thought to be extremely rare, though more recent evidence suggests that it is not as rare as previously believed. Most will go through life without realizing they are chimeras. The difference in phenotypes may be subtle (e.g., having a hitchhiker's thumb and a straight thumb, eyes of slightly different colors, differential hair growth on opposite sides of the body, etc) or completely undetectable. Another telltale of a person being a chimera is visible Blaschko's lines.

Affected persons are identified by the finding of two populations of red cells or, if the zygotes are of opposite sex, ambiguous genitalia and hermaphroditism alone or in combination; such persons sometimes also have patchy skin, hair, or eye pigmentation (heterochromia). If the blastocysts are of the same sex, it can be detected only through DNA testing, although this is a rare procedure. If the blastocysts are of opposite sex, genitals of both sexes are often formed, either ovary and testis, or combined ovotestes, in one rare form of intersexuality, a condition previously known as true hermaphroditism. As of 2003, there were about 30-40 documented human cases in the literature, according to New Scientist. Since hermaphroditic chimeras would be expected to be the one half of all chimeras, with purely male and purely female chimeras being one-quarter each, this would suggest that the condition is not particularly common.

Natural chimeras are almost never detected unless the offspring has abnormalities such as male/female or hermaphrodite characteristics or skin discolouring. The most noticeable are some male tortoiseshell cats or animals with ambiguous sex organs.

Chimerism can be detected in DNA testing. The Lydia Fairchild case, for example, was brought to court after DNA testing showed that her children could not be hers, since DNA did not match. The charge against her was dismissed when it became clear that Lydia was a chimera, with the matching DNA being found in her cervical tissue. Another case was that of Karen Keegan.

The tetragametic state has important implications for organ or stem-cell transplantation. Chimeras typically have immunologic tolerance to both cell lines. Thus, for a tetragametic human, a wider array of relatives and other persons may be eligible to be an organ donor. Chimerism also shows, under a certain spectrum of UV light, distinctive marks on the back resembling that of arrow points pointing downwards from the shoulders down to the lower back; this is one expression of the Blaschko's lines mentioned earlier.

Microchimerism

Main article: Microchimerism

Microchimerism is the presence of a small number of cells that are genetically distinct from those of the host individual. Apparently, this phenomenon is related to certain types of autoimmune diseases, however, the mechanisms responsible for this relationship are unclear.

"Parasitic" chimerism in anglerfish

Chimerism occurs naturally in adult Ceratioid anglerfish and is in fact a natural and essential part of their life cycle. One or more males attach to a female as "parasites" (they must do so, as they will never fully mature alone), eventually fusing into a single, hermaphroditic individual with a shared circulatory system. Once fused to a female, the males will reach sexual maturity, developing large testicles as their other organs atrophy.

Germline chimerism

Germline chimerism is when the germ cells (for example, sperm and egg cells) of an organism are not genetically identical to its own. It has recently been discovered that marmosets can carry the reproductive cells of their (fraternal) twin siblings, because of placental fusion during development. (Marmosets almost always give birth to fraternal twins.)

Chimeras in research

In biological research, chimeras are artificially produced by physically mixing cells from two different organisms. Chimeras are not hybrids, which form from the fusion of gametes from two species (like a donkey and a horse) that form a single zygote that will develop as much as it can (in this case into a live mule if the parents are jackass and mare, or a hinny if the parents are stallion and jenny); in comparison, chimeras are the physical mixing of cells from two independent zygotes: for example, one from the donkey and one from the horse. "Chimera" is a broad term and is often applied to many different types of mixing of cells from two different species.

Some chimeras can result in the eventual development of an adult animal composed of cells from both donors, which may be of different species — for example, in 1984 a chimeric geep was produced by combining embryos from a goat and a sheep. The "geep" has been a very important contributor to answering fundamental questions about development, and the techniques used to create it may one day help save endangered species. For example, if one tried to let a goat embryo gestate in a sheep, the sheep's immune system would reject the developing goat embryo; however, if one used a geep that shared markers of immunity with both sheep and goats, the goat embryo might survive. It may be possible to extend this practice for the purpose of preventing the extinction of some endangered animal species.

Such interspecies chimeras such as the "geep" are made in the laboratory and rarely with the purpose of generating living hybrid animals. Intraspecies chimeras are created by transplanting embryonic cells from an animal with one trait into an embryo of an animal with a different trait. This practice is common in the field of embryology and has been a very important contributor to our current understanding of human and animal biology. For example, by mixing embryonic cells of differently coloured or otherwise genetically distinct mice (of the same species), researchers have been able to see how embryos form and which organs and tissues are related (arise from the similar cell lineages).

Hybridomas are not true chimeras as described above because they do not result from the mixture of two cell types but result from fusion of two species' cells into a single cell and artificial propagation of this cell in the laboratory. Hybridomas have been very important tools in biomedical research for decades.

In August 2003, researchers at the Shanghai Second Medical University in China reported that they had successfully fused human skin cells and dead rabbit eggs to create the first human chimeric embryos. The embryos were allowed to develop for several days in a laboratory setting, then destroyed to harvest the resulting stem cells. Because of the high therapeutic potential of human embryonic stem cells and the United States moratorium on using discarded embryos from in vitro fertilization clinics as well as other concerns about using human embryos directly for research, scientists are trying to find alternative paths of research. However, increasingly realizable projects using part-human, part-animal chimeras as living factories not only for biopharmaceutical production but also for producing cells or organs (see hybridomas) for xenotransplantation raise a host of ethical and safety issues.

During November 2006, UK researchers from Newcastle University and King's College London applied to the Human Fertilisation and Embryology Authority for a three-year license to fuse human DNA with cow eggs. The proposal is to insert human DNA into a cow's egg which has had its genetic material removed and then create an embryo by the same technique that produced Dolly the Sheep. This research was attempted in the United States several years before and failed to yield such an embryo. In April 2008 the researchers from Newcastle University reported that their research had been successful. The resulting embryos lived for 3 days and the largest grew to a size of 32 cells. The researchers are aiming for embryos that live for 6 days so that embryonic stem cells can be harvested.

In 2007, scientists at the University of Nevada School of Medicine created a sheep that has 15% human cells and 85% sheep cells.

Legislation

US and Western Europe have strict codes of ethics and regulations in place that expressly forbid certain kind of experimentation using human cells. Even between the US and Europe however, there is a vast difference in the regulator framework. . In May 2008, a robust debate in the House of Commons in the UK took place on the ethics of creating chimeras with human stem cells. It was decided that embryos would be allowed to be made in laboratories only if guarantees of destroying them within the first 14 days were given. In the United States as well, a heated discussion rages whether human stem cells should be allowed in the creation of chimeras. At times this has become a religious issue, with the Republicans arguing that it is against Judeo Christian beliefs. Senator Sam Brownback has been one of the strong opponents of this technology.

See also

• Blaschko's lines
• Chimerism in human intersexuality
• Genetic chimerism in fiction
• Lydia Fairchild
• Mosaic (genetics)
• Parahumans
• Vanishing twin

References

• Yu N, Kruskall MS, Yunis JJ, Knoll JH, Uhl L, Alosco S, Ohashi M, Clavijo O, Husain Z, Yunis EJ, Yunis JJ, Yunis EJ (2002). "Disputed maternity leading to identification of tetragametic chimerism". N Engl J Med. 346 (20): 1545–52. doi:10.1056/NEJMoa013452. PMID 12015394.{{cite journal}}: CS1 maint: multiple names: authors list (link)
• Appel, Jacob M. "The Monster's Law", Genewatch, Volume 19, Number 2, March-April 2007.
• Ainsworth, Claire (November 15, 2003). The Stranger Within. New Scientist (subscription). (reprinted here)
• Nelson, J. Lee (Scientific American, February 2008). Your Cells Are My Cells
• Weiss, Rick (August 14, 2003). Cloning yields human-rabbit hybrid embryo. The Washington Post.
• Weiss, Rick (February 13, 2005). U.S. Denies Patent for a too-human hybrid. The Washington Post.
• Interesting Article with a very easy explanation of Chimera [2]
• L. M. Repas-Humpe, A. Humpe, R. Lynen, B. Glock, E. M. Dauber, G. Simson, W. R. Mayr, M. Köhler, S. Eber (1999). "A dispermic chimerism in a 2-year-old Caucasian boy". Journal Annals of Hematology. 78 (9): 431–434. doi:10.1007/s002770050543. {{cite journal}}: horizontal tab character in |journal= at position 8 (help)CS1 maint: multiple names: authors list (link)
• Lisa Strain, John Dean, Mark Hamilton, David Bonthron: A True Hermaphrodite Chimera resulting from Embryo Amalgamation after in Vitro fertilization. The New England Journal of Medicine, Volume 338: 166-169, January 15, 1998, Number 3.
• Chimerism and cellular mosaicism, Genetic Home Reference, U.S. National Library of Medicine, National Institute of Health.

• Article: "Expert evidence: the genetic chimerism and its implications for the world of law Bevenuto, Daniel Bezerra, Natal/RN, Brazil.