Genetics of chimerism: Being your own twin

Chimerism vs mosaicism

A chimera is an organism that originates upon the fusion of two or more zygotes. In contrast, a mosaic is an organism that originates as a combination of two distinct cell lines of a single zygote [].

Both chimerism and mosaicism may result from genetic mutations and involve meiosis. Molecular techniques are used for their identification.

How common is chimerism?

The prevalence of natural human chimeras in the general population is unknown, but it has been hypothesised to be as high as 10% []. According to the , the majority of human chimeras remain undiagnosed [].

What are the types of chimerism? How are they caused?

Natural human chimeras are classified into three groups []:

• Microchimerism is formed by feto-maternal cell trafficking across the placenta
• Fusion chimerism is formed by fusion of two zygotes
• Twin chimerism, also known as blood chimerism or transfusion chimerism, is caused by transfer of cells between dizygotic twins via fused placentas

Microchimerism

It is known that foetal cells can pass the placental barrier. This fact has been exploited for the development of non-invasive prenatal tests (), a prenatal test using cell-free foetal DNA. Foetal cells are not only present during pregnancy but can persist in a mother’s body for up to 30 years, causing microchimerism. Cell transfer can also occur in the other direction and cause microchimerism in the foetus.

Microchimerism has both positive and negative effects on maternal health [, ]. For example, foetal cells have been associated with autoimmune diseases and cancer, but they also have been found to play a role in repairing maternal injuries [, ].

Fusion chimerism

Fusion chimerism occurs if two eggs that have been fertilised by two sperm fuse together, producing a tetragametic individual (an individual arise from four gametes) []. For example, this happens if one embryo dies in the womb after an initial twin pregnancy. The surviving fetus may absorb some of the cells of the deceased twin. As a result, the surviving fetus has two sets of DNA: its own DNA, and DNA from its twin. This type of chimerism may also be known as the “vanishing twin” phenomenon. Among twin embryos, about 30% will end up as single embryo pregnancies [].

The different tissues of fusion chimeras are made up of cells derived from one or both zygotes. Indications of fusion chimerism include differences in eye colour, patchwork skin colouration, and ambiguous external genitalia, which is a sign of hermaphroditism (having both male and female reproductive organs). However, in most cases, there are no observable symptoms of fusion chimerism. Fusion chimeras are also known as “dispermic”, “tetragametic”, “primary” and “amalgamated” chimeras [].

Twin chimerism (blood group chimerism)

Twin chimeras arise when two zygotes do not undergo fusion but exchange cells and genetic material during development []. The most common example of twin chimerism is blood chimerism. This happens when blood anastomoses (connections) form between the placentas of dizygotic twins, allowing the transfer of stem cells between the developing embryos. When blood chimerism involves male and female twins, female exposure to male hormones results in freemartin syndrome, in which the female is masculinised. This phenomenon is frequently seen in cattle but rarely in humans.

What are the symptoms of chimerism?

People with chimerism rarely show visible signs of their condition []. Some may have physical signs such as []:

• Two different coloured eyes
• Two different skin tones, e.g., increased skin darkness (hyperpigmentation) or increased skin lightness (hypopigmentation) in small patches or across larger areas of the body
• Patches of different coloured or textured hair
• Disorder of sexual development, e.g., genitals that have both male and female parts (intersex), or that look sexually unclear which may result in infertility

Though rare, individuals with chimerism have also reported the following []:

• Originating as a twin pregnancy, but the other twin did not survive (vanishing twin syndrome)
• A failed parental (paternity or maternity) DNA test for unexplained reasons
• Identifying as transgender; when chimerism also involves the sex chromosomes (X and Y), brain cells can have different sex chromosomes than other cells in the body, which is theorised to contribute to having a transgender identity
• Left-handedness or being ambidextrous
• Having two blood types

How is chimerism diagnosed? What tests can be done?

The majority of laboratories use short tandem repeats (STR) for chimerism detection, with some reporting use of multiple methodologies []. Higher sensitivity methods reported including qPCR, NGS and ddPCR were also reported.

The STR method measures the relative quantities of STR allele products between the donor and recipient. The test evaluates the mixture of donor and recipient DNA in the recipient’s blood or bone marrow. To perform chimerism analysis, pre-transplant recipient and donor samples are collected and used for comparison with recipient samples post-transplant. Donor and recipient cells are distinguished from each other using unique CNV (copy number variation) markers that give unique genetic profiles.

Chimerism analysis can be used:

• To monitor engraftment after blood stem cell transplant (engraftment means your new cells are working properly and starting to rebuild your immune system)
• To detect relapse or rejection after a blood stem cell transplant
• To determine maternal engraftment
• To test genetic identity: STR testing can distinguish between monozygotic and dizygotic twins
• To detect sample exchanges

If undiagnosed, chimerism can result in a false-negative parental DNA paternity test []. In fact, there are several cases where chimeric mothers or fathers almost lost parental rights. A chimerism diagnosis can also benefit the mental health of people going through an identity crisis.

Usually, chimerism does not negatively affect a person’s health. But a diagnosis can help to understand and prepare for unexplained events.

High-profile media reports of chimerism

1. Case 1: a woman, Karen, who was told, following DNA tests of family members for a kidney donor, that two of her three sons could not be hers []
2. Case 2: a woman, Lydia, who claimed welfare for her children in Washington State, was accused of fraud as DNA tests showed they were not her children. She was unable to obtain legal help as DNA evidence was considered irrefutable until her attorney came across the story of Karen []
3. Case 3: a man in California who failed a paternity test after the child was found to have an AB blood group while both parents were A []

All three turned out to be chimeras, each made up of two individuals of the same sex. Further studies showed that DNA profiles from certain tissues of the parents did match those of the disputed children.