Mosaicism, Chimerism and X-Inactivation

Contents

Introduction

On rare occasions, a coat colouring can grab the attention of the gerbil community and usually these coats with their unusual markings involve mosaicism or chimerism. These animals are usually bi-coloured or tri-coloured when combined with Spotting.  Significantly, their markings are usually distinct and their coat patterns are unlike those seen in all other white marked gerbils.

For example, almost all white marked gerbils caused by Dominant spotting have a white mark on their nose, one on the forehead and one on the back of the neck. Also, large white patches are often seen on the chest and ventral region on non-agouti.  White feet and a white tip to the tail are also common.  The action of modifying genes can extend this pattern into a collared variety, where the neck spot will form a collar joining up with the white chest patch.  The nose and forehead spot also tends to join up, forming a blaze and further modifying genes can increase the markings further to create mottled and variegated coats.

However, while these unusual  markings could very well be due to a new mutation and present us with a different type of markings to what we are used to, there are several other ways of getting these random patterns of colour without a new form of spotting mutation appearing.

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Mosaics

A mosaic or mosaicism occurs when two or more distinct populations of cells with differing genotypes develop from a single fertilised egg.  Different types of mosaicism exist and are caused by one or two things. This is either a mutation in the body cells or a chromosomal mishap early in development.  Mosaics that result from a mutation during development may go on to only affect a subset of the adult cells.

In humans, some genetic disorders can cause additional chromosomes, and in turn they will only occur in some cells of the body.  When this is expressed in the skin it can create patches or areas that are of different textures or colours or even patches with hair while other areas remain hairless.  Similarly in animals, this is often noticed in their fur colouring and a normally recessive gene will go on to express itself creating a bi-coloured animal.

An example similar to what we see occurring with mosaicism is dark-patching in the gerbil. Dark–patching appears occasionally on spotted gerbils and causes patches or larger areas of the base coat colour to appear undiluted by the effect of spotting. Spotting is known to dilute the base colour on which it is applied.   The often random patches can vary considerably in amount and size and appear considerably darker than the overall base colour.

Dark-patching, or D.P for short, hasn’t appeared on non-spotted animals and seems linked to the Dominant spotting gene and as such it can occur on all spotting variants.  So we can have a dark-patch spot (D.P.S.) right through to a dark-patch variegated (D.P.V.).  This effect can look very attractive and give us coat colours that appear almost tri-coloured in appearance, with the gerbils displaying the white markings plus the base colour being apparent in two shades.

Another very rare form of dark-patching has been documented with ‘ee’ or Extension of Yellow.  In these instances, the normal masking effect of this gene breaks down in areas of the fur allowing the recessive gene underneath to express itself.  A young nutmeg (aaee) pup with patches of black fur is an interesting sight to see, but most often after they have moulted into their adult coats these patches become hard to distinguish from normal fur.

A similar phenomenon has also been documented in Saffron coloured gerbils (aaeepp) where large areas of the fur display a lilac colouring while other areas remain orange.  Very recently this occurred in a mottled saffron gerbil (see gallery) which effectively created  tri-coloured fur.

Mosaics and other “mis-marks” seem common to extension of Yellow and similar examples can be seen in Hamsters and Dogs, especially Golden Retrievers.  A notable report on an extension locus mosaic in the Journal of Heredity (Sponenberg and Bigelow 1986) (1)on a male Labrador Retriever whose fur exhibited random black and yellow patches sounds similar to those examples we have recently documented in the gerbil.  Mis-marks such as brindling, white spots, tan points and rings around the tail are common in Labradors and while each marking can have underlying genetic factors, environmental factors could play a role too.  Some notable examples of mis-marked Labradors can be seen here.

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Chimeras

Chimeras are similar to mosaics, but where mosaics have two or more distinct and different populations of cells of differing genotypes that develop from a single zygote; chimeras have two or more populations of genetically distinct cells that are derived from different zygotes.  When two fertilised eggs or early embryos fuse together, each population of cells retain their own characteristics and the resulting organism is a mixture of tissues from both embryos.  Although chimeras are typically seen in animals there are reports of human chimerism.

Macro chimerism, is a form of congenital chimerism and the organism is usually formed from the merging of non-identical twins.  As such, they can be male, female, or hermaphroditic. Although exceptionally rare there is a much greater chance for this occurring in rodents as there is greater opportunity for embryos to fuse together in the womb. If the embryos were of different colours then these colours would be expressed in the resulting organism.

Most human chimeras can go through life without the realisation they are chimeras and the condition can be undetectable. Quite often chimerism can have a subtle phenotype.  For example, a hitch hikers thumb on one hand while the other thumb is normal, eyes of slightly different colour (see heterochromia), differing hair growth on opposite sides of the body, or patchy skin. Sometimes, chimeras can be identified by two populations of red blood cells, or ambiguous genitalia can result if the zygotes are of the opposite sex.  Chimeras may often show Blashko’s lines under a certain spectrum of UV light.  These lines or whorls are an expression of uneven pigment distribution and are believed to trace the migration of embryonic cells. (see Blaschko's lines).  Chimeras are problematic for DNA testing which has implications on both the family and criminal law.  In the well known Lydia Fairchild case in the UK, she was brought to court where fraud charges were filed against her and the custody of her children were under threat.  The charges against her were eventually dismissed when it was proven that she was a chimera and matching DNA was found in her cervical tissue. (See Lydia Fairchild-The twin inside me)

Interestingly, one of the most distinct forms of chimerism in animals occurs in male tortoiseshell cats. Recent studies of tortoiseshell male cats and unusually coloured tortoiseshell-like cats suggest that natural chimerism occurs more often than was once thought and that it frequently goes undetected. A male tortoiseshell or calico cat is exceptionally rare, the rate is said to be around 1:3,000. Sometimes this is due to a disorder called Klinefelter's syndrome and it carries an extra X chromosome and will nearly always be sterile. The other way for a male tortoiseshell to occur is through chimerism when, two embryos that are distinct for two different colours will fuse together.

Recent research shows that the majority of Marmosets are chimeras and share DNA with their fraternal twin.  Marmosets almost always give birth to fraternal twins and because of placental fusion during their development, the germ cells (sperm or egg cells) may not be genetically identical to their own and carry the reproductive cells of their fraternal twin sibling.  This example is referred to as germ-line chimerism

Microchimerism is the presence of a small number of cells that are genetically distinct from those of the host individual.  In humans and all placental mammals the most common form of this occurs when cells from a foetus pass through the placenta and establish cell lineages within the mother. These cells can persist, be immunologically active and multiply in the mother for several decades.  Although the exact types of cells are often unknown, several cell types have been identified, including various immune lineages, mesenchymal stem cells and placental-derived cells.  During pregnancy the two-way traffic of immune cells can also cause the maternal immune cells to be found in the offspring although maternal ⇒foetal microchimerism is approximately half as frequent as foetal cells being found in the mother.

Microchimerism often occurs in most pairs of twins in cattle and when a cow gives birth to a pair of calves it is quite common for the calves to carry cells from the other calf.  This is due to both calves sharing a single blood supply.  This can be an issue if the twins are a male-female pair because the male hormones from the bull calf can partially masculinise the heifer (female).  These are known as martin heifers or freemartins.  Freemartins can appear female but are infertile so cannot be used for breeding or dairy production.

With chimeras, the condition can either be inherited or acquired. Technically speaking, every time a human undergoes an organ transplant they become a chimera, some of their cells are their own, the others are derived from another human, and are genetically distinct. However, in biological research, chimeras are produced by transplanting embryonic cells from one organism onto the embryo of another.  In 1984, the chimeric “Geep” was created by combining embryos from a goat and a sheep which then survived to adulthood. (2)  By August 2003, researchers in China reported they had successfully fused human skin cells and dead rabbit eggs to create the first human chimeric embryos.  These embryos were allowed to develop for several days before harvesting them for their stem cells.(3)  In 2007, scientists at the University of Nevada created a sheep whose blood contained 15% human cells. (4) According to several articles in the media and in leading newspapers, as of 2011, more than 150 human-animal hybrid embryos were created in British laboratories alone since the Human Fertilisation and Embryology Act 2008  (5)

Scientists have been splicing genes and mixing cells for a long while now but these developments have largely gone unnoticed by the public.  Adding human and/or other animal genes to bacteria and farm animals to mass produce insulin and spider silk proteins (see spider goat) and introducing human cells into mouse embryos have been possible for many years.  Despite early warnings that a single “Trojan gene” could wipe out an entire species of fish (See Trojan gene) ,  the growth of experimentation continues and in the US the FDA is set to approve  GM Salmon which will become the first gene altered food for human consumption, despite well founded disapproval and controversy over the entire issue (6, 7)

While many transhumanists see this technology as progress and one of the ways to overcome human limitations such as disease or ageing and biopharmaceutical companies see it as being very lucrative, others see this as a literal genetic Armageddon with the subject raising a whole host of ethical and safety issues.

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X-Inactivation

Mosaicism or chimerism shouldn’t be confused with X-inactivation.  This occurs when all the cells in an organism have the same genotype, but a different copy of the X chromosome.  Mammalian females have two X chromosomes (XX) and X-inactivation causes one or the other X-chromosomes to be turned off at random in each cell in their very early development.   A visible manifestation of this phenomenon can be seen in female Tortoiseshell cats and Hamsters where they are recognised as sex-linked genes which create a bi-coloured coat.  A calico coat can be created by the addition of a spotting gene to bring about a tri-coloured coat.

Because these events usually most often occur in the body cells and not in the sex cells, mosaicism and chimerism in coat colour isn't inherited in the normal way like a dominant or recessive gene.   In biological terminology, a mosaic is referred to for non-inherited cases where an animal may appear bi-coloured but the trait isn’t passed on.  If the condition is genetic and can be passed on from generation to generation, it is then termed bi-coloured.

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Gallery

Photo Credits:  Chimera Mainpage-Chimera 3, Eduardo. Chimera 4-chimera 18-Lisette Van der Plas. DP Nutmegs-Alicia. Mosaic 3-mosaic 6-Elisabeth Arblaster. Mosaic 7-Mosaic 12-Ed Cope-Tortoiseshell1-Gnissah. Tortoiseshell 2- Riosafari. Tortoiseshell 3-Ed Cope

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References

  1. Sponenberg, D.P. and B.J. Bigelow 1986. "An Extension Locus Mosaic Labrador Retriever Dog." The Journal of Heredity 78:406
  2. "It's a Geep". Time. 27 February 1984.
  3. Mar 2007.Animal-Human Hybrids Spark Controversy-Maryann Mott, National Geographic News January 25, 2005
  4. "Iranian scientist creates sheep with half-human organs". Press TV
  5. Martin D., Caldwell S. 150 human animal hybrids grown in UK labs: Embryos have been produced secretively for the past three years Daily Mail
  6. FDA considers approving genetically modified salmon for human consumption By Lyndsey Layton Washington Post Staff Writer Monday, September 6, 2010
  7. Exposed: Genetically-modified salmon found to be contaminated with infectious salmon anemia - Tuesday, December 20, 2011 by: Ethan A. Huff

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