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15.7F: Genetic Mosaics - Biology

15.7F: Genetic Mosaics - Biology


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A genetic mosaic is a creature whose body is built of a mixture of cells of two or more different genotypes. In mammals they arise by several different mechanisms:

  • The fusion of two different zygotes, or early embryos, into one. (The reverse of the process that produces identical twins!) The resulting animal is called a chimera (after the monster in Greek mythology with a lion's head, goat's body, and serpent's tail). The tetraparental mouse is a chimera formed this way. But on rare occasions, the same process can occur spontaneously in humans (especially those using in vitro fertilization).
  • The sharing of blood supplies by separate embryos. This occurs with the occasional fraternal cattle twins and also — less often — with human fraternal twins who have shared the same placenta. Blood stem cells of each twin seed the bone marrow of the other. Only their blood cells are mosaic.
  • During early development, errors during mitosis can produce stem cells that go on to populate a tissue or organ with, for example, a chromosomal aberration (e.g., aneuploid).

    Example: Occasionally a baby is born with blood cells that have three copies of chromosome 21 (the same set responsible for Down syndrome). This can produce a leukemia-like illness that, fortunately, often disappears as that cell population declines.

  • All female mammals are mosaic for the genes on the X chromosome because of the random inactivation of one or the other X chromosome in all their somatic cells.
  • Anyone unlucky enough to have a cancer is a genetic mosaic because all cancers are made up of the descendants of cells carrying a suite of mutations not found in normal cells.
  • Recent advances have enabled the coding portions of the genome of single cells to be sequenced. Early results indicate than even normal cells in an adult have accumulated a suite of somatic mutations that differs from cell to cell. So all of us are genetic mosaics! However, the rate of somatic mutations in these normal cells is only a fourth of that in cancer cells.

The Tetraparental Mouse

As the name suggests, tetraparental mice have four parents: two fathers and two mothers (not including the foster mother that gives birth to them!). This is how they are made:

  • Early embryos at the 8-cell stage are removed from two different pregnant mice and placed in tissue culture medium.
  • Two different embryos are gently pushed together and, often, will fuse into a single embryo.
  • After a period of further growth in culture, the fused embryo is implanted in a foster mother (whose uterus has been prepared for implantation by mating her with a vasectomized male).
  • The mouse that is born is a chimera, all (usually) of whose organs are made of some cells derived from one pair of parents and some cells derived from the other pair.

The photograph shows a tetraparental mouse derived from a pair of inbred mice with black fur and a pair with white fur. Note the intermingling of black and white patches. This mouse is not the same as an F1 hybrid produced by mating a white mouse with a black one. In that case, all the cells would be of the same genotype, and the coat would have been a uniform brown.

A Tetragametic Human

A report by Yu, et. al. in the May 16, 2002 issue of The New England Journal of Medicine documents the discovery of a tetragametic woman; that is a woman derived from four different gametes, not just two. She came to the doctors' attention because she needed a kidney transplant.

  • Tissue typing, which is done with blood cells, showed her to have inherited the "1" HLA region of her father (who was 1,2) and the "3" region of her mother (who was 3,4).
  • She had two brothers,
  • One who inherited 1 from their father and 3 from their mother
  • The other who inherited 2 from their father and 3 from their mother.
  • Her husband typed 5,6
  • Of her three sons,
    • One was 1,6 which was to be expected
    • the other two were both 2,5. The 5 they got from their father, but where did the 2 come from?
  • The first thought was that she could not have been their mother, but clearly she knew better. (Paternity may sometimes be in doubt, but not maternity.)
  • A clue came from typing other tissues. DNA analysis of her skin cells, hair follicles, thyroid cells, bladder cells, and cells scraped from inside her mouth revealed not only 1 and 3 but also 2 and 4. It is not clear why her bone marrow was an exception - containing only 1,3 stem cells.
  • How were these results possible?The most reasonable explanation is that
  • Her mother had simultaneously ovulated two eggs one containing a chromosome 6 with HLA 3 and the other with HLA 4.
  • Her father would, of course, have produced equal numbers of 1-containing and 2-containing sperm.
    • A 1-sperm fertilized the 3-egg.
    • A 2-sperm fertilized the 4-egg.
  • Soon thereafter the resulting early embryos fused into a single embryo.
  • As this embryo developed into a fetus, both types of cells participated in constructing her various organs including her oogonia (but not, apparently, the blood stem cells in her bone marrow).
  • Although she was a mosaic for the HLA (and other) genes on chromosome 6, all her cells were XX. So both the father's successful sperm cells had carried his X chromosome.

    However, tetraparental humans have been found that were mosaic for sex chromosomes as well; that is, some of their cells were XX; the other XY. In some cases this mosaic pattern results in a hermaphrodite - a person with a mixture of male and female sex organs.

    So what are her chances for finding a suitable kidney donor?

    The HLA region on chromosome 6 carries a set of genes that encode the major transplantation antigens; that is, the antigens that trigger graft rejection. Ordinarily, there is only a 1 in 4 chance that two siblings share the same transplantation antigens if both parents were heterozygous as in her case. But because this woman has all four sets of transplantation antigens, she can accept a kidney from any one of her brothers as well as her mother (her father was dead) without fear of rejecting it.Laboratory tests confirmed that she was unable to generate T cells able to react against the cells of either brother or her mother.

In the 3 September 2010 issue of Cell, Kobayashi et al. report the creation of healthy rat-mouse chimeras:

  • mice with functioning rat tissues
  • rats with functioning mouse tissues.

Their procedure:

  • Generate induced pluripotent stem cells (iPSCs) from embryonic fibroblasts of each species.
  • Inject:
    • mouse iPSCs into rat blastocysts
    • rat iPSCs into mouse blastocysts.
  • Implant these blastocysts into the uterus of pseudopregnant foster mothers of the same species as the blastocyst.

The Pdx-1−/− Mouse

Pdx-1 encodes a transcription factor that is essential for the development of the pancreas. Transgenic mice lacking a functioning Pdx-1 gene (Pdx-1−/−) die shortly after birth.

However, Kobayashi et al. found that injecting rat induced pluripotent stem cells (iPSCs) into mouse Pdx-1−/− blastocysts produced a few viable mouse chimeras complete with a pancreas made up almost exclusively of rat cells. The pancreas was fully functional producing both exocrine secretions (e.g., pancreatic amylase) and endocrine secretions (e.g., insulin, glucagon, and somatostatin).


Genetic mosaics *

Genetic mosaics can be used to gain insight into the cell specificity of gene function. How Caenorhabditis elegans mosaics are typically generated is reviewed, and several examples with relevance to developmental studies are mentioned. One example is mpk-1, which encodes a member of the Ras-MAP-kinase pathway. mpk-1 mosaics have been a means of studying the distinct cells that require the gene for distinct fates during development. The gene bre-5 is used as an example of the usefulness of mosaic analysis for non-developmental studies. Potential problems with mosaic analysis are discussed, and the power of combining mosaic analysis with cell- or tissue-specific promoters is mentioned.


15.7F: Genetic Mosaics - Biology

In genetic medicine, a mosaic or mosaicism denotes the presence of two populations of cells with different genotypes in one individual, who has developed from a single fertilized egg. Mosaicism may result from a mutation during development which is propagated to only a.
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A genetic mosaic is an individual in which different cells have different genotypes. In Caenorhabditis elegans, genetic mosaics have been generated, identified, and .
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A genetic mosaic is an individual in which different cells have different genotypes. . genetic mosaics have been generated, identified, and analyzed for the .
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Mosaic A term referring to a genetic situation, in which an individual's cells do not have the exact same composition of chromosomes
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Genetic Mosaics. A genetic mosaic is a creature whose body is built of a . unlucky enough to have a cancer is a genetic mosaic because all cancers are made .
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Support group for patients and families of those with xy/xo or a related genetic mosaicism. . About genetic mosaics. Each cell in the human body has bits of .
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All females are genetic mosaics . Indeed, a high proportion of Turner syndrome individuals are mosaics. Mosaicism poses problems for genetic screening .
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Genetic mosaic techniques for studying Drosophila development -- Blair . In genetic medicine, a mosaic or mosaicism denotes the presence of two .
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For example, in a human mosaic, some of the cells might be 46, XX and some 47, XXX. . for understanding the pathophysiology of X-linked genetic diseases. .
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Scientific Handreading in Psychological Diagnosis for the Professional . he Mosaic Condition is a genetic phenomenon where any tissue in a body may .
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. not be mosaic, but will simply have the genetic disease caused by that particular mutation. . Signs, like symptoms, depend on which genetic change is mosaic. .
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Mosaicism, used to describe the presence of more than one type of cell in a person, is usually . babies born with mosaic Down syndrome can have .
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What are the genetic changes related to Pallister-Killian mosaic syndrome? . tetrasomy 12p, mosaic. See How are genetic conditions and genes named? in the Handbook. .
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. or physical structure exists for these two genetic makeup's we see a mosaic. . feathers can be either genetic or somatic but by definition they are all mosaics. .
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. in their clonal behavior in genetic mosaics to imaginal disk cells. . In germ-line genetic mosaics, cell selection may affect the number of gametes of .
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COBRA is an open access, scholar-driven repository of biostatistics . A genetic mosaic is a genetically composite organism, within whose tissues two .
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Contents

Germline mosaicism disorders are usually inherited in a pattern that suggests that the condition is dominant in either or both of the parents. That said, diverging from Mendelian gene inheritance patterns, a parent with a recessive allele can produce offspring expressing the phenotype as dominant through germline mosaicism. A situation may also arise in which the parents have milder phenotypic expression of a mutation yet produce offspring with more expressive phenotypic variance and a more frequent sibling recurrences of the mutation. [6] [7] [8]

Diseases caused by germline mosaicism can be difficult to diagnose as genetically-inherited because the mutant alleles are not likely to be present in the somatic cells. Somatic cells are more commonly used for genetic analysis because they are easier to obtain than gametes. If the disease is a result of pure germline mosaicism, then the disease causing mutant allele would never be present in the somatic cells. This is a source of uncertainty for genetic counselling. An individual may still be a carrier for a certain disease even if the disease causing mutant allele is not present in the cells that were analyzed because the causative mutation could still exist in some of the individual's gametes. [9]

Germline mosaicism may contribute to the inheritance of many genetic conditions. Conditions that are inherited by means of germline mosaicism are often mistaken as being the result of de novo mutations. Various diseases are now being re-examined for presence of mutant alleles in the germline of the parents in order to further our understanding of how they can be passed on. [10] The frequency of germline mosaicism is not known due to the sporadic nature of the mutations causing it and the difficulty in obtaining the gametes that must be tested to diagnose it.

Autosomal dominant or X-linked familial disorders often prompt prenatal testing for germline mosaicism. This diagnosis may involve minimally invasive procedures, such as blood sampling or amniotic fluid sampling. [9] [11] [12] [13] [14] Collected samples can be sequenced via common DNA testing methods, such as Sanger Sequencing, MLPA, or Southern Blot analysis, to look for variations on relevant genes connected to the disorder. [14] [15]

The recurrence rate of conditions caused by germline mosaicism varies greatly between subjects. Recurrence is proportional to the number of gamete cells that carry the particular mutation with the condition. If the mutation occurred earlier on in the development of the gamete cells, then the recurrence rate would be higher because a greater number of cells would carry the mutant allele. [11]


Additions and improvements to mosaic techniques

The stable insertion of DNA constructs into the fly genome via engineered transposable elements (most commonly the P element)(Rubin and Spradling, 1982 Spradling and Rubin, 1982) has made several modifications of and additions to the early mosaic techniques possible (see Duffy, 2002). The initial insertion of a new P element construct into the genome is still somewhat laborious, requiring the injection of many embryos to generate one transformant. However, constructs that have already been incorporated into the genome can be remobilized, and thus `hopped' from one position to another in the genome, by mating the transformed fly strain to another that carries a constitutively expressed transposase(Robertson et al., 1988).

The mosaic techniques discussed in the following sections use variations on two different systems, both derived from yeast. The first uses targeted DNA recombination at FLPase recombination targets (FRTs), which can be driven in flies by the FLP recombinase (FLPase)(Golic and Lindquist, 1989). The second uses the Gal4 transcription factor to drive the expression of constructs that are coupled to the UAS enhancer sequence(Brand and Perrimon, 1993). Flies carrying most of the constructs discussed below are available as community-wide resources through the Bloomington Drosophila Stock Center(http://flystocks.bio.indiana.edu/).

FRT-mediated mitotic recombination

FRTs have been inserted into proximal locations on each of the chromosome arms, and several stocks have been generated that express FLPase under the control of the hsp70 heat-shock promoter (hs-FLPase)(Chou and Perrimon, 1992 Golic, 1991 Xu and Rubin, 1993). If a fly has two FRTs in identical positions on homologous chromosomes,heat-shock-induced expression of FLPase can cause recombination between the FRT sites (Fig. 3). This technique has several advantages over irradiation-induced recombination. FRT-mediated mitotic recombination rates are much higher than those caused by irradiation, although they are still low enough to ensure that only a small percentage of cells will be homozygous. The site of the recombination is also controlled, so that one no longer has to worry about recombination occurring in the chromosomal region distal to the mutation, or between the mutation and the marker. Heat shock also induces less cell death than irradiation. However,there are also disadvantages to FRT-mediated recombination. Mutations and markers must first be meiotically recombined onto the appropriate FRT-bearing chromosome before the technique can be used. Not only does this take time, it also prevents the technique from being used for extant mutations on the fourth chromosome, where meiotic recombination does not occur. Moreover, the technique cannot be used for those genes that are proximal to any available FRT insertion.


A Tetragametic Human

    , which is done with blood cells, showed her to have inherited the "1" HLA region of her father (who was 1,2) and the "3" region of her mother (who was 3,4).
  • She had two brothers,
    • one who inherited 1 from their father and 3 from their mother
    • the other who inherited 2 from their father and 3 from their mother.
    • One was 1,6 which was to be expected, but
    • the other two were both 2,5. The 5 they got from their father, but where did the 2 come from?

    How were these results possible?

    • Her mother had simultaneously ovulated two eggs:
      • one containing a chromosome 6 with HLA 3
      • the other with HLA 4.
      • A 1-sperm fertilized the 3-egg
      • A 2-sperm fertilized the 4-egg.

      Although she was a mosaic for the HLA (and other) genes on chromosome 6, all her cells were XX. So both the father's successful sperm cells had carried his X chromosome.

      However, tetraparental humans have been found that were mosaic for sex chromosomes as well that is, some of their cells were XX the other XY. In some cases this mosaic pattern results in a hermaphrodite &mdash a person with a mixture of male and female sex organs.

      So what are her chances for finding a suitable kidney donor?

      The HLA region on chromosome 6 carries a set of genes that encode the major transplantation antigens that is, the antigens that trigger graft rejection.
      Link to a discussion.

      Ordinarily, there is only a 1 in 4 chance that two siblings share the same transplantation antigens if both parents were heterozygous as in her case. [Link to explanatory diagram]

      But because this woman has all four sets of transplantation antigens, she can accept a kidney from any one of her brothers as well as her mother (her father was dead) without fear of rejecting it.

      Laboratory tests confirmed that she was unable to generate T cells able to react against the cells of either brother or her mother.


      Genetic variation controls predation: Benefits of being a mosaic

      A genetically mosaic eucalyptus tree is able to control which leaves are saved from predation because of alterations in its genes, finds an study published in BioMed Central's open access journal BMC Plant Biology. Between two leaves of the same tree there can be many genetic differences -- this study found ten SNP, including ones in genes that regulate terpene production, which influence whether or not a leaf is edible.

      Organisms collect somatic genetic mutations throughout their lives. These mutations may have no effect or they may occur in genes important to how the cell behaves. Cancer cells often have genetic mutations which permit the cell to divide more times than an unmutated cell, and in plants it is somatic mutation which allows a single tree to produce both nectarines and peaches.

      Researchers from the Australian National University found that in the long-lived eucalyptus tree (Eucalyptus melliodora) somatic mutation is also responsible for their interesting ability to produce some branches with leaves that are readily predated, while others are pest resistant.

      At a genetic level there were ten genes which contained differences between these leaves. Amanda Padovan, who led this project, explained, "The main defence against predation of Eucalyptus is a cocktail of terpene oils, including monoterpenes, sesquiterpenes, and FPCs, which give the tree its distinctive smell. Leaves which were resistant to predation had five fewer monoterpenes and nine fewer sesquiterpenes than the tastier leaves. However the concentration of FPCs and the remaining monoterpenes was far higher -- so it seems that these mutations reduce the tight control over terpene production."

      While this loss of control probably has a high evolutionary cost, it allows the tree to survive the insect-plant war. The tree investigated had one branch which was untouched by insects when the rest of the tree was completely defoliated.


      Neurologic disorders

      Genetic counseling

      Identification of a de novo cause of epilepsy in a young child greatly reduces the recurrence risk for subsequent children for a couple. Because of germline mosaicism , however, the risk is not lowered to the population risk. When the same diagnosis is made in a young adult with intellectual disability and refractory epilepsy, the risk for his or her unaffected siblings’ children is reduced to the population risk. The risk to inherit the genetic cause should clearly be differentiated from the ability to predict the risk of epilepsy or intellectual disability. In tuberous sclerosis complex (TSC), the children of an affected patient are at 50% risk to inherit TSC, but accurate predictions regarding risk of epilepsy or intellectual disability are not possible.


      Genetic Analysis of Synaptogenesis

      29.2.3.2 Phototaxis-Defective Mutants with Abnormal Electroretinograms in the Genetic Mosaic Drosophila

      Phototaxis in Drosophila is a robust behavior that has been used since the earliest genetic screens to study photoreceptor function in vision ( Hotta and Benzer, 1969 Pak et al., 1969 ) and later adapted as a screening platform for synaptic defects manifested in genetic mosaics carrying eye-specific homozygous mutations in an otherwise heterozygous wild-type animal ( Stowers and Schwarz, 1999 ). The Drosophila compound eye is accessible to recording of electrical activity against a reference electrode, producing electroretinograms (ERGs) as a readout of the visual integration process from phototransduction to synaptic transmission in higher order secondary neurons ( Pak et al., 1969 ). ERGs have two easily distinguishable components: a ‘negative component’ contributed by the membrane conductance of the photoreceptor cells in the retina and ‘transient deflections’ at the initiation and cessation of light stimulus contributed by the depolarizing ‘on-transient’ and hyperpolarizing ‘off-transient’ from synchronous neurotransmission in the optic ganglia ( Heisenberg, 1971 Meinertzhagen and Hanson, 1993 Pak, 1979 ). Therefore, the combination of visual behaviors and direct ERG recording approach has been applied to identify genetic programming beyond photoreceptor cell fate specification (reviewed by Nagaraj and Banerjee, 2004 ) into processes in the visual system depending on the endocytosis of synaptic vesicles ( Babcock et al., 2003 Koh et al., 2004 Verstreken et al., 2003 ) and synaptic connectivity required for optomotor responses (reviewed by Choe et al., 2005 Clandinin and Zipursky, 2002 Sanes and Zipursky, 2010 ).

      While early ethane methyl sulfonate (EMS) screens for phototaxis-defective mutants with abnormal ERGs in the 1960s and 1970s succeeded in identifying components of phototransduction, they fell largely short of identifying genes associated with synaptic connectivity outside of the visual system because animals carrying homozygous mutations of such genes typically die as embryos or early larvae. In recent years, breakthroughs in the dissection of optomotor response circuitry, which directs movement guided by perceived motion, were made by harnessing the Gal4/UAS-shibire ts system ( Section 29.3.4.2 ) to genetically silence synaptic activity in separate regions of optic ganglia during the visual behavioral assay ( Rister et al., 2007 Zhu et al., 2009 ). More notably, lethal synaptic transmission mutants Syntaxin and Synaptotagmin, and novel classes of molecules in NMJ synaptogenesis, such as kinesin, voltage-gated calcium channel subunit and importin ( Table 29.1 ), emerged from a combined phototaxis–ERG screen using eye-specific mosaic animals ( Section 29.3.4.3 ) that have homozygous mutant eyes critical for the screen to discriminate phototaxis and ERG defects in otherwise heterozygous flies ( Dickman et al., 2008 Higashi-Kovtun et al., 2010 Kurshan et al., 2009 Ly et al., 2008 Pack-Chung et al., 2007 Stowers and Schwarz, 1999 ). These examples illustrate the great impact conditional gene expression methods have on fulfilling the unrealized potential of earlier visual behavioral screens in Drosophila.


      Mosaic evolution

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      Mosaic evolution, the occurrence, within a given population of organisms, of different rates of evolutionary change in various body structures and functions. An example can be seen in the patterns of development of the different elephant species. The Indian elephant underwent rapid early molar modification with little foreshortening of the forehead. The African elephant underwent parallel changes but at different rates: the foreshortening of the forehead took place in an early stage of development, molar modification occurring later.

      Similarly, in man there was early evolution of structures for bipedal locomotion, but during the same time there was little change in skull form or brain size later, both skull and brain evolved rapidly into the state of development associated with modern human species.

      The phenomenon of mosaic evolution would seem to indicate that the process of natural selection acts differently upon the various structures and functions of evolving species. Thus, in the case of human development, the evolutionary pressures for upright posture took precedence over the need for a complex brain. Furthermore, the elaboration of the brain was probably linked to the freeing of the forelimbs made possible by bipedal locomotion. Analysis of incidences of mosaic evolution adds greatly to the body of general evolutionary theory.