Lecture 14: Mosaicism and Chimerism

Define mosaicism and chimerism

Mosaicism - cells with different genetic complements in an individual derived from one zygote

Chimerism - cells with different haploid complements in an individual derived from 2 separate zygotes

How can twins derived from a single conceptus be discordant in chromosome complement or even sex? (list more than one mechanism)

Discordant for sex: mostly 47XXY cells make up baby A, while 46XX cells make up baby B

Sesquizygotic twinning

Discordant for chromosome complement: mostly 46,XY make up baby A while 47XY+21 cells make up baby B

How common is mosaicism? Can the incidence of abnormal cells increase or decrease over time? Explain.

Very! We are all mosaic, every cell division accumulates DNA damage and errors → persist if no negative selection

All female mammals are mosaic for X-chromosome inactivation

Increase over time: if mosaic chagne does not impact survival or creates an advantage

Decrease over time: change creates a survival disadvantage and is selected against

Animals that are gynandromorphs are half male and half female. How many mechanisms can you think of by which this might theoretically arise? Can this also occur in humans? Explain.

• Fertilization of both the single egg and the polar body by two sperm

• Mutation in sex-determining genes

• Mosaicism for sex chromosome complement during early cell divisions

• Other factors including temperature variation

• Bilateral gynandomorphs don’t arise in humans - we lack bilateral symmetry

  • disorders of sex development make different phenotypes possible

What are some challenges in the diagnosis of mosaicism or chimerism

• present at low levels

• present in only certain cell populations or tissues

• hard to detect: easily-accessible tissues are not affected, hard to reach are

• below level of detection of assay technique

• not well studied!

Why might it be missed and why is it hard to interpret when it is found?

You are an obstetrician and deliver twins with a single placenta, but the two twins appear to be of opposite sex. As we have learned, there are various mechanisms by which this might occur. Provide two possible mechanisms and explain what you would expect to see in a genome wide SNP array if the proposed mechanism was correct.

Mechanisms

Arrays

• trisomy rescue SNP array

  • twins will have same result

  • one is XXY and one is XX → both Xs are the same

• sesqui-zygotic twins SNP array

  • both twins have same maternal allele but different paternal

  • one egg fertilized by 2 sperm → 3n zygote

A professional bicyclist was accused of blood doping, as foreign antigens were detected in his blood. He was accused of blood doping, but his defense lawyers claimed that he is actually a chimera. If you were the defense attorney, what evidence might you provide to support your claim that the testing results could be the result of chimerism. If you were the prosecutor, how might you refute this claim?

Mother-fetal chimerism

• trafficking of cells between mother and fetus that can remain throughout life time

• at very low levels only

What is something interesting in this course that helped you learn more about early development?