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5.6 Mitotic Recombination and Genetic Mosaics 167

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Mitotic Recombination and Cancer Formation
In humans, some tumors, such as those found in retinoblastoma, because they are homozygous for the newly mutant, nonfunc-
may arise as a result of mitotic recombination. Recall from the tional allele.
discussion of penetrance and expressivity in Chapter 3 that reti- The role of mitotic recombination in the formation of retino-
noblastoma is a form of eye cancer. The retinoblastoma gene (RB) blastoma helps explain the incomplete penetrance and variable
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resides on chromosome 13, where the normal wild-type allele expressivity of the disease. People born as RB /RB heterozy-
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(RB ) encodes a protein that regulates retinal growth and differen- gotes may or may not develop the condition (incomplete pene-
tiation. Cells in the eye need at least one copy of the normal wild- trance). If, as usually happens, they do, they may have tumors in
type allele to maintain control over cell division. The normal, one or both eyes (variable expressivity). It all depends on whether
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wild-type RB allele is thus known as a tumor-suppressor gene. and in what cells of the body mitotic recombination (or some
People with a genetic predisposition to retinoblastoma are other “homozygosing” event that affects chromosome 13) occurs.
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born with only one functional copy of the normal RB allele; their
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second chromosome 13 carries either a nonfunctional RB al- Figure A How mitotic crossing-over can contribute to
lele or no RB gene at all. If a mutagen (such as radiation) or a cancer. Mitotic recombination during retinal growth in an RB /RB
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mistake in gene replication or segregation destroys or removes heterozygote may produce an RB /RB daughter cell that lacks a
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the single remaining normal copy of the gene in a retinal cell in functional retinoblastoma gene and thus divides out of control. The
either eye, a retinoblastoma tumor will develop at that site. In crossover must occur between the RB gene and its centromere.
one study of people with a genetic predisposition to retinoblas- Only the arrangement of chromatids yielding this result is shown.
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toma, cells taken from eye tumors were RB homozygotes,
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while white blood cells from the same people were RB /RB het- Transient Pairing
erozygotes. As Fig. A shows, mitotic recombination between of Homologous Mitotic Daughter
the RB gene and the centromere of the chromosome carrying Chromosomes 13 Metaphase Cells
During Mitosis
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the gene provides one mechanism by which a cell in an RB /
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RB individual could become RB /RB . Once a homozygous RB Normal
cell is generated, it can divide uncontrollably, leading to tumor RB +
formation. RB + RB +
Only 40% of retinoblastoma cases follow the preceding RB + RB +
scenario. The other 60% occur in people who are born with two RB + – – – –
RB
normal copies of the RB gene. In such people, it takes two mu- RB RB RB
tational events to cause the cancer. The first of these must con- RB – RB –
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vert an RB allele to RB , while the second could be a mitotic
recombination producing daughter cells that become cancerous Retinoblastoma
essential concepts
• Twin spots are a form of genetic mosaicism; these spots • Mitotic recombination can also produce sectored colonies
occur when mitotic recombination gives rise to two in diploid yeast, in which part of a colony has a
clones of cells having reciprocal mutant genotypes recognizable mutant phenotype.
and phenotypes.

WHAT’S NEXT

Medical geneticists have used their understanding of link- tightly coupled. In fact, the genetic distance between the
age, recombination, and mapping to make sense of the ped- two genes is only 3 m.u. The sample size in Fig. 5.1a was so
igrees shown at the beginning of this chapter (see Fig. 5.1). small that none of the individuals in the pedigree were re-
The X-linked gene for red-green color blindness must lie combinant types. In contrast, even though the hemophilia B
very close to the gene for hemophilia A because the two are locus is also on the X chromosome, it lies far enough away
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