Download Mosaicism—Switch or Spectrum?

Mosaicism−−Switch or Spectrum?
Brian R. Davis and Fabio Candotti
Science 330, 46 (2010);
DOI: 10.1126/science.1195991
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PERSPECTIVES
GENETICS
A high rate of recombination restores the
function of a mutated gene that encodes
keratin, giving rise to the “confetti” spots
in a rare skin disorder.
Mosaicism—Switch or Spectrum?
Brian R. Davis1 and Fabio Candotti2
1
Centre for Stem Cell Research, Brown Foundation Institute
of Molecular Medicine, University of Texas Health Science
Center, Houston, TX 77030, USA. 2Genetics and Molecular
Biology Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA. E-mail: brian.r.davis@uth.
tmc.edu
46
Somatic cell population
Mutated gene
Corrected gene
Substitution, insertion, or
deletion of base pair(s)
or mitotic recombination
Germline
mutation
Mutant cells
Downloaded from www.sciencemag.org on December 10, 2012
Somatic
mutation
Revertant cell
Partial or full restoration of
disease-causing gene product
Selective pressures (intrinsic
and extrinsic) favor
emergence and/or expansion
Mixed cell population
Emergence of mosaicism. Somatic revertant mosaicism involves the three stages shown. Somatic mutations can arise in a disease-causing gene spontaneously or in response to DNA damage. If the mutation
restores gene function (blue), this originates a revertant cell. If the revertant cell is capable of self-renewal
and proliferation, selection pressures can act to favor expansion and detection. If the somatic mutation is
not beneficial (black), the event is unlikely to rise above the detection threshold.
reports from primary immunodeficiency syndromes, such as the Wiskott-Aldrich syndrome (in which reversion occurs in 10 to 15%
of patients) and severe combined immunodeficiency (caused by mutations in CD3 zeta or
RAG1 genes), have also documented multiple independent reversion events in patients
(6–12). For example, at least 35 distinct revertant mutations were identified in one WiskottAldrich syndrome patient (6, 7).
Taken together, these findings suggest
that mosaicism develops through the ongoing generation of somatic mutations that
affect the disease-causing gene in cells of
self-regenerating organ systems. Although
most of these somatic mutations will provide
no benefit, some will result in partial or full
functional restoration of the gene. Model cal-
culations—taking into account the spontaneous DNA mutation rate and the number of cell
divisions occurring in the newborn thymus—
predict that cells that have corrections for specific immune gene mutations (e.g., correction
of a stop codon) likely originate in most (or
all) patients. A possible principal factor that
distinguishes those individuals in which such
events result in detectable revertant mosaicism
is whether beneficial reversion mutations originated in a cell sufficiently early in its developmental pathway to provide for substantial
expansion of revertant cells (such as epidermal stem cells for epidermolysis bullosa, and
hematopoietic stem cells or lymphoid and thymic precursor cells for Wiskott-Aldrich syndrome), or perhaps otherwise in a particularly
long-lived cell that is capable of expansion
1 OCTOBER 2010 VOL 330 SCIENCE www.sciencemag.org
Published by AAAS
CREDIT: C. BICKEL/SCIENCE
S
omatic revertant mosaicism—the
coexistence of cells carrying inherited
genetic mutations with cells that have
undergone spontaneous changes that correct the mutant phenotype—was previously
thought to be extremely rare in terms of the
frequency of patients in which it occurs and
the frequency with which cells bearing revertant mutations arise in a given patient. A number of recent findings, including the report by
Choate et al. on page 97 of this issue (1), challenge this perspective.
Somatic revertant mosaicism has been
described in several genetic disorders affecting self-regenerating organ systems such as
the skin, blood, and liver (2). Its development involves at least three steps: the occurrence of a correcting mutation in the already
mutated gene; the survival of cells that have
acquired partial or full functional restoration
of the gene (revertant cells); and the selection
and enrichment of these cells (see the figure).
At present, little is known about the specific
molecular mechanisms leading to revertant
mutations (either during normal DNA replication or in response to genotoxic agents) or
the precise selection processes for revertant
cells. This limited knowledge derives from
isolated reports of revertant patients carrying only one or a small number of revertant genotypes (2). As such, the commonly
accepted picture has been that reversion is a
highly inefficient stochastic process, possibly
associated with unique characteristics of the
patient exhibiting reversion.
Reports of multiple, independently arising, correcting, or second-site revertant
mutations in the same patient have changed
this notion and indicate that reversion is less
unusual than had been thought. For example,
revertant patches of healthy skin surrounded
by the easily blistered skin in the disease junctional epidermolysis bullosa can arise from
different molecular reversion events in the
mutated genes (COL17A1 or LAMB3) in the
same patient (3, 4). This was not an infrequent
occurrence; multiple revertant patches, each
caused by a different molecular event, were
identified in up to 30% of patients (5). Recent
PERSPECTIVES
the various KRT10 mutations is the expression of a mutant keratin protein that mislocalizes to the nucleus. Although another skin disease, epidermolytic ichthyosis, is caused by
dominant negative or recessive mutations in
the same KRT10 gene, revertant clones have
not been identified in this condition. As such,
Choate et al. postulate a link between IWC
mutant keratin 10 proteins and the high number of observed mitotic recombination events.
If this is correct, increased mitotic recombination should affect chromosomes other than
chromosome 17q. However, it may not be
necessary to invoke a specific facilitating role
of the mutant keratin 10 proteins in determining the occurrence of revertant skin patches in
IWC. Indeed, the function of keratin 10 may
be more severely affected by the IWC frameshift mutations than by the missense substitutions responsible for epidermolytic ichthyosis.
If that is the case, revertant cells may be conferred a stronger selective advantage in IWC
than in epidermolytic ichthyosis, thus allowing them to rise above the detection threshold
by forming the “confetti” spots.
Somatic revertant mosaicism can be likened to a natural form of gene therapy, and
the findings of Choate et al. have potential
relevance to therapeutic options for affected
patients. These include using revertant stem
cells (from patches of corrected skin) for
engraftment; expanding preexisting corrected cells in vivo; and guiding efforts to
induce targeted (site-specific) revertant mutations in vivo. For the latter, studies of revertant patients are particularly important, as
they could inform the levels of correction that
need to be achieved by gene therapy to obtain
meaningful clinical effects.
References
1. K. A. Choate et al., Science 330, 97 (2010); published
online 26 August 2010 (10.1126/science.1192280).
2. R. Hirschhorn, J. Med. Genet. 40, 721 (2003).
3. A. M. Pasmooij, H. H. Pas, F. C. Deviaene, M. Nijenhuis,
M. F. Jonkman, Am. J. Hum. Genet. 77, 727 (2005).
4. A. M. Pasmooij, H. H. Pas, M. C. Bolling, M. F. Jonkman,
J. Clin. Invest. 117, 1240 (2007).
5. M. F. Jonkman, A. M. Pasmooij, N. Engl. J. Med. 360,
1680 (2009).
6. B. R. Davis, F. Candotti, Immunol. Res. 44, 127 (2009).
7. B. R. Davis et al., Blood 111, 5064 (2008).
8. B. R. Davis et al., Clin. Immunol. 135, 72 (2010).
9. K. Boztug et al., Clin. Genet. 74, 68 (2008).
10. M. I. Lutskiy, J. Y. Park, S. K. Remold, E. RemoldO’Donnell, PLoS ONE 3, e3444 (2008).
11. F. Rieux-Laucat et al., N. Engl. J. Med. 354, 1913 (2006).
12. T. Wada et al., Blood 106, 2099 (2005).
Downloaded from www.sciencemag.org on December 10, 2012
(such as a T lymphocyte for Wiskott-Aldrich
syndrome). In this context, somatic revertant
mosaicism is less likely a binary switch in
which a given patient is either revertant or not.
Rather, it appears to be a spectrum in which a
patient originated revertant cells at some time,
with the frequency, diversity, and functionality of the revertant cells dependent on various
factors including the strength of selection. It is
very possible that ultradeep sequencing methods that can detect rare gene variants can test
the accuracy of this picture.
In their investigations on the skin disease
ichthyosis with confetti (IWC, also known
as congenital reticular ichthyosiform erythroderma), Choate et al. show that independent revertant clones, originating by loss of
a heterozygous mutation on chromosome
17q, give rise to the thousands of normal
skin spots that appear early in life in affected
patients and increase in number and size over
time. By mapping the location of common
genetic recombination events in the revertant clones, the authors determined that dominant frameshift mutations in the KRT10 gene
cause the disease and discovered an unprecedented diversity of independent recombination events in humans. A common feature of
10.1126/science.1195991
ASTRONOMY
A Dance of Extrasolar Planets
The Kepler space telescope has found a system
of planets whose orbital timing varies due to
gravitational coupling.
Gregory Laughlin
L
aunched in March 2009, the Kepler
mission is tasked with searching for
extrasolar planets. It continuously
monitors 156,000 stars in a ~100-squaredegree patch of sky covering a portion of the
galactic disk centered on a direction lying in
the constellation Cygnus (1). On page 47 of
this issue, Holman et al. (2) report the discovery of a transiting planet whose orbit of 38.9
days varies by up to 1 hour due to the interaction with other planets in the system. This
Saturn-sized world, known as Kepler-9c, circles a Sun-like star 2300 light-years away in
the direction of the constellation Lyra, and is
part of a bizarre system containing three transiting planets, whose mutual gravitational
tugs generate an exquisitely choreographed
orbital dance. Far from being mere curiosities, the planets of the Kepler-9 system may
Department of Astronomy and Astrophysics, UCO/Lick
Observatory, University of California at Santa Cruz, Santa
Cruz, CA 95064, USA. E-mail: [email protected]
provide vital clues to the mechanisms of planetary formation and orbital evolution.
Kepler can detect a 1/10,000 dip in brightness that occurs when an Earth-sized planet
on an Earth-like orbit makes a ~12-hour passage (transit) in front of a Sun-sized star.
The goal is to continuously monitor its target stars for a long enough period (at least 3.5
years) to observe repeated passages by Earthsized planets on Earth-like orbits, leading to
an estimate of the occurrence frequency of
potentially habitable worlds.
Although Earth-sized planets have not yet
been reported, Kepler has been remarkably
productive in finding hot short-period planets with orbits ranging from days to weeks.
In January of this year, its first five discoveries of four “hot Jupiters” and a “hot Neptune”
were announced (3), and in June, an additional 312 candidate planets were reported
(4). Although the members of this latest batch
of planets require follow-up observations for
individual confirmation, their bulk statistics
suggest that an important, and perhaps even
the dominant mode of planet formation in
our galaxy looks nothing like what happened
in the Solar System: “Super-Earths” with
masses between 5 and 15 times that of Earth
are commonly found on orbits with periods
of 50 days or less, with recent indications that
up to a half of nearby Sun-like stars harbor
objects of this type (5).
Kepler’s discoveries are contributing to a
rapidly growing catalog of transiting extrasolar planets, yielding planetary masses, radii,
bulk compositions, atmospheric constituents,
and even weather reports (6). Furthermore,
transiting planets in favorably constructed
multiple-planet systems will exhibit measurable variations from strict orbital periodicity that can operate as detailed probes of the
orbital dynamics (7, 8).
Although extrasolar transit-timing variations have proved elusive until now, astronomers have had centuries of experience with
the transit-timing technique in our own Solar
www.sciencemag.org SCIENCE VOL 330 1 OCTOBER 2010
Published by AAAS
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