Chromosoma (2006) 115: 241­249
DOI 10.1007/s00412-006-0058-4
REVIEW
Rhea U. Vallente . Edith Y. Cheng . Terry J. Hassold
The synaptonemal complex and meiotic recombination in humans:
new approaches to old questions
Received: 20 December 2005 / Revised: 7 February 2006 / Accepted: 8 February 2006 / Published online: 18 March 2006
# Springer-Verlag 2006
Abstract Meiotic prophase serves as an arena for the
interplay of two important cellular activities, meiotic
recombination and synapsis of homologous chromosomes.
Synapsis is mediated by the synaptonemal complex (SC),
originally characterized as a structure linked to pairing of
meiotic chromosomes (Moses (1958) J Biophys Biochem
Cytol 4:633­638). In 1975, the first electron micrographs
of human pachytene stage SCs were presented (Moses et al.
(1975) Science 187:363­365) and over the next 15 years
the importance of the SC to normal meiotic progression in
human males and females was established (Jhanwar and
Chaganti (1980) Hum Genet 54:405­408; Pathak and Elder
(1980) Hum Genet 54:171­175; Solari (1980) Chromo-
soma 81:315­337; Speed (1984) Hum Genet 66:176­180;
Wallace and Hulten (1985) Ann Hum Genet 49(Pt 3):215­
226). Further, these studies made it clear that abnormalities
in the assembly or maintenance of the SC were an
important contributor to human infertility (Chaganti et al.
(1980) Am J Hum Genet 32:833­848; Vidal et al. (1982)
Hum Genet 60:301­304; Bojko (1983) Carlsberg Res
Commun 48:285­305; Bojko (1985) Carlsberg Res
Commun 50:43­72; Templado et al. (1984) Hum Genet
67:162­165; Navarro et al. (1986) Hum Reprod 1:523­
527; Garcia et al. (1989) Hum Genet 2:147­53). However,
the utility of these early studies was limited by lack of
information on the structural composition of the SC and the
identity of other SC-associated proteins. Fortunately,
studies of the past 15 years have gone a long way toward
remedying this problem. In this minireview, we highlight
the most important of these advances as they pertain to
human meiosis, focusing on temporal aspects of SC
assembly, the relationship between the SC and meiotic
recombination, and the contribution of SC abnormalities to
human infertility.
Tools of the trade
Three major technical developments were essential to the
recent advancement in human meiosis research. The first of
these occurred during the late 1980s to early 1990s and
involved the application of molecular tools to the analysis
of meiosis in lower organisms. Early studies focused on
Saccharomyces cerevisiae, initially characterizing tempo-
ral aspects of meiotic prophase (Sun et al. 1989; Padmore et
al. 1991; Weiner and Kleckner 1994) and subsequently
identifying molecular players involved in the formation of
the synaptonemal complex (SC) and SC-associated
proteins important for the induction of double strand
breaks (DSBs), DNA-damage checkpoints, cell-cycle pro-
gression, chromatid cohesion, chromosome pairing, and
recombination and crossover interference (for review, see
Roeder 1995; Kleckner 1996; Murakami and Nurse 2000;
Roeder and Bailis 2000; Yamamoto and Hiraoka 2001;
Solari 2002; Bishop and Zickler 2004; Krogh and
Symington 2004). These analyses were followed by
comparable studies in other model organisms, especially
Drosophila melanogaster (Kerrebrock et al. 1992;
Theurkauf and Hawley 1992; McKim et al. 1993) and
Caenorhabditis elegans (Dernburg et al. 1998; Pasierbek et
al. 2001; Siomos et al. 2001; MacQueen et al. 2002),
facilitating the identification of homologous proteins
involved in chromosome pairing, synapsis, and
recombination.
Secondly, and initially somewhat unexpectedly, cancer
geneticists played an important role in the development of
mammalian meiosis research. Beginning in the mid-1990s,
several groups generated mutant mice carrying null alleles
(knockout mice) for cancer-causing genes. For several of
Communicated by R. Benavente
The synaptonemal complex­50 years
R. U. Vallente (*) . T. J. Hassold
School of Molecular Biosciences, Washington State University,
Pullman, WA 99164, USA
e-mail: rhea@wsu.edu
Tel.: +1-509-3354932
E. Y. Cheng
Department of Obstetrics and Gynecology,
University of Washington,
Seattle, WA 98195, USA
these (e.g., the mismatch repair genes Mlh1 and Pms2),
homozygous knockouts were found to have severe meiotic
defects, resulting in subfertility or infertility (Baker et al.
1995, 1996). Targeted disruption studies of other loci--
some associated with human cancers, others not--have
now provided a long list of mouse mutations exhibiting
meiotic phenotypes (e.g., see Cooke and Saunders 2002;
Wei et al. 2002; de Rooij and de Boer 2003; Scherthan
2003; Ashley 2004; Eichenlaub-Ritter 2005). The genes
associated with these mutations were obvious targets in
initial studies of human meiosis.
A third keystone was the recent development of
straightforward antibody-based immunolocalization tech-
niques. Earlier localization attempts were often time-
consuming, labor intensive (e.g., immunogold staining
using electron microscopy), and were limited by the
reagents available at that time. Fortunately, the rapid
maturation of fluorescence microscopy for immunostaining
and fluorescence in situ hybridization (FISH) mapping,
coupled with the dramatic increase in the number of
antibodies recognizing epitopes of SC and SC-associated
proteins, resulted in an array of cytological markers for the
systematic probing and visualization of the kinetics of
meiotic events in germ cells (Moens et al. 1987; Dobson et
al. 1994; Moens 1995; Moens and Spyropoulos 1995;
Offenberg et al. 1998; Plug et al. 1998; Schalk et al. 1998;
Eijpe et al. 2000a,b, 2003; Revenkova et al. 2004). As
discussed below, the application of this methodology now
made it possible to visualize the important steps and
structures in the human meiotic process.
Temporal aspects of SC assembly
A hallmark feature of meiosis is the SC, the prophase-
specific supramolecular proteinaceous structure that forms
between and holds homologues together. The SC provides
a favorable location for binding of recombination machin-
ery proteins and is intimately associated with proteins
involved in sister chromatid cohesion (cohesins). In
addition, the SC serves as a reliable chronometer for
substaging meiotic prophase based on its degree of
formation or morphology (Fig. 1). One major structural
template of the SC is the SC protein SCP3, which
undergoes major transformations during prophase. At
leptotene, SCP3 is initially visualized as well-distributed
short linear segments (axial elements, AEs) forming along
each chromosome with chromatin loops extending out
from the protein backbone. These eventually lengthen and
condense into a filamentous meshwork. At zygotene, the
AEs appear as distinct full-length structures and are
brought together by transverse filaments composed of the
SC protein SCP1. At pachytene, completely synapsed
chromosome cores are distinct and cells have 23
centromeres. The SC begins to disassemble at diplotene
and homologous chromosomes move apart except at the
sites of recombination (chiasmata).
Results of immunolocalization studies on the temporal
expression patterns of SCP3 and other SC-associated
proteins in human spermatocytes and oocytes are summa-
rized in Fig. 2. To date, relatively few meiotic proteins were
analyzed in humans but, nevertheless, they have allowed us
to address a number of important questions regarding the
chronology of meiotic processes. One of the more
interesting of these was the relative ordering of events
involved in synapsis with those associated with recombi-
nation. In yeast, plants, and mammals, induction of DSBs
is a prerequisite to normal SC formation (Zickler and
Kleckner 1999). In contrast, initiation of recombination is
not required for SCs in Drosophila and C. elegans and
presynaptic alignment appears to be mediated by specific
chromosomal domains (McKim et al. 2002; MacQueen et
al. 2002). Another investigation showed that expression of
RAD51 recombinase, which attaches to processed DSBs
and promotes homologous DNA exchanges, occurs much
later in C. elegans than in S. cerevisiae (Colaiacovo et al.
2003), suggesting that homologue pairing, not SC forma-
tion, is required for DSB formation in C. elegans.
Furthermore, in both Drosophila and C. elegans, the
number of DSBs per cell is much lower than in S.
cerevisiae, plants, and mammals, suggesting that recombi-
nation is not required for chromosome alignment (Jang et
al. 2003).
In human meiocytes, preliminary data now indicate that
we follow the yeast paradigm. That is, two protein families
are evident early at prophase recombination-associated
proteins (e.g., RAD51, H2AX, RPA, MSH4, and MSH5)
(Moens et al. 1998; Plug et al. 1998; Tarsounas et al. 1999;
Cohen and Pollard 2001; Roig et al. 2004; Lenzi et al.
2005; Oliver-Bonet et al. 2005) and cohesion proteins (e.g.,
REC8 and STAG3) (Prieto et al. 2004). The appearance of
DSB "markers" (e.g., RAD51 and H2AX) occurs in
advance of fully formed SCs and indicates that initiation of
the human meiotic recombination pathway does not require
homologues to be completely synapsed (Brown et al. 2005;
Lenzi et al. 2005).
In other studies of DSB-associated proteins, it was
suggested that RAD51 foci are of different sizes: large and
bright in synapsed regions and somewhat smaller on
asynapsed AEs (Barlow et al. 1997), possibly reflecting
their short-term existence during synapsis. RPA and
H2AX appear to be maximally expressed at late zygo-
tene/early pachytene, coincident with the completion of
synapsis between homologous chromosomes and these
proteins diminish at pachytene (Lenzi et al. 2005; Oliver-
Bonet et al. 2005). The MutL homologues MLH1 and
MLH3 appear on synapsed SCs (Lynn et al. 2002; Tease et
al. 2002; Lenzi et al. 2005).
Sex-specific temporal patterns of protein expression
were observed in around half of the proteins studied in
human meiocytes. Generally, it appears that oocytes have
more prolonged expression patterns than spermatocytes.
For example, the MutL homologue MLH1 is observed in
oocytes in zygotene and as early as leptotene (Vallente,
Cheng, and Hassold, unpublished observations; Fig. 1a,b)
while in males, it is not evident until pachytene (Lynn et al.
2002; Brown et al. 2005; Gonsalves et al. 2005; Oliver-
Bonet et al. 2005). The number of MLH1-MLH3 foci are
242
maintained during pachytene, yet there is an tenfold
variation of MLH1-MLH3 foci numbers between oocytes,
which is also evident at the chromosome level as frequent
achiasmate chromosome arms and whole chromosomes
and chromosome arms overloaded with MLH1 foci (Lenzi
et al. 2005). Another protein that is variably expressed in
oocytes is MSH4, a component of the MSH4-MSH5
heterodimer complex that is thought to act as a stabilizing
clamp for recombination intermediates. MSH4 is detect-
able in leptotene in females but does not associate with
SCP3 until zygotene (Lenzi et al. 2005), while it appears
later at zygotene in males (Oliver-Bonet et al. 2005).
In oocytes, RAD51 remains associated with the
chromosomes at high numbers until early pachytene
(Lenzi et al. 2005), suggesting that these represent the
late H2AX events that have either failed to be processed
or that are induced later during prophase. It is interesting to
note that by late pachytene, the numbers of RAD51 foci
and H2AX foci are not statistically different, which
suggests that all H2AX sites are targeted by RAD51.
Most of the H2AX protein diminishes at pachytene, but
some are expressed at a prolonged period in the XY body in
males (Lenzi et al. 2005; Oliver-Bonet et al. 2005). In
spermatocytes, RAD51 protein is depleted by late pachy-
tene while H2AX persists (Lenzi et al. 2005; Oliver-
Bonet et al. 2005), possibly representing late-processing
DSBs, improper dephosphorylation, or changes within the
chromatin architecture from SPO11-independent damage
(Hamer et al. 2003). Unfortunately, the cohesion proteins
REC8 and STAG3 were only investigated in oocytes and
these remain colocalized to SCP3 only until early diplotene
(Prieto et al. 2004).
The SC and meiotic recombination
Until recently, all information on meiotic recombination
levels in humans were based on one of two approaches:
cytogenetic studies of chiasmata (the sites of crossovers) in
diakinesis stage meiocytes (Hulten 1974; Laurie et al.
1981; Laurie and Hulten 1985a,b) or, more commonly,
genetic linkage analyses using DNA polymorphisms
(either restriction fragment length polymorphisms, mini-
or microsatellite polymorphisms, or single nucleotide
polymorphisms) to trace inheritance of alleles in family
pedigrees and generate sex-specific or sex-averaged ge-
netic maps (e.g., Broman et al. 1998; Nievergelt et al. 2004;
Gibson et al. 2005; Serre et al. 2005). Each approach has
advantages and disadvantages. The cytogenetic approach
provides a useful tool for examining chiasma patterns on
individual chromosomes and for estimating genome-wide
chiasma frequencies. However, even under the best of
circumstances, the morphology of diakinesis chromosomes
is suboptimal, interfering with banding and thus with
3Fig. 1 Visualization of prophase substages using immunofluores-
cence staining for SCP3 (axial elements, red), CREST (kineto-
chores, blue), and MLH1 (late recombination nodules, green) in
human oocytes. a Leptotene oocyte with patchy SCP3 staining,
approximately 46 CREST signals and small, dispersed MLH1 foci.
b Zygotene oocyte with full-length axial elements and MLH1
signals. c Pachytene oocyte with SCP3 fibers showing complete
synapsis of homologous chromosomes and distinct MLH1 foci
243
chromosome identification. Further, the chromosomes are
typically highly condensed, making localization of chias-
mata to specific chromosome regions difficult. Finally,
invasive techniques are required to obtain the cells of
interest (fetal oocytes and spermatocytes) and there are
relatively few cells at the appropriate stage, further limiting
the power of the technique.
Genetic linkage analysis stands in stark contrast to the
cytogenetic methodology because it provides a powerful,
high resolution approach to studies of recombination.
Highly detailed chromosome-specific genetic maps can be
constructed and compared to physical maps, narrow hot
and cold spots of recombination can be identified, and
patterns of male and female recombination can be
compared. However, genetic linkage analysis relies on
studying transmitted haploid meiotic products rather than
the cells undergoing meiosis; as a result, only one half of all
exchanges can be detected (e.g., after a single exchange,
only two of the four chromatids will be recombinant).
Thus, any recombination-associated selection against
gametes will be missed. Further, genetic linkage analyses
are not well suited to analyses of genome-wide recombi-
nation events in individual meiocytes.
Recently, a third approach--immunolocalization studies
of crossover associated proteins in pachytene meiocytes--
has attracted considerable attention. The rationale for this
approach is based on studies in mice, which indicated that a
number of proteins, including the mismatch repair protein
MLH1, had meiotic localization patterns that paralleled
those of crossovers (Baker et al. 1995, 1996; Anderson et
al. 1999). Thus, it was suggested that if applicable to
humans, this approach had the potential to provide a
"medium" level of resolution (higher than that using
conventional cytogenetics but lower than that afforded by
linkage analyses) and because pachytene stage cells are
plentiful in fetal oocytes and testicular biopsies, a large
amount of data on individual samples.
Accordingly, several groups initiated studies of MLH1
in human germ cells. Most of the initial data has come from
males attending infertility clinics. Many such individuals
are infertile for "mechanical" reasons (e.g., vasectomized
males), making it possible to construct "control" genetic
maps based on MLH1 localization patterns and to compare
them with maps generated from cytogenetic or linkage
studies. The results were remarkable because the maps are
virtually identical regardless of the method used (Table 1).
Fig. 2 List of immunofluorescence studies performed on human oocytes (pink) and spermatocytes (blue) showing expression profiles for
cohesins, recombination-associated proteins, and SC proteins
244
Specifically, analyses of MLH1 foci indicate that there are
approximately 50 exchanges per spermatocyte, translating
to a genome-wide map of approximately 2,500 cM; this
value agrees well with previous estimates from chiasma
studies and with most genetic linkage analyses. Further, the
distribution of MLH1 foci exhibits several features
expected of crossover-associated proteins (Anderson et
al. 1999). For example, consistent with genetic linkage data
on human males (Kong et al. 2002; Mohrenweiser et al.
1998), MLH1 foci are preferentially distally located. In
addition, MLH1 foci exhibit strong positive interference,
the meiotic property that ensures "spacing" between
adjacent crossovers on the same chromosomes. Finally,
the number of MLH1 foci per chromosome is tightly
regulated in human males with virtually all chromosome
arms (except short arms of acrocentric chromosomes)
having at least one focus, but seldom more than two foci;
this agrees with previous data suggesting that "achiasmate"
chromosomes are rare in humans (Hassold et al. 1995).
Taken together, these results have demonstrated that MLH1
foci, indeed, do localize to sites of exchanges, providing a
powerful surrogate for analyses of meiotic recombination
events in the human male.
The initial results from human males also provide
evidence of a role of the SC in mediating recombination
levels. That is, Lynn et al. (2002) reported a simple linear
relationship between the length of the SC and the number
of MLH1 foci in human males and in mouse males and
females; from this, they suggested that a physical structure
(the SC) "measures" genetic distance in mammalian
species. Other groups have now confirmed the relationship
between SC length and recombination levels in humans
(Tease and Hulten 2004; Sun et al. 2005a), although the
basis for the association remains unclear. Possibly, chro-
matin loop sizes are responsible for the total SC length, i.e.,
smaller loop sizes generate longer SCs, which in turn
provide more room for DSBs to occur along the SC length
(Kleckner et al. 2003). A constant SC length may also be
considered as a factor behind this covariation wherein the
length remains unaffected despite mutations on DSB
machinery and/or SC formation. From an evolutionary
point of view, it may also be possible that hot spots are
being replaced by cold spots (negative selection), resulting
in restrictions in recombination (Myers et al. 2005; Pineda-
Krch and Redfield 2005).
In contrast to the human male, relatively little MLH1
data are yet available on the human female, partly because
of the difficulties inherent in ascertaining the appropriate
material (i.e., ovaries from female fetuses). Nevertheless,
the initial observations were intriguing with both expected
and unexpected results. Included among the expected
outcomes: as in the male, MLH1 foci display positive
interference (Vallente, Cheng, and Hassold, unpublished
observations) and consistent with linkage analysis, MLH1
foci are preferentially interstitially located. However, there
also were two surprises. First, the MLH1-based estimates
of genome-wide genetic length are significantly lower than
those based on genetic linkage analyses. Indeed, in the
largest study (Lenzi et al. 2005), the estimated genetic
length is approximately the same as that observed in human
males and only 55­65% that of genetic linkage analyses of
human females. These MLH1-based data almost certainly
do not represent the real situation in fertilized female
oocytes because genetic linkage analyses indicate that
females have approximately 1.6 the amount of recombi-
nation as males (Kong et al. 2002). Nevertheless, it is still
possible that these data reflect the situation in the fetal
ovary, e.g., selection may preferentially cull out oocytes
with low levels of recombination so that the oocytes that
are eventually ovulated are those with the highest levels of
recombination. Clearly, additional analyses of fetal ovaries
will be useful in confirming or refuting this idea and, more
importantly, in determining the range of recombination
values in individual human fetal oocytes. Secondly, the
Table 1 Summary of genome-wide human genetic maps
Male Female
Method of
analyses
No. of
meioses
Mean no.
chiasmata
Mean no.
MLH1
foci
Genetic
length
(cM)*
No. of
meioses
Mean no.
MLH1 foci
Genetic
length
(cM)*
Reference
Chiasmata 389 53.7 --- 2,700 --- --- --- (McDermott 1973)
55 49.6 --- 2,480 --- --- --- (Laurie and Hulten 1985b)
MLH1 foci 46 --- 50.9 2,545 3 95.0 4,750 (Barlow and Hulten 1998)
1,384 --- 49.1 2,455 --- --- --- (Lynn et al. 2002)
1,231 --- 45.9 2,295 --- --- --- (Gonsalves et al. 2004)
2,182 --- 49.8 2,490 --- --- --- (Hassold et al. 2004)
102 --- 50.0 2,500 49 70.3 3,515 (Tease and Hulten 2004)
--- --- --- --- 250 50.3 2,515 (Lenzi et al. 2005)
1,100 --- 48.0 2,400 --- --- --- (Sun et al. 2005b)
Genetic linkage --- --- --- 2,625 --- --- 3,799 (Matise et al. 1994)
--- --- --- 2,730 --- --- 4,435 (Broman et al. 1998)
--- --- --- 2,590 --- --- 4,460 (Kong et al. 2002)
--- --- --- 2,642 --- --- 4,414 (Matise et al. 2003)
--- --- --- 2,813 --- --- 4,600 (Kong et al. 2004)
--- --- --- 2,654 --- --- 4,320 (Jorgenson et al. 2005)
*Genetic map lengths may be directly estimated from the number of meiotic crossovers (chiasmata or MLH1 foci); each crossover
corresponds to a genetic distance of 50 cM
245
timing of localization of MLH1 foci to SCs was surprising:
In contrast to reports from human males and mouse males
and females, MLH1 is visualized early in zygotene and
even as early as leptotene in human oocytes (Vallente,
Cheng, and Hassold, unpublished observations; Fig. 1a,b).
Whether this reflects additional functions for MLH1 in
human oocytes or variation in the processing of recombi-
nation events, is not yet clear.
The SC and human infertility
The chronology of events in oogenesis makes it difficult to
link early meiotic abnormalities to female infertility but in
the male, abnormalities in meiotic recombination and/or
SC assembly have long been known to be associated with
cases of infertility (Chaganti et al. 1980; Vidal et al. 1982;
Templado et al. 1984; Navarro et al. 1986). However, these
early studies were largely descriptive and not geared to
examining the underlying reasons for the infertility. The
recent reinvigoration in human meiotic research now
provides the opportunity to revisit this question and to
ask whether specific mutational processes can be identi-
fied. In general, investigators addressing this question have
taken one of two approaches: either using sequencing
methodology to identify mutations in known meiotic genes
or using cytological methodology to identify specific
meiotic arrest phenotypes. Both approaches have yielded
positive results. For example, Miyamoto et al. (2003)
screened for SCP3 mutations in controls and in 19
individuals diagnosed with idiopathic infertility. In the
infertile group, they identified two unrelated individuals
heterozygous for identical deletions that led to a premature
stop codon; presumably, the resultant truncated protein
acted as a dominant negative, interfering with normal AE
assembly. Similarly, Christensen et al. (2005) identified
heterozygous missense mutations in SPO11 in a small
proportion (2 of 192) of azoospermic/oligospermic in-
dividuals, but not in controls, suggesting a causative
relationship between the mutation and azoospermia.
Several groups have now taken the other approach, i.e.,
using immunofluorescence methodology to examine mei-
otic progression, SC assembly, or localization of cohesions
or recombination-associated proteins in meiosis I
spermatocytes of populations of infertile individuals. In
an initial study, Judis et al. (2004) analyzed 13 individuals
with nonobstructive azoospermia/oligospermia and identi-
fied one individual with a complete zygotene stage arrest.
AE formation appeared normal, but there was no evidence
of synapsis, leading the authors to suggest a defect in
assembly of the transverse filament (e.g., a mutation in
SCP1). Similarly, Sun et al. (2004) recently reported a
variety of pairing defects and reduced MLH1 counts in a
single azoospermic individual; Gonsalves et al. (2004)
reported on three azoospermic individuals with partial or
complete zygotene stage arrest phenotypes. Taken together,
these results suggest that a proportion of azoospermic
individuals is infertile because of abnormalities in pairing,
synapsis, or recombination that lead to prophase arrest. In
future studies, it will be important to carefully analyze the
meiotic phenotypes of these individuals to ask whether
they might have subtle differences in the timing of the
meiotic arrests indicative of different mutational origins.
Indeed, in such individuals, it may be possible to use
immunofluorescence analysis as an initial screening tech-
nique before subsequent mutation detection analysis. For
example, initial immunofluorescence observations may
simply implicate a protein family (e.g., abnormalities in
sister chromatid cohesion could be due to one of several
sister chromatid cohesion proteins), while others may
suggest a specific genetic lesion (e.g., failure to detect the
transverse filament of the SC implies a mutation in the
SCP1 locus). Thus, subsequent studies would vary
depending on the initial observations: They might involve
additional protein localization studies or might move
immediately to mutation detection assays.
Perspective
Researchers studying human meiosis have long been
envious of their colleagues who examine meiosis in
lower organisms. Short breeding times, relatively easy
access to the cells of interest, and the ability to generate
mutations and analyze their effects on germ cell behavior,
all have combined to produce extraordinary insights into
the meiotic process in a variety of model organisms.
Clearly, such successes will be virtually impossible to
replicate in humans: Both the biology of human gameto-
genesis and ethical considerations necessitate different
approaches to the study of human meiosis. Nevertheless,
the advances from model organisms now have provided us
with a set of tools to begin the work of human gameto-
genesis and the initial results are encouraging. The ability
to directly visualize spermatogenesis and oogenesis means
that we can finally characterize the normal process and,
hopefully, we will ultimately be able to apply this
information to treat the abnormal process, i.e., those
abnormalities that lead either to infertility or to chromo-
somally abnormal gametes.
Acknowledgement Work conducted in the Hassold and Cheng
laboratories as discussed in this review was supported by NIH grant
HD21341.
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