Download Minireview

BIOLOGY OF REPRODUCTION 79, 2–8 (2008)
Published online before print 9 April 2008.
DOI 10.1095/biolreprod.107.065607
Minireview
Heredity—Venturing Beyond Genetics
Marie-Christine Maurel1,2 and Colette Kanellopoulos-Langevin3
Laboratoire de Biochimie de l’Evolution et Adaptabilité Moléculaire2 and Laboratoire des Régulations Immunitaires et
Développement, Institut Jacques-Monod,3 UMR 7592, CNRS and Universités Paris 6 and 7,
75251 Paris Cedex 05, France
Fertilization is the starting point for the hereditary
transmission of the characteristics contained in the maternal
and paternal gametes. Recently, our knowledge regarding
heredity has undergone major upheaval, particularly in light of
recent studies concerning epigenetic phenomena [1, 2]. Clearly,
neither the sequence nor the number of genes is sufficient to
explain the complexity of a living organism. One cannot
‘‘calculate’’ the embryo. The term epigenetic, which was coined
in 1953 by Waddington [3], covers the interactions that exist
between genes and their environment and hereditary modifications other than those based on changes in the nucleotide
sequence. Waddington therefore placed epigenetics at the
junction between genetics, developmental biology, and ecology—all based on evolutionary biology. The concept of
epigenetics itself has had ample time to evolve during the last
50 years, but today, epigenetic studies are being focused on the
influence of internal and external environments on genes and
their products and their effects on cells and organisms [4]. This
significantly broadens the concept of heredity, moving it into
realms beyond that of the gene-centered neo-Darwinism.
One consequence of the belief that everything is genetic is
illustrated by the disappearance of what was known previously
as embryology, which today has been replaced by developmental biology. Along the lines of an idea put forward by
Canguilhem et al. [5], the term development, which according
to its etymology means the unrolling or unfolding of something
that is already present (i.e., preformed), does not, in fact,
correctly represent the process it is meant to describe. Today,
developmental biology focuses on genes, with the environment
being perceived as a background—that is, a context that
provides the necessary conditions, just as a photographic film
is the background that expresses the latent image when dipped
into a chemical solution (i.e., developer).
In the 17th century, the preformationists often depicted the
spermatozoon with a miniature, fully formed human (in a fetal
position) inside [6]. The preformationists considered that once
this homunculus had been deposited in a cavity (i.e., the
uterus), it simply had to increase in size, with the egg of the
mother merely supplying the nutrients necessary for its growth.
This is why, if one takes a conceptual shortcut, the entire future
organism could be said to be contained within the information
carried by the DNA. In this context, the egg grows and
differentiates in the uterus, which thus becomes a passive
repository—a theory that some scientists (and the novelist
Aldous Huxley in Brave New World [7]) have used to imagine
the possibility of an artificial uterus. In his book The Selfish
Gene, Dawkins [8] theorizes that a self-sufficient gene has only
one aim—namely, to locate the proper vehicle that will ensure
its perpetuation. Linking these ideas, many evolutionists
ABSTRACT
Our knowledge of heredity has recently undergone major
upheaval. Heredity transmits considerably more than just
genetic elements. First, the oocyte is full of maternal cytoplasmic
components that subsequently are present in each new cell.
Second, maternal cells can pass to the progeny, where they
remain active into adult life (microchimerism). Here, we
examine the notion that the transmission of characters involves
at least two processes in addition to that of mendelian heredity,
long considered to be the only hereditary mechanism. These
processes all involve epigenetic processes, including the
transmission of macromolecules, subcellular organelles, and
living cells solely from the mother to her offspring, whether
female or male, during pregnancy and lactation. We postulate
that cytoplasmic heredity and maternal transmission of cells
leading to a long-term state of microchimerism in progeny are
two good examples of matrilineal, nonmendelian heredity. A
mother’s important contribution to the development and health
of her progeny seems to possess many uncharted depths.
cytoplasmic heredity, developmental biology, heredity,
immunology, maternal-fetal exchanges, microchimerism,
pregnancy
INTRODUCTION
The hereditary transmission of characters brings into play at
least three types of processes. One, mendelian heredity, is well
known. Two others involve transmission of characters from the
mother to both male and female offspring. The first of these,
cytoplasmic heredity, another well-established process, has
made it possible to identify our common female ancestor. The
second and more recently examined, microchimerism, or
maternal-fetal exchange of cells, has been suggested to be
involved in tissue repair and/or immune dysregulation. The
present paper is not an extensive review of the state of the art in
any of these three domains; rather, it brings this knowledge into
a novel and wider perspective—namely, the until-now underevaluated role of the mother in the hereditary transmission of
characters.
1
Correspondence: Marie-Christine Maurel, Laboratoire de Biochimie
de l’Evolution et Adaptabilité Moléculaire, UMR 7592, CNRS and
Universités Paris 6 and 7, Tour 43, 2 place Jussieu, 75251 Paris Cedex
05, France. FAX: 33 1 4427 9916; e-mail: [email protected]
Received: 14 September 2007.
First decision: 8 October 2007.
Accepted: 30 January 2008.
Ó 2008 by the Society for the Study of Reproduction, Inc.
ISSN: 0006-3363. http://www.biolreprod.org
2
3
HEREDITY—VENTURING BEYOND GENETICS
FIG. 1. Three main paths of heredity.
consider the body to be this vehicle for molecules to transmit
and reproduce the information they contain. If this is so,
however, what of the major concepts of evolution, such as
coevolution, conjugation, symbiosis, and sexual reproduction,
one of the major transitions in biological evolution?
heredity). Characters are transmitted to both male and female
offspring by the mother, however, via at least two other
processes, cytoplasmic heredity and microchimerism.
AT LEAST THREE TYPES OF HEREDITY
In their nucleus, human germinal cells contain 46
chromosomes (22 pairs of autosomes and two sex chromosomes). Chromosomes contain DNA, the chemical component
of genes. Often, DNA is compared to a book of instructions—a
vast encyclopedia written in a coded language read by the cell,
which then transforms the material found in its environment to
produce a living being. In each cell, within a pair of
chromosomes, one chromosome comes from the mother and
one from the father. The pair of sex chromosomes is XX for the
female and XY for the male. Sex is determined genetically and,
in turn, determines the nature of the gonads—that is, the
primary sex characteristics (e.g., ovaries or testicles). In the
female, only one X chromosome is functional in somatic cells;
the other X chromosome remains a highly condensed,
heterochromatic seed, which is known as the Barr body [9].
This inactivation of the X chromosome is a genetically
controlled event that involves epigenetic regulation of sex
chromosome gene expression [10]. Interestingly, we now know
that certain genes contained in this second X chromosome are
expressed and, therefore, that this chromosome is not
completely silent.
Genetically, the X and Y chromosomes are completely
different from each other. A gene in an X chromosome has no
homologous counterpart in a Y chromosome, and vice versa.
The human body is composed of a million billion cells—at
least a thousand times as many as the total number of stars in
the galaxy. The 1015 cells all derive from one cell, the fertilized
egg, which is formed by the encounter between a female oocyte
and the male spermatozoon.
The fertilized egg divides into embryonic totipotent cells
that are capable of participating in the formation of all types of
tissue, ultimately producing a complete, unique organism that
will bear the hereditary characteristics of its two parents. This
series of events reveals a transition between two periods—one
that depends essentially on factors stored within the oocyte
(i.e., factors that make up the maternal heritage), followed by
another that results from the activity of the newly formed
genome built from the two parental genomes.
The fertilized egg possesses all the components of the
translational apparatus in amounts sufficient to perform the first
rounds of protein synthesis. Thus, after fertilization, the
cytoplasm of the oocyte itself is what constitutes the initial
cytoplasm of the embryo.
The transmission of characters brings into play several
processes or paths (Fig. 1), one of which relies on the wellknown mechanism of mendelian inheritance (i.e., nuclear
THE FIRST PATH: MENDELIAN (NUCLEAR) HEREDITY
4
MAUREL AND KANELLOPOULOS-LANGEVIN
The human X chromosome (165 Mb) harbors approximately
1000 genes with a variety of functions [11]. In the ribbed newt
(Pleurodeles sp.), the chromosomal composition is ZZ for
males and ZW for females; the W chromosome bears the
factors for female sex determination. In humans, numerous
factors are responsible for genetic sex determination. Some are
located in the autosomes, and the X chromosome contains sexand reproduction-related genes [12]. The equilibrium and level
of expression of certain autosomal and/or heterochromosomal
genes are believed to play an important role in sex
determination.
At 60 Mb, the human Y chromosome is much smaller than
the human X chromosome, and it contains few genes. It
encodes 45 unique proteins with functions regarding sex or
fertility [13]. The presence of a Y chromosome (with its SRY
gene) determines the masculinization of the embryonic gonad.
Ohno [14] proposes that sex chromosomes evolved from a pair
of autosomes. The origin of the human XY pair can be traced
back by comparison to related mammals and other vertebrates.
As a result of the heterology of the X and Y chromosomes,
recessive characters coded by the X chromosome are expressed
differently in the two sexes. In males, a recessive allele carried
by the X chromosome has no homologous counterpart in the Y
chromosome and, therefore, is expressed. In females, this allele
is only expressed in homozygotes. The frequently quoted
examples, such as daltonism (i.e., color blindness) and
hemophilia (i.e., defective blood coagulation), result from
mutations in genes carried by the X chromosome. All
heterozygous females who carry these mutated genes will
have a normal phenotype and be apparently healthy, but one in
two of their sons will carry the mutated phenotype, regardless
of whether the father’s chromosome is normal. Indeed, the X
chromosome of a male is always inherited from the mother;
consequently, the disease only appears in sons. In vision, for
instance, a protein pigment, rhodopsin, enables the rod cells in
the retina to distinguish black and white, whereas cone cells are
responsible for color vision thanks to three rhodopsins that are
sensitive to red, green, and blue light, respectively. In humans,
this trichromatic vision makes it possible to distinguish
approximately 200 different colors. The genes coding for the
green and red opsins are located in one region of the X
chromosome. Thus, abnormalities in this region of the
chromosome will be transmitted with the X chromosome,
leading to daltonism. On the positive side, however, various
evolutionary stages of the genetic system of rhodopsins exist in
primates, which suggests that genetic recombinations on the X
chromosome one day might constitute the starting point for
quadrichromatic vision (i.e., blue, red, green, and red/green) in
humans, which at present is inconceivable.
THE SECOND PATH: CYTOPLASMIC HEREDITY
In addition to the nucleus, the oocyte contains the
cytoplasm, in which organelles, such as mitochondria, are
located. Mitochondria are the factories that produce the energy
of the cells through aerobic respiration. They possess their own
genome, which is circular and single-stranded, like those of
prokaryotes with asexual reproduction. They are themselves
derived from an ancient, aerobic, purple eubacterium that today
lives endosymbiotically with a larger cell [15]. Consequently,
they possess their own matrix and their own DNA. They
multiply by rapid divisions (;1 min), and their volume
occupies 10–40% of the cell.
It is important to emphasize that the 250 000 mitochondria
contained in the egg all originate from the oocyte and are
transmitted directly to the fetus, whether female or male. Thus,
during the first stages of development, our metabolic system,
which both allows and regulates nutritional, energetic, and
respiratory exchanges, originates from that of the mother. At an
evolutionary level, Ohno [16] underlines the strictly maternal
inheritance of the mitochondrial genome in each mammalian
species.
Moreover, by studying this mitochondrial DNA, we can
trace back some 150 000 years the origins of Man (Homo
sapiens sapiens)—or, to be more precise, the origins of
Woman. The more stable mitochondrial DNA is less prone to
mutation, so it has been possible to identify our common
ancestor by matrilineal descent, as demonstrated by the studies
of Cann et al. [17] as well as Cavalli-Sforza and Minch [18].
Oocytic factors other than mitochondria have been shown to
have a transgenerational influence [19]. Roemer et al. [20] were
the first to present evidence in mice for the epigenetic
inheritance of specific alterations of gene expression through
the germline. These alterations are triggered by pronuclear
transfer at the one-cell stage. Furthermore, the importance of
cytoplasmic factors in the development of transplanted nuclei
was demonstrated in elegant experiments carried out by Sun et
al. [21] with two different species of fish.
Subsequently, nuclear transfer experiments have emphasized the significant role of the maternal cytoplasmic
environment in the reprogramming of the sperm, but not the
oocyte, genome [22, 23]. Moreover, recent studies that
analyzed the effects of environment (e.g., maternal lifestyle
or low food supply) on early embryonic development have
shown that these effects can last for several generations (for
review, see Gluckman and Hanson [24]).
THE THIRD PATH: MOSAIC HEREDITY
Microchimerism corresponds to the presence of two
genetically distinct cell populations within one organism. In
other words, low concentrations of the cells of one individual
are contained in a given organ of another individual.
Although the fetal and maternal blood circulations are
separate, numerous studies have demonstrated the passage of
cells across the maternal-fetal interface, in both directions, in
both humans and mice (Fig. 2). Other sources of microchimerism include blood transfusions and organ transplants
(i.e., grafts). In humans, the passage of fetal cells or DNA into
the maternal circulation was first detected by procedures
originally designed to provide noninvasive methods for
prenatal genetic diagnosis [25–28]. Transfer of fetal cells to
the mother occurs in most, if not all, normal pregnancies and
can be observed from the fourth month of pregnancy onward.
Fetal cells have been detected in all types of maternal tissues,
including the spinal cord, skin, lungs, thyroid gland, liver,
intestine, lymph nodes, and blood vessels [29]. Interestingly,
fetal cells have even been detected in maternal blood up to 27
years after the birth of the last child [30]. Such microchimerism
persists throughout life [31], and a role in the development of
adult autoimmune diseases in the female has been proposed
[32–35].
Conversely, the transfer of maternal DNA [36, 37],
antibodies [38], or nucleated cells [39–42] into the fetal
circulation and organs [43] also has been described. If maternal
antibodies are important to confer protective immunity on the
newborn, it appears that in some cases, specific maternal
antibodies might induce in the progeny diseases such as
autoimmune ovarian disease or autoimmune diabetes [44, 45].
Therefore, maternal microchimerism seems to have benefits as
well as potentially harmful repercussions. The presence of
maternal leukocytes in the fetal circulation might be a
HEREDITY—VENTURING BEYOND GENETICS
5
FIG. 2. Maternal-fetal interface and migration of maternal cells to placenta in
mouse pregnancy. Tg(ACTB-EGFP)1Osb
(Tg) B6 females were mated with non-Tg B6
males. Placentas from non-Tg offspring
were harvested at 10–12 days postcoitum
(dpc; A–C), 13–16 dpc (D–F), or 17–19 dpc
(G–I) and then cryosectioned (6 lm sections) and stained with Hoechst (Sigma).
Arrowheads show maternal cells present in
the fetal part of the placenta. D, Decidua; F,
fetal part of the placenta; gc, giant cells
(secondary); lab, labyrinth; M, maternal
decidua and uterus; sp, spongiotrophoblast.
Bar ¼ 100 lm (A, D, and G) and 50 lm (B,
C, E, F, H, and I). (Reprinted from Vernochet
et al. [55]. Copyright 2007, with permission
from Elsevier.)
significant risk when umbilical cord blood is used for bone
marrow transplantation [31, 46, 47]. The transmission of
maternal cells also could be responsible for the vertical transfer
of infectious agents, such as human immunodeficiency virus
type 1 [48, 49]. Engraftment of maternal cells has been
reported in immunodeficient children [50, 51] as well as
normal offspring, in whom maternal cells can persist for
decades [52]. It has been postulated that these maternal cells
play a role in the pathogenesis of juvenile inflammatory
myopathies [53].
Microchimerism can have various origins. It can derive
from cells that have already been passed on to the mother by
the grandmother or by the fetuses of previous pregnancies.
Transfer of maternal cells also can occur during breast-feeding;
in this case, maternal cells can infiltrate the progeny via the
digestive tract. The organism therefore contains genetically
different cells that consequently express foreign antigens [54,
55]. In most cases, microchimeric cells are tolerated perfectly
well and produce no illnesses [56] for reasons we are just
beginning to understand: Most probably, in vivo regulatory
mechanisms prevent cells from being activated and harming
the host [57–59]. The migration of maternal cells into the fetus
can induce a state of tolerance to its noninherited maternal
antigens (NIMAs) and contribute to the partial immunological
tolerance observed in the adult [60].
Regarding hemolytic anemia of the newborn because of Rh
incompatibility, approximately 5% of Rh-negative women
carrying Rh-positive fetuses produce anti-Rh antigen antibodies that induce the destruction or lysis of fetal red blood cells.
Among the Rh-negative women who do not produce hemolytic
antibodies, many have an Rh-positive mother. Consequently,
these mothers do not cause the disease in their offspring,
because they have become unresponsive or tolerant to the Rh
antigen, which is a NIMA [61].
In 1988, Claas et al. [62] observed that 50% of highly
sensitized patients, waiting for a renal allograft and producing
anti-human leukocyte antigen (HLA) antibodies that react to
virtually all donors, do not form antibodies to NIMAs. In 1998,
Burlingham et al. [63] studied the outcome of kidney
transplantations between haplo-identical siblings. Those authors found that the graft survival of kidneys donated by haplo-
FIG. 3. NIMA effect on transplantation tolerance: graft survival in
recipients of kidney transplants from HLA-identical sibling donors and
from sibling donors mismatched for one HLA haplotype. The donors
mismatched for one HLA haplotype expressed either maternal (NIMA) or
paternal (NIPA) HLA antigens not inherited by the recipient. (Reprinted
from [57] van den Boogaardt et al. [57]. Copyright 2005, with permission
from the Massachusetts Medical Society. All rights reserved.)
6
MAUREL AND KANELLOPOULOS-LANGEVIN
identical siblings mismatched for the NIMA haplotype was
similar to that of kidneys donated by HLA-identical siblings.
A more recent study by Andrassy et al. [64] showed that
mice exposed to noninherited maternal H2-D1 alloantigens
tolerated heart or skin grafts bearing H2-D1 alloantigens much
longer than control animals that were not exposed to NIMA
H2-D1 (Fig. 3) [64]. Those authors suggested that exposure to
NIMAs during gestation and suckling inhibited anti-NIMA Tcell responses in the offspring, thus predisposing to NIMAspecific transplantation tolerance as an adult. This hypothesis
implies that the progeny’s immune repertoire and reactivity are
shaped not only via genetically inherited maternal and paternal
major histocompatibility complex antigens but also via NIMAs
borne by maternal cells entering the offspring during life in
utero or through milk during suckling. Genetically modified
mice provide useful experimental models to dissect the cellular
and molecular mechanisms underlying the induction and
maintenance of the so-called NIMA effect [53, 64].
These observations should have beneficial clinical applications in the field of organ transplants. For instance, once the
mechanisms involved are elucidated, one could conceivably
mimic the NIMA effect in a recipient about to receive a
transplant to induce a specific unresponsiveness to the donor
antigens, thus leaving the other protective immune responses
unaffected.
Finally, microchimerism might be involved in tissue repair.
The presence of maternal cells in tissues of the offspring raises
important questions concerning the benefits of such microchimerism during both development and adult life. Certain
authors suggest that these maternal cells might help in tissue
repair and with resistance to infections. For instance, Nelson et
al. [65] reported that maternal microchimerism contributes to
functional and tissue repair processes in the pancreas.
Rinkevich [66] proposed that microchimerism participates in
growth, development, and immunological ‘‘apprenticeship.’’
Such phenomena also might explain, in part, how maternal
immunization against oxidized, low-density lipoproteins before
pregnancy protects the progeny from atherosclerosis in adult
life [67]. Consequently, to the well-studied concept regarding
transfer of protective immunity from mother to child, one
should add that of a maternal contribution to the regulation of
immune functions in the progeny, a phenomenon that is
overlooked at present.
CONCLUSION
Our working hypothesis is based on evidence that heredity
transmits considerably more than just genetic elements and that
the cytoplasm of the oocyte is full of maternal cytoplasmic
components subsequently present in each new cell. Interestingly, maternal cytoplasmic components play an important role
in the reprogramming of the sperm genome [22]. Moreover,
Sun et al. [21] emphasized the significant influence that the egg
cytoplasm can have on the development of transplanted nuclei.
Those authors produced cross-genus cloned fish by transferring
carp nuclei into goldfish enucleated eggs. Subsequently, these
cloned fish presented somite development and numbers
consistent with those of the goldfish recipient species, but
not with those of the carp nucleus donor. Considerable
quantities of enzymes, ribosomes, RNA, and so on are
transmitted intact from one generation to the next, and
increasing clinical and experimental evidence supports the
following hypotheses.
First, the presence of maternal cells in the embryo, fetus, or
neonate—cells that later are found in the descendants—plays a
role in the acquisition of a variety of immune mechanisms, just
as infections caught during childhood shape the immune
system and, possibly, steer it away from allergic reactions.
These maternal cells, which are present in small numbers (on
the order of one or fewer maternal cell per 105 cells), might
have beneficial as well as harmful effects in the progeny, such
as the induction of tolerance to specific transplantation antigens
(i.e., NIMAs) or a shift in the balance toward autoimmunity,
respectively.
Second, this type of microchimerism affects the progeny’s
immune system and may have participated in the evolution of
the mammalian immune system. Before one can speculate on
its overall importance from an evolutionary point of view,
however, microchimerism needs to be studied in several
different species and its physiological roles better understood.
Third, a somatic maternal form of heredity exists, the
functional and evolutionary traces of which are to be found in
mitochondria and in maternal-fetal transfers. This concept
needs to be further studied and developed to establish the
conceptual and conceptional contributions of maternal heredity
to genealogical transmission.
To conclude, we are now in a position to challenge the
dogma according to which everything is genetic and the
transmission of the ‘‘selfish’’ gene is monolithic and vertical.
Heredity transmits considerably more than just genetic
elements; it also entails mitochondrial inheritance, cytoplasmic
influences, and maternal cell transmission which leads to a
long-term state of microchimerism. We would like to
emphasize that all the mechanisms of hereditary transmission
discussed in the present paper can be strongly influenced by
epigenetic processes. These considerations shed new light on
the relevance of recent, highly publicized scientific projects
involving the transplantation of human nuclei into animal (i.e.,
bovine) cytoplasms. Such embryonic chimeras are likely to be
significantly different from whole human embryos—and their
study to be less useful than expected.
The novel view of heredity presented in this paper opens
exciting horizons in many fields, and the potential applications
are numerous. Perhaps in the future, the fantasy of physiological self-repair might even become a reality.
ACKNOWLEDGMENTS
We are indebted to Dr. Anne-Lise Haenni, Dr. Giuseppe Zaccai, Prof.
Michel Vervoort, and Dr. Evani Viegas-Pequignot for helpful discussions,
Martine Dombrosky for Figure 1, and to Antonia Kropfinger for revising
the manuscript. We are grateful to our past and present collaborators for
their work and stimulating exchanges.
REFERENCES
1. Pigliucci M. Epigenetics is back! Hsp90 and phenotypic variation. Cell
Cycle 2003; 2:34–35.
2. Queitsch C, Sangster TA, Lindquist S. Hsp90 as a capacitor of phenotypic
variation. Nature 2002; 6:618–624.
3. Waddington CH. Epigenetics and evolution. In: Brown R, Danielli JF
(eds.), Evolution. SEB Symposium VII. Cambridge, UK: Cambridge
University Press; 1953:186–199.
4. Jablonka E, Lamb MJ. The changing concept of epigenetics. Ann N Y
Acad Sci 2002; 981:82–96.
5. Canguilhem G, Lapassade G, Piquemal J, Ulmann J. Du développement à
l’évolution au XIXème siècle. Paris: Presses Universitaires de France,
1962.
6. Hartsoeker N. Essai de Dioptrique. Paris: J. Anisson, 1694.
7. Huxley A. Brave New World. London: Harper Perennial Modern Classics;
1932.
8. Dawkins R. The Selfish Gene. New York: Oxford University Press; 1989.
9. Ng K, Pullirsch D, Leeb M, Wutz A. Xist and the order of silencing.
EMBO Rep 2007; 8:34–39.
10. Clerc P, Avner P. Random X-chromosome inactivation: skewing lessons
for mice and men. Curr Opin Genet Dev 2006; 16:246–253.
HEREDITY—VENTURING BEYOND GENETICS
11. Graves JAM. Sex chromosome specialization and degeneration in
mammals. Cell 2006; 124:901–914.
12. Saifi GM, Chandra HS. An apparent excess of sex- and reproductionrelated genes on the human X chromosome. Proc R Soc Lond B Biol Sci
1999; 266:203–209.
13. Lahn BT, Page DC. Four evolutionary strata on the human X
chromosome. Science 1999; 286:964–967.
14. Ohno S. Sex chromosomes and sex linked genes. New York: SpringerVerlag; 1967.
15. John P. Mitochondrial regulation of cell surface components in relation to
carcinogenesis. J Theor Biol 1984; 110:377–381.
16. Ohno S. The one ancestor per generation rule and three other rules of
mitochondrial inheritance. Proc Natl Acad Sci U S A 1997; 94:8033–
8035.
17. Cann RL, Stoneking M, Wilson AC. Mitochondrial DNA and human
evolution. Nature 1987; 325:31–36.
18. Cavalli-Sforza LL, Minch E. Paleolithic and neolithic lineages in the
European mitochondrial gene pool. Am J Hum Genet 1997; 61:247–251.
19. Heasman J. Maternal determinants of embryonic cell fate. Semin Cell Dev
Biol 2006; 17:93–98.
20. Roemer I, Reik W, Dean W, Klose J. Epigenetic inheritance in the mouse.
Curr Biol 1997; 7:277–280.
21. Sun YH, Chen SP, Wang YP, Hu W, Zhu ZY. Cytoplasmic impact on
cross-genus cloned fish derived from transgenic common carp (Cyprinus
carpio) nuclei and goldfish (Carassius auratus) enucleated eggs. Biol
Reprod 2005; 72:510–515.
22. Jaenisch R. Human cloning—the science and ethics of nuclear
transplantation. N Engl J Med 2004; 351:2787–2791.
23. Yang X, Smith SL, Tian XC, Lewin HA, Renard J-P, Wakayama T.
Nuclear reprogramming of cloned embryos and its implications for
therapeutic cloning. Nat Genet 2007; 39:296–302.
24. Gluckman PD, Hanson MA. Living with the past: evolution, development,
and patterns of disease. Science 2004; 305:1733–1736.
25. Bianchi DW, Flint AF, Pizzimenti MF, Knoll JH, Latt SA. Isolation of
fetal DNA from nucleated erythrocytes in maternal blood. Proc Natl Acad
Sci U S A 1990; 87:3279–3283.
26. Herzenberg LA, Bianchi DW, Schroder J, Cann HM, Iverson GM. Fetal
cells in the blood of pregnant women: detection and enrichment by
fluorescence-activated cell sorting. Proc Natl Acad Sci U S A 1979; 76:
1453–1455.
27. Little MT, Langlois S, Wilson RD, Lansdorp PM. Frequency of fetal cells
in sorted subpopulations of nucleated erythroid and CD341 hematopoietic
progenitor cells from maternal peripheral blood. Blood 1997; 89:2347–
2358.
28. Lo YM, Tein MS, Lau TK, Haines CJ, Leung TN, Poon PM, Wainscoat
JS, Johnson PJ, Chang AM, Hjelm NM. Quantitative analysis of fetal
DNA in maternal plasma and serum: implications for noninvasive prenatal
diagnosis. Am J Hum Genet 1998; 62:768–775.
29. Nguyen Huu S, Oster M, Uzan S, Chareyre F, Aractingi S, Khosrotehrani
K. Maternal neoangiogenesis during pregnancy partly derives from fetal
endothelial progenitor cells. Proc Natl Acad Sci U S A 2007; 104:1871–
1876.
30. Bianchi DW, Zickwolf GK, Weil GJ, Sylvester S, DeMaria MA. Male
fetal progenitor cells persist in maternal blood for as long as 27 years
postpartum. Proc Natl Acad Sci U S A 1996; 93:705–708.
31. Lo YMD, Lo ESF, Watson N, Noakes L, Sargent IL, Thilaganathan B,
Wainscoat JS. Two-way cell traffic between mother and fetus: biological
and clinical implications. Blood 1996; 88:4390–4395.
32. Kuroki M, Okayama A, Nakamura S, Sasaki T, Murai K, Shiba R,
Shinohara M, Tsubouchi H. Detection of maternal-fetal microchimerism in
the inflammatory lesions of patients with Sjogren’s syndrome. Ann Rheum
Dis 2002; 61:1041–1046.
33. Evans PC, Lambert N, Maloney S, Furst DE, Moore JM, Nelson JL. Longterm fetal microchimerism in peripheral blood mononuclear cell subsets in
healthy women and women with scleroderma. Blood 1999; 93:2033–2037.
34. Artlett CM, Smith JB, Jimenez SA. Identification of fetal DNA and cells in
skin lesions from women with systemic sclerosis. N Engl J Med 1998;
338:1186–1191.
35. Klintschar M, Schwaiger P, Mannweiler S, Regauer S, Kleiber M.
Evidence of fetal microchimerism in Hashimoto’s thyroiditis. J Clin
Endocrinol Metab 2001; 86:2494–2498.
36. Lo YM, Lau TK, Chan LY, Leung TN, Chang AM. Quantitative analysis
of the bidirectional fetomaternal transfer of nucleated cells and plasma
DNA. Clin Chem 2000; 46:1301–1309.
37. Scaradavou A, Carrier C, Mollen N, Stevens C, Rubinstein P. Detection of
maternal DNA in placental/umbilical cord blood by locus-specific
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
7
amplification of the noninherited maternal HLA gene. Blood 1996; 88:
1494–1500.
Adeniyi-Jones SC, Ozato K. Transfer of antibodies directed to paternal
major histocompatibility class I antigens from pregnant mice to the
developing fetus. J Immunol 1987; 138:1408–1415.
Shimamura M, Ohta S, Suzuki R, Yamazaki K. Transmission of maternal
blood cells to the fetus during pregnancy: detection in mouse neonatal
spleen by immunofluorescence flow cytometry and polymerase chain
reaction. Blood 1994; 83:926–930.
Piotrowski P, Croy BA. Maternal cells are widely distributed in murine
fetuses in utero. Biol Reprod 1996; 54:1103–1110.
Zhou L, Yoshimura Y, Huang Y, Suzuki R, Yokoyama M, Okabe M,
Shimamura M. Two independent pathways of maternal cell transmission
to offspring: through placenta during pregnancy and by breastfeeding after
birth. Immunology 2000; 101:570–580.
Marleau AM, Greenwood JD, Wei Q, Singh B, Croy BA. Chimerism of
murine fetal bone marrow by maternal cells occurs in late gestation and
persists into adulthood. Lab Invest 2003; 83:673–681.
Srivatsa B, Srivatsa S, Johnson KL, Bianchi DW. Maternal cell
microchimerism in newborn tissues. J Pediatr 2003; 142:31–35.
Setiady YY, Samy ET, Tung KS. Maternal autoantibody triggers de novo
T cell-mediated neonatal autoimmune disease. J Immunol 2003; 170:
4656–4664.
Greeley SA, Katsumata M, Yu L, Eisenbarth GS, Moore DJ, Goodarzi H,
Barker CF, Naji A, Noorchashm H. Elimination of maternally transmitted
autoantibodies prevents diabetes in nonobese diabetic mice. Nat Med
2002; 8:399–402.
Hall JM, Lingenfelter P, Adams SL, Lasser D, Hansen JA, Bean MA.
Detection of maternal cells in human umbilical cord blood using
fluorescence in situ hybridization. Blood 1995; 86:2829–2832.
Socie G, Gluckman E, Carosella E, Brossard Y, Lafon C, Brison O. Search
for maternal cells in human umbilical cord blood by polymerase chain
reaction amplification of two minisatellite sequences. Blood 1994; 83:
340–344.
Sprecher S, Soumenkoff G, Puissant F, Degueldre M. Vertical
transmission of HIV in 15-week fetus. Lancet 1986; ii:288–289.
Schwartz DH, Sharma UK, Perlman EJ, Blakemore K. Adherence of
human immunodeficiency virus-infected lymphocytes to fetal placental
cells: a model of maternal fetal transmission. Proc Natl Acad Sci U S A
1995; 92:978–982.
Geha RS, Reinherz E. Identification of circulating maternal T and B
lymphocytes in uncomplicated severe combined immunodeficiency by
HLA typing of subpopulations of T cells separated by the fluorescenceactivated cell sorter and of Epstein Barr virus-derived B cell lines. J
Immunol 1983; 130:2493–2495.
Knobloch C, Goldmann SF, Friedrich W. Limited T cell receptor diversity
of transplacentally acquired maternal T cells in severe combined
immunodeficiency. J Immunol 1991; 146:4157–4164.
Maloney S, Smith A, Furst DE, Myerson D, Rupert K, Evans PC, Nelson
JL. Microchimerism of maternal origin persists into adult life. J Clin Invest
1999; 104:41–47.
Artlett CM, Ramos R, Jiminez SA, Patterson K, Miller FW, Rider LG.
Chimeric cells of maternal origin in juvenile idiopathic inflammatory
myopathies. Childhood Myositis Heterogeneity Collaborative Group.
Lancet 2000; 356:2155–2156.
Vernochet C, Caucheteux SM, Gendron MC, Wantyghem J, Kanellopoulos-Langevin C. Affinity-dependent alterations of mouse B cell development by noninherited maternal antigen. Biol Reprod 2005; 72:460–469.
Vernochet C, Caucheteux SM, Kanellopoulos-Langevin C. Bidirectional
cell trafficking between mother and fetus in mouse placenta. Placenta
2007; 28:639–649.
Nelson JL. Microchimerism in human health and disease. Autoimmunity
2003; 36:5–9.
van den Boogaardt DE, van Miert PP, Koekkoek KM, de Vaal YJ, van
Rood JJ, Claas FH, Roelen DL. No in vitro evidence for a decreased
alloreactivity toward noninherited maternal HLA antigens in healthy
individuals. Hum Immunol 2005; 66:1203–1212.
Ichinohe T, Teshima T, Matsuoka K, Maruya E, Saji H. Fetal–maternal
microchimerism: impact on hematopoietic stem cell transplantation. Curr
Opin Immunol 2005; 17:546–552.
Matsuoka K, Ichinohe T, Hashimoto D, Asakura S, Tanimoto M, Teshima
T. Fetal tolerance to maternal antigens improves the outcome of allogeneic
bone marrow transplantation by a CD4 þ CD25 þ T-cell-dependent
mechanism. Blood 2006; 107:404–409.
van Rood JJ, Claas F. Both self and noninherited maternal HLA antigens
influence the immune response. Immunol Today 2000; 21:269–273.
8
MAUREL AND KANELLOPOULOS-LANGEVIN
61. Owen RD, Wood HR, Foord AG, Sturgeon P, Baldwin LG. Evidence for
actively acquired tolerance to Rh antigens. Proc Natl Acad Sci U S A
1954; 40:420–424.
62. Claas FH, Gijbels Y, van der Velden-de Munck J, van Rood JJ. Induction
of B cell unresponsiveness to noninherited maternal HLA antigens during
fetal life. Science 1988; 241:1815–1817.
63. Burlingham WJ, Grailer AP, Heisey DM, Claas FH, Norman D,
Mohanakumar T, Brennan DC, de Fijter H, van Gelder T, Pirsch JD,
Sollinger HW, Bean MA. The effect of tolerance to noninherited maternal
HLA antigens on the survival of renal transplants from sibling donors. N
Engl J Med 1998; 339:1657–1664.
64. Andrassy J, Kusaka S, Jankowska-Gan E, Torrealba JR, Haynes LD,
Marthaler BR, Tam RC, Illigens BM, Anosova N, Benichou G,
Burlingham WJ. Tolerance to noninherited maternal MHC antigens in
mice. J Immunol 2003; 171:5554–5561.
65. Nelson JL, Gillepsie KM, Lambert NC, Stevens AM, Loubiere LS,
Rutledge JC, Leisenring WM, Erickson TD, Yan Z, Mullarkey ME,
Boespflug ND, Bingley PJ. Maternal microchimerism in peripheral blood
in type 1 diabetes and pancreatic islet (beta) cell microchimerism. Proc
Natl Acad Sci U S A 2007; 104:1637–1642.
66. Rinkevich B. Human natural chimerism: an acquired character or a vestige
of evolution? Hum Immunol 2001; 62:651–657.
67. Yamashita T, Freigang S, Eberle C, Pattison J, Gupta S, Napoli C, Palinski
W. Maternal immunization programs postnatal immune responses and
reduces atherosclerosis in offspring. Circ Res 2006; 99:51–64.