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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everything is genetic is illustrated by the disappearance of what was known previously as embryology, which today has been replaced by developmental biology.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. 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