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Discordance in monozygotic twins has traditionally been explained in terms of environmental influences. A recent investigation has found a difference in epigenetic markers in older but not in younger twins. However, phenotypic differences that depend on an individual's postnatal life style do not address the problem of discordance in congenital malformations, or the reason why malformations are frequently unilateral, often with a preference for one or the other side. One such condition, cleft lip with or without cleft palate, which is preferentially expressed on the left, is a multifactorial condition, that is caused by a failure of the critical timing necessary for different groups of cells to meet and develop into a normal face. This process is dependent on cell proliferation and migration, which are energy-dependent, while the additional requirement for apoptosis to allow cell fusion suggests the involvement of mitochondria. Recent progress in two separate areas of research could lead to a better understanding of the problem of facial clefts: (1) the recognition of an interaction between gene products and mitochondria in the aetiology of neurodegenerative diseases and (2) the discovery of an increasing number of genes, including transcription factors, growth factors and members of the TGF-beta signalling family, that are differentially expressed on the left and right side, thus pointing to a difference in their micro-environment. These findings emphasize the importance of investigating the activity of candidate genes for complex developmental processes separately on the left and right sides. Data presented in this review suggest that differential growth rates may lead to an inversion of laterality. A method is described to test for a possible mitochondrial difference between left and right sides, using a mouse model with cleft lip.

The discovery of SRY ended the search for the male-determining gene, but the much sought after molecular pathway that connects the gene to its phenotype remains elusive. It is timely, therefore, to consider an alternative route of inheritance that can simulate mendelian segregation. The term "threshold dichotomy" is applied to contrasting phenotypes that have their origin in multiple genes with quantitative effects and are divided by a physiological threshold. I suggest that this mechanism provides a plausible basis for male development in mammals, which is known to depend on enhanced rates of cell proliferation in the developing embryo and can be expected to require increased levels of cellular energy. The system is affected by the genetic and environmental background. I also propose that the Y chromosome minimizes the effects of these variables on XY embryos so that, barring rare exceptions, the inheritance of sex resembles a single gene effect.

The history of ideas on how the sexes became divided spans at least three thousand years. The biblical account of the origin of Eve, and the opinions of the philosophers of classical Greece, have unexpected bearings on present-day ideas. The scientific study of sex determination can be said to have begun in the 17th century with the discovery of spermatozoa, but the origin and function of the "spermatic animalcules" eluded investigators until 1841. The mammalian egg was discovered in 1827, and in the last quarter of the century fertilization was observed. The view current at that time, that sex determination was under environmental control, gave way to the idea of chromosomal determination in the first quarter of the 20th century. The study of human and other mammalian chromosomes during the third quarter of the century, and the discovery of sex-chromosome abnormalities, emphasized the importance of the Y chromosome for male sex determination. The last quarter of the century witnessed a hunt for the "testis-determining" gene, thought to be responsible for the differentiation of Sertoli cells, and culminating in the isolation of SRY (Sry in the mouse). However, an increasing number of additional genes and growth factors were found to be required for the establishment of male sex. During the same period evidence emerged that male development was accompanied by enhanced growth, both of gonads and whole embryos. An unexpected finding was the demonstration of temperature-dependent sex determination in reptiles. With the advent of the 21st century, it was shown that Sry induces cell proliferation in fetal mouse gonads, and it has been suggested that male sex differentiation in mammals requires a higher metabolic rate. These insights could lead to a better understanding and improved treatment of abnormalities of sexual development.

According to the accepted dogma of mammalian sex determination, the Y-linked gene SRY initiates male development by inducing hitherto uncommitted somatic cells of the fetal gonad to develop into Sertoli cells. However, it has become evident that the correct functioning of an increasing number of genes on other chromosomes is required for testicular organogenesis. They include the SRY-related gene, SOX9, which plays important roles in both sex determination and chondrogenesis, as well as genes responsible for the production of growth factors, i.e. fibroblast growth factor 9, platelet derived growth factor A, and the members of the insulin-receptor family of genes. It is known, moreover, that differences between the sexes begin to develop long before the differentiation of Sertoli cells, including an increase in gonadal size and cell proliferation, and accelerated development of XY embryos at early pre-implantation stages. There is also evidence of transcription of Y-linked, and of X-linked, genes and of an enhanced metabolic rate in XY embryos. Furthermore, the condition of true hermaphroditism does not fit into a simple genotype/phenotype relationship. The proposal that "testis-determining" genes act by increasing metabolic rates rather than directly determining Sertoli cell differentiation can account for a number of observations that do not fit the current model, including pregonadal sex differences, the activity of the same gene in different organ systems, and the frequent co-existence of sexual and somatic abnormalities. It also sheds light on the pervasive differences between metabolic rates of mammalian males and females, while the facts of true hermaphroditism can be viewed as remnants of temperature-dependent sex determination in ectothermic vertebrates. Growing interest in mitochondria, which play a central role in the provision of energy to eukaryotic cells, makes a shift of paradigm from gonadal histology to energy metabolism timely, particularly since new techniques have become available for testing the hypothesis, and for widening the experimental approach to sex determination. If the hypothesis is correct, it would mean that male sex is determined by nuclear genes inherited from the father regulating the activity of maternally derived mitochondria.

The word 'clone' is in the forefront of scientific terms that are familiar to the general public. But what exactly does it mean? Suprisingly, there is no simple answer, for different scientists are using the term for different entities.

The genetics of sex determination is a child of the twentieth century, which overturned the previously held view that sex was determined by the environment. The last quarter of the century witnessed an active search for sex-determining genes in mammals. Although successful, the modus operandi of these genes remained unknown, and the relationship between the sex-determining systems of mammals and other vertebrates remained enigmatic. To overcome these problems, scientists in the 21st century should heed William Bateson's counsel to treasure exceptions, for they point the way to progress. One exception to conventional concepts of sex determination is the bilaterally asymmetrical distribution of ovaries and testes in true hermaphroditism. Ovaries favour the left side in humans and the right side in mice. Observations suggesting that a reversal of asymmetry may occur with increasing organ size may point to a possible explanation. A reevaluation is also required regarding the beginning of sex differentiation, in view of mounting evidence of a sex difference in growth rates of early embryos. Another question to be settled is whether the function of SRY is confined to the fetal gonad. The recent demonstration that Sry induces cell proliferation in the fetal mouse gonad (Schmahl et al., 2000) further emphasizes the importance of differential growth in sex determination and differentiation. It is suggested that SRY represents an additional growth-promoting gene sequestered by mammals to enable the XY embryo to undergo male sex differentiation in the female hormonal environment of the uterus. An increased awareness of the relationship between growth and gonadal differentiation should lead to a better understanding of sex determination in mammals and an ability to relate the function of sex-determining genes to the effects of environmental factors. J. Exp. Zool. 290:484-489, 2001., (Copyright 2001 Wiley-Liss, Inc.)

The dogma that male and female embryos develop in identical fashion until SRY initiates Sertoli cell differentiation in the hitherto bipotential gonad is in need of reevaluation in the light of data that do not fit into this scheme. One of the exceptions that proves the rule of sex determination is true hermaphroditism, the existence of individuals with both testicular and ovarian tissue. Furthermore, the two types of tissues are asymmetrically distributed, ovaries being more common on the left side and testes and ovotestes on the right. Hermaphrodite mice also exhibit bilateral asymmetry of gonad differentiation, but in the opposite direction: ovaries on the right, testes and ovotestes on the left. To explain these asymmetries, it is necessary to consider the relationship between growth and gonadal differentiation. The idea that accelerated growth precedes histological differentiation of the testis has recently been confirmed by the finding that Sry induces cell proliferation in fetal mouse gonads, suggesting that the differentiation of Sertoli cells may be dependent on a critical cell number. Recent evidence has also shown that XY embryos develop faster than their XX counterparts at very early stages of development, and it has been reported that SRY and ZFY are expressed in early human and murine embryos. The relationship between growth and sex differentiation links the mammalian system with those of nonmammalian vertebrates with temperature-dependent sex determination. Early growth differences between male and female human embryos question the belief that all sex differences in later life are due to gonadal hormones., (Copyright 2000 Academic Press.)

Of all the inborn differences that distinguish individual humans, as well as other animals, sex exerts the most far-reaching effects, and the question, what determines it, has been debated throughout history. A discriminating reading of Biblical and Ancient Greek sources reveals surprising insights that are relevant to present-day biology. The material basis of generation was inaccessible until, following the invention of the microscope and the discovery of "spermatic animalcules" in the 17th century, the 19th century witnessed the discovery of the mammalian egg, the nature of sperm, and the process of fertilization. Sex was thought to be determined by external conditions. The 20th century developed the genetics of sex determination. The search for the mammalian testis-determining gene during the last quarter century culminated in the discovery of SRY, soon to be accompanied by non-Y chromosome sex- determining genes. During the same period, data accumulated that testicular differentiation was accompanied by accelerated gonadal growth; subsequently, differences in growth were shown to distinguish early XX from early XY embryos. Other research showed that temperature-dependent sex determination was widely distributed among reptiles, thus illustrating that the mammalian system of sex determination is of recent evolutionary origin, adopted in response to homoiothermy and placentation. The recent discovery that Sry induces cell proliferation in the gonads of fetal mice suggests that the task for the 21st century will be to aim beyond simple genotype/phenotype correlations by unraveling the relationship between genes and epigenetic factors acting on cell growth during development and affecting the phenotype in later life., (Copyright 2001 S. Karger AG, Basel)

The dominant embryonic gonad--testis in mammals and ovary in birds--secretes one or more morphogenetic substances that exert a major effect on the phenotype of the embryo. When deprived of their gonads, mammalian embryos develop into females, and avian embryos assume predominantly male characteristics, although retaining both oviducts. In order to fulfill their task of masculinizing the reproductive tract, mammalian testes grow and differentiate faster than ovaries. In birds the pattern is less straightforward. In 5-day-old embryos of White Leghorn chickens, sexual differentiation manifests itself in two different ways: (1) the gonads of ZZ embryos are larger, and on day 6 contain more protein and DNA than those of ZW embryos; (2) in both sexes, left gonads are larger than right gonads and contain a thick "germinal epithelium" capable of giving rise to an ovarian cortex under the influence of oestrogen. The pattern changes in embryos aged between 7 and 8 days, when the left gonad of ZW embryos outgrows all others, developing into an ovary, and when the bilateral asymmetry between left and right gonads increases in female embryos. A remnant of gonadal bilateral asymmetry is seen in the distribution of gonads in cases of true hermaphroditism in humans and other mammals. Whereas the initial fast growth of the mammalian testis is assumed to be due to one or more Y-chromosomal genes, that of the early avian testis is mostly simply explained as the effect in the disomic state of one or more genes on the Z chromosome. However, the later growth of the avian ovary is more likely to be due to oestrogen than to a direct gene effect. It is postulated that oestrogen has lost its power to determine ovarian development in mammals, in which both sexes are exposed to the oestrogen-rich environment of the uterus. Hence, the task of sex determination devolves on the fetal testis, whose early development and hormonal function are required to induce the male phenotype, the female phenotype arising in default mode.