The Human Female Paradox: Biological Disadvantage Preimplantation, Biological Advantage, Thereafter

The vital statistics show that human females outlive males at every biological stage. Once the embryo arrives in the uterus, more males die at every stage, at least until the eighth decade when the majority of survivors are female. Unexpectedly, the same statistics also show that more boys are born than girls, which is difficult to explain, because the sperm that determine the sex of the fetus, are not skewed toward males. Recently, new data reveal the reason for the increased number of male births; they imply the significant loss of females before the fetus arrives in the womb. Thereafter, there is an excessive loss of males – not only in utero but throughout their lives. One likely reason for the sex differences in fetal survival is the way that humans compensate for the sex difference in number of X chromosomes.

live-born populations. In fact, human females are malformed, and retarded, when they express only a minute piece of their second X chromosome [5]. We also know that the transcription of X chromosomes is regulated in both males and females in order to equalize the RNA output from the X chromosomes [6]. This process, which is called X chromosome dosage compensation, occurs during embryogenesis in every species with an XX/ XY sex determining mechanism [7].
The details of the compensatory process differ from species to species because of differences in the staging of embryogenesis, and evolutionary changes to the blueprint of the relevant genes [8]. On one hand, flies compensate by increasing the transcription of the X in males so that it equals the two X's in a female; on the other hand, in mammals, all but one X chromosomes is silenced in each cell, regardless of its parental origin [7]. The mammalian method of dosage compensation is called X inactivation, a term initiated by Mary Lyon who was the first to suggest that only a single X was expressed in each cell of female mammals; any X chromosome in addition to one is silenced in males as well as females [9].
Although a female has only one working X in each of her cells, she differs from most males, because she is mosaic for the X chromosome that is expressed; that is, which of her two X chromosome is the active one, differs from cell to cell [10]. The process of X-silencing happens during early embryogenesis -about the time of implantation, when gastrulation occurs in the human fetus. This means that unlike males, who have the same X chromosome in each one of their cells, (the one inherited from their mother), females have some cells, which express her paternal X, as well as other cells, which transcribe her maternal X.
Having two kinds of cells would be meaningless, if the genes on the human maternal X did not differ from those on the paternal X. However, recent studies show that the two sets of genes are often dissimilar because of chance mutations that have occurred, which alter the function of the proteins that they encode [4,11].
Also, the genes on all chromosomes, except the sex chromosomes, come in pairs, (we have two copies of each autosome, one derived from our mother, the other from our father). Having two copies of a gene usually protects us from the effect of mutations that interfere with their function; if one copy of a gene is disabled, then the other copy of that gene still retains its function [11]. Fortunately, 50% of normal gene activity often provides enough gene products. However, for males with the same X chromosome in every cell, the effect of mutations in any of its 1000 genes can be devastating [11,12].
Unlike males, the same mutations in genes on the active X chromosome of females affect only some of their cells, because the normal copy on her second X chromosome is expressed in the other cells [12].
The female advantage is that gene products in the cell that can synthesize them often are transferred to the defective cells; the have-cells with a normal amount of gene product share their product with the have-nots -by means of blood, gap junctions, and other means of intercellular communication. When sharing cannot occur, then the defective cells often divide less often, and they are overgrown by the normal cell [12]. Product-sharing and cell selection convey a tremendous advantage to females of our species. With some rare exceptions, only males have hemophilia, or Duchenne muscular dystrophy, and many other X-linked diseases. The only X-linked diseases invariably affecting females are those that are lethal to the male fetus [12].
The vital statistics tell us that having the same X chromosome in every cell is hazardous for males, contributing to their excessive loss at every stage of life after implantation (Table 1 and 2). Only after age 75 years does the ratio of male to female deaths become equal (Table 2); thereafter, more females die than males because by that time, most males have already died.
Because more males are lost after implantation, it was difficult to understand why more males are born than females; the ratio of M: F births are ~1.05, based on many years of vital statistics [13] see table 3. This sex bias in births is the same for most nations in the United Nations that record such data [13]. As skewing of numbers of Y bearing sperm does not occur [14,15], there has been no compelling explanation for the excess of male births -until recently.   Table 16 Latest availble data 2018a(Reporting data from 2015 only, and less age-groups were reported.) The novel information, which explains at least some of the excess male births, comes from the DECIPHER database [16] that records the numbers of common population variants, such as chromosomal duplications, deletions and single gene variants in human males and females. Because the precise location of many of our genes is known, chromosomal duplications and deletions can be defined at the level of nucleotide pairs in the DNA; the DECIPHER database enables us to look for sex differences in the incidence of such variations. A recent survey of the whole human genome showed sex differences in the incidence of duplications and deletions all along the chromosomes, involving only one or two genes that may be responsible for sex differences in some diseases [17]. However, on chromosome 19, there is a region about half the size of the short arm of the chromosome (~8 mega bases), in which inherited tandem duplications are seen only in human males [18]. The implied loss of human females is highly significant (p < ~10 -23 ), and specific to tandem duplications, as the incidence of deletions of the same region is essentially the same for the two sexes. These results have been interpreted in light of what is known about how X inactivation is achieved in human fetuses [19].
What we know is that one X-linked gene is responsible for silencing the inactive X chromosome in every cell [20]. This gene, called XIST for X Inactive Specific Transcript, does not code for a protein, but synthesizes an RNA that coats its own X chromosome; once spread on the chromosome, XIST functions to attract epigenetic factors that bring that X towards the nuclear lamina and change its chromatin from active to inactive [21]. Therefore, XIST transcribes a noncoding RNA that silences the very chromosome from which it is expressed.
Based on studies of human aneuploid fetuses, only one X is active in any cell with a diploid karyotype (46 chromosomes), but more than one X is active in human triploid fetuses (69 chromosomes) [22]. In contrast to the single active X in normal individuals, triplication of our genome enables the activity of two X chromosomes in most triploid cells [23]. These observations suggest that at least one of the triplicated genes enables the transcriptional activity of more than one X, by repressing the XIST locus on a second X chromosome, permitting that X to be transcribed as well [23].
Although we know how the inactive X is silenced by its XIST locus -a powerful chromosome inactivator that can silence any chromosome from which it is expressed [24] -we do not yet know what protects the active X in the cells of both sexes from inactivation by its own XIST locus? It seems likely that XIST on the future active X needs to be repressed to keep that chromosome active. Therefore, the two active X's in triploid fetuses suggest that the XIST repressor is encoded by an autosome [23].
A tandem duplication of the XIST repressor gene on one autosome of the pair-resulting in an extra dose of XIST repressor-would not be harmful for human males, as they have only one X chromosome. However, if the putative repressor locus on chromosome 19p were duplicated in human females, the amount of repressor could silence the locus on both X chromosomes, resulting in two active X chromosomes, a known embryonic lethal event [5]. Therefore, duplications of the relevant region would be tolerated by males, but would be lethal to females, with two X chromosomes. The fact that tandem duplications of this region of chromosome 19p are lethal to females but not to males, are consistent with these expectations. That the short arm of chromosome 19 is the only extensive region of the human genome that shows a sex difference with respect to survival of duplications strongly suggests that this is the region that includes the XIST repressor [18]. New data in the Decipher database suggests that the number of 19ps is relevant as only tandem duplications produce lethality [25].
Among the genes in the exceptional region of chromosome 19 are potential XIST repressors [18]. All of them could theoretically repress XIST, and all are expressed in human embryos, prior to implantation. Among these candidate repressors are DNA methyltransferase 1, which when deleted in mice induces Xist expression on the active X of males [26], and its co-factor, UHRF1, two satellite attachment factors SAFB and SAFB2 and a cluster of zinc finger proteins that arrived on chromosome 19 after humans evolved from rodents. In addition, these human genes, which are found on chromosome 19 in all primates, reside on two different chromosomes in rodents, which strongly suggest that the way we repress XIST on the single active X may differ from rodents. Therefore, the mouse models of X inactivation are unlikely to reflect the process in human cells. Unfortunately, the earliest human embryonic stem cells currently available may have already undergone this part of the process of X inactivation [27]. In edition human embryonic stem cells need to be rendered more immature and the derivation of less mature stem cells requires the use of transcription factors and other agents; these derived cells may, or may not, reflect what is happening during early human development.
What remains to be done is to demonstrate that candidate genes on chromosome 19 are able to repress XIST in preimplantation human embryos. Such studies are still forbidden in our country because of NIH guidelines and some state laws, so they can be carried out only in some states if supported by private funds [28,29]. However, many other countries carry out such studies until the human embryo reaches day 14. In effect, this reflects their appraisal that the embryo before 14 days of development is not the equivalent of a fetus or person and, thus, may be studied. I suggest that it is time to reconsider the United States guidelines for scientific experimentation, and to extend our ability to study human embryos to embryonic day 14, so that we will know the early developmental events that occur in our species. It is likely that mice will not be useful models as they differ from humans in regard to many early developmental events like this one [8].