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Institute of medicine (US) Committee on expertise the biology of Sex and Gender Differences; Wizemann TM, Pardue ML, editors. Trying out the organic Contributions to human being Health: go Sex Matter? Washington (DC): national Academies push (US); 2001.


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Institute of medication (US) Committee on understanding the biological of Sex and also Gender Differences; Wizemann TM, Pardue ML, editors.

ABSTRACT

The organic differences in between the sexes have actually long been well-known at the biochemical and cellular levels. Rapid advancements in molecule biology have actually revealed the genetic and molecular bases the a number of sex-based distinctions in health and human disease, some of which space attributed to sex-related genotype—XX in the female and also XY in the male. Genes on the sex chromosomes deserve to be to express differently in between males and females since of the existence of either solitary or dual copies that the gene and because that the phenomena of various meiotic effects, X inactivation, and genetic imprinting. The inheritance of either a male or a mrs genotype is more influenced by the resource (maternal or paternal) that the X chromosome. The loved one roles the the sex chromosome genes and their expression describes X-chromosome-linked an illness and is likely to illuminate the factors for heterogeneous expression of some illness within and also between the sexes.

The concept that there are organic differences between the sexes is most evident and also comfortable once it is applied to the reproductive system. However, sex distinctions have been determined or said at countless levels of organic organization, from biochemical to behavioral. Because that the bulk of the population, as well as a substantial fraction of scientists, no all known distinctions are obvious, and also not every one of those that have actually been said or doubt are conveniently explainable in organic terms.

In terms of genetic mechanisms, two general models effort to explain how an individual"s genes give rise come sex differences (Figure 2–1). In the first model, a series of crucial hormone-responsive genes, mutual by both males and females, space influenced differently in the alternative hormonal milieus of the male or female throughout your life spans, for this reason leading to or contributing to the countless differences observed between the sexes. In the 2nd model (which is no necessarily exclusive of the very first one), one or more genes, located on the sex chromosomes and also thus expressed in different ways in the 2 sexes, encode proteins associated in ratelimiting or rate-influencing actions in biochemical or physiological pathways that are critical to developing differences between the sexes.


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FIGURE 2–1

Schematic depiction of two basic models supplied to define sex differences in gene expression. In design I, hormone in males and also females differentially affect the level the expression of various genes (Gene 1 to Gene N) in the genome. Arrows (more...)


The function of this thing is twofold: (1) to describe those differences that exist in between males and also females in ~ the biochemical and also cellular levels and that an outcome directly from the specifying genotypic difference in between male and also female mammals, namely, an XY (male) sex chromosome constitution versus an XX (female) sex chromosome constitution, and also (2) to explain how males and also females may transmit to their offspring hereditary information that is the same however that is transmitted at different observed phenotypic or genotypic ratios. This details will then offer as a structure for factor to consider of the start of sex distinctions during breakthrough and transparent life in an answer to both intrinsic and also extrinsic exposures.


SEX and THE person GENOME

Males and also females have partially different genomes. Viewed from a purely reductionist standpoint, many differences in between the male and female sexes space predicted to be rooted in differences in between the genetic materials of male and female cells and also differences in the expression the those hereditary contents. As the finish DNA sequence of the human genome has now to be determined, the is essential to ar the discussions that this chapter right into the context of the human genome.

The human being genome contains, by current measurements, a little much more than 3 billion basic pairs of DNA (Lander, 1996; National human being Genome research study Institute, 2000). Earlier estimates suspect an estimated 50,000 come 100,000 various genes (National human Genome research Institute, 2000). The most recent estimates, based on the existing drafts that the human being genome sequence, indicate that there are approximately 30,000 person genes (International person Genome Sequencing Consortium, 2001; Venter et al., 2001). However, this lower figure may be a minimum estimate since it is acquired using one algorithm that identifies gene on the basis of their similarity come a usually sized panel of already characterized human genes.

The hallmark of person biology is variation, and much that the it was observed variation both within and between the sexes is encoded within the person genome. At the DNA level, an estimated 1 the every 1,300 bases on the autosomes (non-sex-determining chromosomes) different between any two individuals (International SNP Map functioning Group, 2001; Nickerson et al., 1998; Venter et al., 2001). In various other words, the genomes of individuals may different at part 4 to 6 million base positions. Some of these differences will result in gene assets that are functionally distinct, because that example, receptors that differ in your affinity or rate of turnover, enzymes the differ in their steady-state levels, and also genes the differ in their degree of hormone responsiveness. Although continuous studies of person DNA variation will soon provide a much more robust estimate, one have the right to calculate from previous research studies of enzyme sports and more recent investigations of gene variation (Zwick et al., 2000) that the precise composition and functioning of countless proteins will differ between any kind of two individuals.

Notwithstanding this level of population-level sport in the DNA sequence, most of the genes in the genome room thought to not differ in one of two people sequence or level of expression as a simple an effect of the sex that the individual. However, as will be portrayed more totally in the following sections, there space three types of gene (see additionally Box 2–1) in i m sorry an individual"s sex every se is likely to play a role.


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BOX 2–1

Genetic determinants That may Differentially affect the an easy Biochemistry of Male and also Female Cells.


First, genes on the Y chromosome room expressed only in males, and many of these have actually no equivalent on the X chromosome or autosomes; thus, expression of this genes will be limited to males.

Second, some genes top top the X chromosome are expressed at higher levels in females than in males. Although the process of X-chromosome inactivation equalizes the reliable dosage of many X-chromosome genes between male and female cells by inactivating one of the 2 X chromosomes in woman cells, not all gene on the inactivated X chromosome respond come this mechanism. The relatively few genes that room not equalized deserve to have far-ranging effects top top the phenotypes of cells.

Third, the expression of countless genes is likely to be affected by hormonal differences between the two sexes. For example, few of these may be genes whose expression is restricted to sexually dimorphic organization or cell species (e.g., the ovary, testis, prostate, and also breast), whereas others might be worldwide expressed yet subject to hormone regulation in different tissues or at different times during advance (see thing 3).

Although only a limited number that genes have actually been examined to date, indigenous the standpoint of sex-related dimorphism, new approaches come quantification that the expression of gene in different samples top top a genomewide basis promise to adjust this. DNA arrays, or “gene chips,” containing tens of thousands of human being genes deserve to be queried come compare your levels that expression between different tissues or different sexes under a variety of physiological or hormonal conditions (Lander, 1996; Lockhart and also Winzeler, 2000). Such research studies will yield a huge database the gene expression data. More challenging will be decision of the relative impacts of distinctions in gene expression ~ above the properties phenotypic differences seen between males and females. Nonetheless, this new technology v DNA arrays guarantees to carry out a an extensive functional view of the genome in different cellular states, and studies that address differences in expression transparent the male and female genomes must reap a rich harvest.


BASIC molecular GENETICS: WHAT IS THE POTENTIAL for DIFFERENCES between THE SEXES?

The worry of even if it is there need to be genetic differences in basic cellular biochemistry between female and also male cell (as a direct result of sex chromosome constitution fairly than hormonal influences) (see number 2– 1 and Box 2–1) is frequently approached from two opposing perspectives. Geneticist Jacques Monod"s renowned adage the “What"s true of Escherichia coli is true of one elephant” represents the suggest of view that genes have actually been conserved gradually and among species. This check out has had extraordinary continuing to be power in molecule biology and also genetics, and also if “yeast” to be substituted because that “E.coli,” the statement would have also greater vitality. If the simple biochemistries of organisms separated by a billion year of evolution are therefore similar, then (so walk the logic) why have to one expect that males and also females within the same varieties should exhibition important distinctions in their straightforward biochemistries? an opposing perspective acknowledges that the bulk of human disease-causing mutations exhibit dominant or semidominant results (McKusick, 2000). Thus, a readjust in the activity of a single gene can have a large effect top top the organism the carries the gene. Because the sex chromosomes comprise roughly 5 percent that the full human genome (Figure 2–2), over there is the potential because that 1 in 20 biochemical reactions to it is in differentially affected in masculine versus woman cells. Indigenous this standpoint, that is an overwhelming to imagine the male and female cells will certainly not differ in at least some facets of straightforward biochemistry, offered the intricacy of most biological pathways.


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FIGURE 2–2

to compare of gene contents and also gene institutions on the X and Y chromosomes (see text for details).


Males have a Y Chromosome, Females do Not

The male genome different from the mrs genome in the variety of X chromosomes the it contains, and also by the existence of a Y chromosome. It is the overriding existence of a gene on the Y chromosome (SRY) that outcomes in breakthrough of the masculine gonadal phenotype. However, personally from causing the dramatic divergence from the mrs developmental pathway (which the indeterminate gonad would certainly otherwise follow and also which has been questioned in a variety of reviews ), it to be long taken into consideration a valid biological question come ask even if it is the Y chromosome carried any kind of genes the “importance.” The paucity and also nature the traits the were thought, by hereditary criteria, to segregate through the Y chromosome (“hairy ears,” for example ) often tended to reinforce the concept that the Y chromosome encoded the male gonadal phenotype (Koopman et al., 1991), one or an ext genes associated in masculine fertility (Lahn and Page, 1997), the HY masculine transplantation antigen (Wachtel et al., 1974), and not lot else. Surprisingly, current studies present that the Y chromosome carries some genes that are involved in simple cellular functions and also that room expressed in many tissues (Lahn and also Page, 1997).

Cytologically, the Y chromosome is composed of 2 genetically distinctive parts (Figure 2–2). The most distal part of the Y-chromosome quick arm (Yp) is mutual with the many distal section of the X-chromosome quick arm (Xp) and also normally recombines through its X-chromosome equivalent during meiosis in males. This region is called the “pseudoautosomal region” since loci in this region undergo pairing and exchange in between the two sex chromosomes throughout spermatogenesis, simply as genes on autosomes exchange between homologues. Over there is also a second pseudoautosomal an ar involving order on the distal lengthy arms of the sex chromosomes (Watson et al., 1992) (Figure 2–2). The remainder of the Y chromosome (the Y-chromosome-specific portion) does no recombine v the X chromosome and also strictly comprises “Y-chromosome-linked DNA” (although several of the nonrecombining part of the Y chromosome maintain residual homology come X-chromosome-linked genes, showing the common evolutionary history of the two sex chromosomes ). The pseudoautosomal region(s) shows the role of the Y chromosome as an essential pairing homologue the the X chromosome throughout meiosis in males (Rappold, 1993), vice versa, the Y-chromosome-specific region, consisting of the testis-determining factor gene, SRY, gives the chromosomal communication of sex determination.

The Y chromosome is among the smallest human being chromosomes, with an estimated average dimension of 60 million basic pairs, i m sorry is less than fifty percent the size of the X chromosome. Cytologically, much of the long arm (Yq) is heterochromatic and also variable in dimension within populations, consisting mainly of several families of repeated DNA sequences that have actually no apparent function. A significant proportion of the Y-chromosome-specific sequences on both Yp and Yq are, in fact, homologous (but no identical) to sequences on the X chromosome. This sequences, back homologous, have to not be confused with the pseudoautosomal regions. Pseudoautosomal sequences may be identical on the X and Y chromosomes, reflecting their regular meiotic exchange, conversely, the assignment on Yp and also Yq homologous with the Y and X chromosomes are more distantly concerned each other, reflecting their aberration from a common genealogical chromosome (Lahn and also Page, 1999).

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Only around two dozen different genes space encoded ~ above the Y chromosome (although part are existing in lot of copies). Unlike collections of genes that are located on the autosomes and the X chromosome and also that reflect a broad sampling of different functions without any type of obvious chromosomal coherence, Y-chromosome-linked genes demonstrate functional clustering and also can be categorized into only two unique classes (Lahn and Page, 1997). One course consists of gene that space homologous come X-chromosome-linked genes and also that are, because that the most part, to express ubiquitously in different tissues. Some of these gene are connected in basic cellular functions, thus offering a basis for useful differences in between male and also female cells. For example, the ribosome protein S4 genes on the X and also Y chromosomes encode slightly various protein isoforms (Watanabe et al., 1993); thus, ribosomes in male cells will certainly differ characteristically indigenous ribosomes in female cells, setup up the potential for widespread biochemical differences between the sexes. The 2nd class of Y-chromosome-linked genes consists of Y-chromosome-specific genes that room expressed especially in the testis and that may be involved in spermatogenesis (Figure 2–2). Deletion or mutation of few of these genes has been implicated in instances of male infertility, but otherwise, this genes have no apparent phenotypic impacts (Kent-First et al., 1999; McDonough, 1998).