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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): nationwide Academies push (US); 2001.


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

ABSTRACT

The biological differences between the sexes have long been known at the biochemical and also cellular levels. Rapid advances in molecule biology have revealed the genetic and molecular bases of a variety of sex-based distinctions in health and also human disease, few of which are attributed to sex-related genotype—XX in the female and XY in the male. Gene on the sex chromosomes can be to express differently between males and females since of the presence of either single or twin copies of the gene and because the the phenomena of various meiotic effects, X inactivation, and genetic imprinting. The inheritance of either a masculine or a female genotype is additional influenced by the source (maternal or paternal) that the X chromosome. The loved one roles the the sex chromosome genes and also their expression defines X-chromosome-linked an illness and is likely to illuminate the factors for heterogeneous expression that some diseases within and also between the sexes.

The id that over there are biological differences in between the sexes is most evident and comfortable once it is used to the reproductive system. However, sex differences have been identified or suggested at numerous levels of organic organization, native biochemical to behavioral. For the bulk of the population, and a substantial fraction of scientists, no all known differences are obvious, and not every one of those that have actually been argued or doubt are conveniently explainable in biological terms.

In terms of hereditary mechanisms, two general models effort to describe how an individual"s genes offer rise come sex differences (Figure 2–1). In the first model, a collection of critical hormone-responsive genes, common by both males and females, are influenced in different ways in the alternate hormonal milieus the the masculine or woman throughout their life spans, therefore leading come or contributing to the many differences observed between the sexes. In the 2nd model (which is not necessarily exclude, of the first one), one or an ext genes, situated on the sex chromosomes and thus expressed in different ways in the 2 sexes, encode proteins connected in ratelimiting or rate-influencing steps in biochemical or physiological pathways the are crucial to establishing differences between the sexes.


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FIGURE 2–1

Schematic representation of two general models supplied to describe sex differences in gene expression. In model I, hormone in males and females differentially affect the level the expression of various genes (Gene 1 come Gene N) in the genome. Arrows (more...)


The function of this chapter is twofold: (1) to define those differences that exist in between males and also females in ~ the biochemical and cellular levels and also that an outcome directly indigenous the defining 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 define how males and also females might transmit to your offspring genetic information that is the same but that is transmitted at various observed phenotypic or genotypic ratios. This details will then serve as a structure for consideration of the start of sex differences during development and transparent life in an answer to both intrinsic and extrinsic exposures.


SEX and THE human being GENOME

Males and also females have actually partially various genomes. Viewed from a purely reductionist standpoint, numerous differences between the male and female sexes are predicted to it is in rooted in differences in between the genetic materials of male and also female cells and also differences in the expression of those genetic contents. Together the complete DNA sequence of the human genome has now been determined, that is important to place the discussions of this chapter right into the paper definition of the person genome.

The human genome contains, by existing measurements, a little more than 3 billion basic pairs of DNA (Lander, 1996; National human Genome research Institute, 2000). Previously estimates suspect an approximated 50,000 to 100,000 various genes (National human being Genome research Institute, 2000). The many recent estimates, based upon the present drafts of the human being genome sequence, suggest that over there are approximately 30,000 human being genes (International person Genome Sequencing Consortium, 2001; Venter et al., 2001). However, this lower number may be a minimum estimate because it is obtained using an algorithm that identifies genes on the basis of your similarity come a usually sized dashboard of already characterized human genes.

The hallmark of person biology is variation, and also much that the it was observed variation both within and also between the sexes is encoded within the human being genome. In ~ the DNA level, an estimated 1 of every 1,300 bases on the autosomes (non-sex-determining chromosomes) different between any kind of 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 distinctions will cause gene commodities that room functionally distinct, because that example, receptors that differ in your affinity or price of turnover, enzymes the differ in their steady-state levels, and genes the differ in their degree of hormone responsiveness. Although ongoing studies of person DNA variation will certainly soon provide a more robust estimate, one can calculate native previous studies of enzyme sport and more recent investigations of gene sports (Zwick et al., 2000) the the an exact composition and also functioning of countless proteins will certainly differ between any type of two individuals.

Notwithstanding this level of population-level sport in the DNA sequence, many of the gene in the genome are thought to not differ in either sequence or level the expression as a simple consequence of the sex the the individual. However, as will be depicted more fully in the complying with sections, there space three varieties of genes (see additionally Box 2–1) in which an individual"s sex every se is likely to pat a role.


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BOX 2–1

Genetic components That may Differentially affect the basic Biochemistry that Male and also Female Cells.


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

Second, some genes top top the X chromosome are expressed at greater levels in females 보다 in males. Return the process of X-chromosome inactivation equalizes the reliable dosage of most X-chromosome genes in between male and female cell by inactivating one of the two X chromosomes in female cells, not all gene on the inactivated X chromosome respond to this mechanism. The relatively couple of genes that are not equalized have the right to have far-reaching effects on the phenotypes of cells.

Third, the expression of countless genes is likely to be influenced by hormonal differences between the two sexes. Because that example, few of these might be gene whose expression is minimal to sexually dimorphic tissues or cell types (e.g., the ovary, testis, prostate, and breast), whereas others may be globally expressed but subject to hormone regulation in various tissues or at various times during advancement (see chapter 3).

Although just a minimal number that genes have been check to date, from the standpoint of sexual dimorphism, brand-new approaches to quantification of the expression of genes in different samples ~ above a genomewide basis promise to change this. DNA arrays, or “gene chips,” containing 10s of thousands of human being genes have the right to be queried to compare their levels of expression between different tissues or different sexes under a variety of physiological or hormonal problems (Lander, 1996; Lockhart and Winzeler, 2000). Such researches will yield a huge database of gene expression data. More daunting will be determination of the relative results of differences in gene expression ~ above the characteristics phenotypic differences seen between males and also females. Nonetheless, this brand-new technology with DNA arrays promises to provide a an extensive functional check out of the genome in different cellular states, and also studies that attend to differences in expression throughout the male and female genomes should reap a rich harvest.


BASIC molecule GENETICS: WHAT IS THE POTENTIAL because that DIFFERENCES between THE SEXES?

The worry of even if it is there have to be genetic distinctions in simple cellular biochemistry in between female and also male cell (as a direct an outcome of sex chromosome constitution fairly than hormone influences) (see number 2– 1 and Box 2–1) is frequently approached from 2 opposing perspectives. Geneticist Jacques Monod"s famous adage that “What"s true of Escherichia coli is true of an elephant” to represent the suggest of watch that genes have actually been conserved over time and amongst species. This see has had actually extraordinary remaining power in molecular biology and genetics, and if “yeast” to be substituted because that “E.coli,” the statement would certainly have even greater vitality. If the straightforward biochemistries of biology separated through a billion years of advancement are for this reason similar, climate (so go the logic) why must one intend that males and also females in ~ the same varieties should exhibition important distinctions in their straightforward biochemistries? an opposing perspective acknowledges the the bulk of person disease-causing mutations exhibit dominant or semidominant impacts (McKusick, 2000). Thus, a adjust in the task of a solitary gene can have a huge effect on the organism that carries that gene. Due to the fact that the sex chromosomes comprise roughly 5 percent of the complete 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. From this standpoint, it is challenging to imagine the male and also female cells will certainly not different in at the very least some elements of simple biochemistry, provided the complexity of most biological pathways.


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FIGURE 2–2

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


Males have actually a Y Chromosome, Females execute Not

The masculine genome different from the mrs genome in the variety of X chromosomes that it contains, as well as by the visibility of a Y chromosome. It is the overriding existence of a gene top top the Y chromosome (SRY) that results in advance of the male gonadal phenotype. However, apart from leading to the dramatic aberration from the female developmental pathway (which the indeterminate gonad would otherwise follow and also which has actually been discussed in a number of reviews ), it to be long thought about a valid biological question come ask whether the Y chromosome carried any type of genes of “importance.” The paucity and also nature that traits the were thought, by genetic criteria, to segregate through the Y chromosome (“hairy ears,” for example ) tended to reinforce the id that the Y chromosome encoded the masculine gonadal phenotype (Koopman et al., 1991), one or an ext genes affiliated in masculine fertility (Lahn and Page, 1997), the HY masculine transplantation antigen (Wachtel et al., 1974), and also not lot else. Surprisingly, recent studies present that the Y chromosome carries some genes the are involved in an easy cellular functions and that room expressed in countless tissues (Lahn and Page, 1997).

Cytologically, the Y chromosome consists of 2 genetically distinct parts (Figure 2–2). The many distal portion of the Y-chromosome brief arm (Yp) is shared with the most distal part of the X-chromosome short arm (Xp) and normally recombines through its X-chromosome counterpart during meiosis in males. This region is referred to as the “pseudoautosomal region” because loci in this an ar undergo pairing and exchange in between the 2 sex chromosomes throughout spermatogenesis, just as gene on autosomes exchange between homologues. Over there is additionally a second pseudoautosomal region involving assignment 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 not recombine with the X chromosome and also strictly comprises “Y-chromosome-linked DNA” (although several of the nonrecombining part of the Y chromosome maintain residual homology to X-chromosome-linked genes, reflecting the common evolutionary history of the 2 sex chromosomes ). The pseudoautosomal region(s) mirrors the function of the Y chromosome as an important pairing homologue that the X chromosome throughout meiosis in males (Rappold, 1993), vice versa, the Y-chromosome-specific region, including the testis-determining element gene, SRY, offers the chromosomal basis of sex determination.

The Y chromosome is just one of the smallest human being chromosomes, with an estimated average size of 60 million basic pairs, i m sorry is much less than fifty percent the size of the X chromosome. Cytologically, much of the lengthy arm (Yq) is heterochromatic and variable in dimension within populations, consisting mainly of several households of repetitive DNA order that have actually no noticeable function. A significant proportion of the Y-chromosome-specific order on both Yp and also Yq are, in fact, homologous (but no identical) to sequences ~ above the X chromosome. This sequences, back homologous, need to not be confused with the pseudoautosomal regions. Pseudoautosomal sequences may be the same on the X and Y chromosomes, showing their frequent meiotic exchange, vice versa, the sequences on Yp and also Yq homologous v the Y and X chromosomes are much more distantly regarded each other, reflecting their aberration from a common ancestral chromosome (Lahn and also Page, 1999).

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Only about two dozen various genes room encoded top top the Y chromosome (although part are current in multiple copies). Unlike collection of genes that are located on the autosomes and the X chromosome and that reflect a broad sampling of different functions without any obvious chromosomal coherence, Y-chromosome-linked genes show functional clustering and can be categorized into only two unique classes (Lahn and Page, 1997). One class consists of genes that are homologous to X-chromosome-linked genes and that are, for the many part, express ubiquitously in different tissues. Few of these gene are connected in simple cellular functions, thus giving a basis for useful differences in between male and also female cells. For example, the ribosome protein S4 gene 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 native ribosomes in mrs cells, setting up the potential for prevalent biochemical differences between the sexes. The 2nd class that Y-chromosome-linked genes consists of Y-chromosome-specific genes that space expressed particularly in the testis and also that may be associated in spermatogenesis (Figure 2–2). Deletion or mutation of few of these genes has actually been implicated in instances of masculine infertility, yet otherwise, these genes have no obvious phenotypic effects (Kent-First et al., 1999; McDonough, 1998).