Textbook assignment: Chapter 14, 419 - 433.
Major concepts
Sexual reproduction: The first few pages of chapter 14 discuss the genetic advantages of sexual reproduction and summarize the diversity of sexual systems that are encountered in various types of organisms. The ability to mix together genetic contributions from two different parents promotes genetic diversity and provides a basis for evolutionary selection of more fit combinations. Hermaphroditic species contain the elements of both sexes within a single individual. Depending on the species, they may reproduce by self fertilization, cross fertilization or both, with a full range from obligate self-fertilization to self-sterility that makes cross-fertilization obligatory. Dioecious species, on the other hand, have the two sexes in separate individuals, such that cross fertilization is generally obligatory (although females of some species can reproduce by parthenogenesis without the need for a male). Note that the textbook uses the term monoecy only to describe plants that have separate male and female flowers on the same individual (for example in pumpkins). When applied to animal systems, the terms monoecious and monoecy usually refer simply to having both sexes in the same individual.
Sex determination: In dioecious species, development as a male or a female is achieved by the activation of alternative patterns of gene expression. The trigger signals that activate these alternative cascades of gene expression are amazingly diverse, as summarized briefly on pages 421 - 427 of our textbook. The trigger stimuli can be either environmental or genetic. In cases where genetic signals are involved, they can range from different alleles at one particular locus on otherwise identical chromosomes to major chromosomal differences, or even differences in ploidy.
Chromosomal Sex Determination: Most of our attention in this course will be focused on specific chromosomal determinants, with particular emphasis on the XX/XY system in which a female has two X chromosomes and a male has one X and one Y. This arrangement is present both in mammals and in Drosophila, although the actual mechanisms that lead to sexual dimorphism in these two cases are very different. In humans and other mammals, the presence of a Y chromosome is the primary determinant of maleness, whereas in Drosophila, sex is determined by the ratio of X chromosomes to autosomes. In the next lecture, we will briefly examine an alternative system found in some birds and various other species, in which the male has two Z chromosomes and the female has one Z and one W chromosome.
Homogametic and heterogametic: In the XX/XY sex chromosome system, the female is referred to as the homogametic sex because she has two homologous sex chromosomes, which causes all of her gametes to carry an X chromosome. The male is such species is called heterogametic because he has non-homologous sex chromosomes, and thus produces two different types of gametes. There is a small "pseudoatosomal" region of homology that allows the X and Y chromosomes to pair during meiotic prophase, and to be distributed systematically during the two meiotic divisions, such that each male gamete normally receives one X or one Y chromosome. Since all female gametes contain X chromosomes, the sex of the progeny is determined by whether fertilization is with a sperm cell containing an X chromosome to produce a female or a Y chromosome to produce a male. Despite the similarity of the XX/XY patterns, the actual molecular genetic mechanisms that are involved in determining whether female or male development occurs are very different in humans and other mammals than in Drosophila. In the ZZ/ZW system of sex chromosomes, the male in homogametic and the female heterogametic. The genetic consequences of this difference will be discussed in the next lecture.
X and Y chromosomes: In a typical XX/XY system, the X chromosome is relatively large and carries a substantial amount of genetic informaiton, whereas the Y chromosome is smaller and carries much less genetic information. Genes that are carried on the human Y chromosome are discussed near the end of this lecture.
X:A ratio determines sex in Drosophila: In Drosophila the Y chromosome has no effect on the sex of individuals, which is determined by the ratio of X chromosomes to haploid sets of autosomes (all of the chromosomes except sex chromosomes). A ratio of approximately 1.0 (studied in individuals with extra sets of autosomes or sex chromosomes) results in female development, whereas a ratio of approximately 0.5 results in maleness, with intersex development at intermediate ratios (Fig. 14.7).
Sex-determining genes in Drosophila: Recent analysis of molecular mechanisms has shown that the product of a gene designated Sxl acts as a master switch for a gene regulatory cascade that determines whether the male or female developmental pathways are activated. Sxl stands for "sex lethal" and was originally named that because loss of function mutations at this locus result in total absence of homozygous female progeny, with no effect on males. It is now known that production of the Sxl gene product is required for female development, and that a regulatory element in its promoter is sensitive to the ratio of regulatory proteins produced from genes on the X chromosome (numerator elements) and on autosomes (denomenator elements) respectively. The Sxl gene product in turn regulates a downstream cascade of gene expression changes that will be analyzed in greater detail in the developmental biology course, MCDB 4650. One interesting aspect of this cascade is gender-specific alternative splicing of the mRNAs for several of the gene products in the regulatory cascade.
Gynandromorphs: Although relatively rare, loss of individual chromosomes can occur in mitotic cells. When one X chromosome is lost from one of the nuclei during early development of a female Drosophila, a portion of the body can have an X:A ratio of 0.5, while the remainder has an X:A ratio of 1.0. This can result in the development of a fly in which one side of the body is basically male while the other side is basically female (figure 14.8). Such a fly is called a gynandromorph.
Genes on the Y chromosome determine maleness in mammals: In humans, individuals with one X chromosome and no Y chromosomes develop as females (although with some defects). Individuals with two X chromosomes and one Y chromosome develop as males (again with some defects). Thus, the default pathway of development in the absence of active signals appears to be female, with maleness being determined by the presence of a Y chromosome. The effects of extra or missing sex chromosomes will be explored in greater detail in the next lecture.
Mammalian sex-determining genes: The Y chromosome has been shown to carry a gene designated Sry in mice and SRY in humans, whose gene product is a transcription factor that causes the primitive gonad to develop into a testis. Two testicular hormones are responsible for diverting development of the rest of the reproductive system from the female pattern to the male. Mullerian inhibiting factor (MIF) prevents development of early primordia known as Mullerian ducts into the female oviducts and uterus. Testosterone promotes development of all of the internal and external male reproductive structures other than the testes.
Testicular feminization: One of the most phenotypically spectacular human mutations causes loss of function of testosterone receptors, which results in a syndrome known as testicular feminization. XY males that carry this mutation on their X-chromosomes are totally unable to respond to testosterone and develop as phenotypic females. They lack oviducts and uterus because development of these structures is inhibited by MIF, and they also have undescended abdominal testes. However, their external appearance is fully female, including normal female breast development as they mature. One of few external clues is their extreme lack of body hair, indlucing pubic hair (the hair on their heads is not affected). In some cases, their overall external phenotypes are so completely female that the condition is not fully diagnosed until the individuals go to fertility clinics as married women seeking to find out why they are infertile and have never menstruated.
Inheritance of genes carried on the X-chromosome: In this lecture, we will focus primarily on patterns of inheritance in the XX/XY system in mammals, including humans, and in Drosophila, with some brief references to other systems. The ZZ/ZW system will be discussed in the next lecture. Despite major differences between mammals and Drosophila in their mechanisms of sex determination (discussed above) and dosage compensation (discussed in the next lecture), their patterns of sex-linked inheritance are quite similar.
XY males are hemizygous: One of the features of an XX/XY sex chromosome system is that females have two copies of the X chromosome, one of which is inherited from each parent, whereas males have only one, inherited from the mother, and paired with a Y chromosome inherited from the father. Because there is only one X chromosome in males, any recessive alleles that are carried on that chromosome are fully expressed in a manner comparable to that seen in a homozygous recessive female. Males are therefore described as being hemizygous for genes carried on the X chromosome.
Crisscross pattern of inheritance of X-linked recessive alleles: At the time of its discovery, sex-linked inheritance caused major excitement because it was the first direct evidence that genes were carried on specific chromosomes, as described below. However, that excitement has long since been supplanted by more recent studies showing that DNA is the genetic material and that genetic information is coded into the DNA nucleotide sequence. Thus, for the modern student of genetics, the significance of X-linkage is found primarily in the modification that it imposes on Mendelian patterns of inheritance. In particular, there is a crisscross pattern of inheritance, in which a recessive allele that is expressed in a male is transmitted only to daughters (who usually fail to express the phenotype unless their mothers were also carriers of the same recessive allele), and then from those daughters to half of their sons, who exhibit a hemizygous recessive phenotype identical to that of their grandfather. Another characteristic feature of X-linkage is that homozygous recessive mothers pass X-linked traits to all of their sons, whereas none of their daughters may be phenotypically affected (provided that the father is not affected). The basic patterns associated with inheritance of sex-linked recessive alleles are summarized in figure 14.11.
Inheritance of X-linked dominant alleles: Dominant alleles carried on the X chromosome are expressed in males and all of their daughters, but not in their sons (unless the mother of the sons also expresses the trait). Half of the sons and half of the daughters of a heterozygous woman and an unaffected man will be affected. Overall, more females than males are affected. One example in humans is an X-linked gene that causes defective dentine of the teeth. Bar eyes is an example of an X-linked dominant mutation in Drosophila.
Drosophila white-eyed mutation: The first definitive data linking genes to chromosomes (published in 1910 by Thomas Hunt Morgan) came from studies of the white-eyed mutation in Drosophila. When a white-eyed male was crossed with a wild-type female, all F1 progeny were phenotypically wild-type. However, half of the F2 males were white-eyed, whereas all of the females were phenotypically wild-type (figure 14.11a)
X chromosome linkage: Phenotypic expression of the white-eyed mutation in F2 males was thus directly associated with the X chromosome that had been passed from the white-eyed parental male to the phenotypically wild type F1 females and then to one-half of their F2 male progeny, where the recessive mutation was expressed because of the hemizygous nature of the male X chromosome. Because all of the F1 males had received a wild-type X chromosome from their wild-type female parent, all of the F2 females received a wild-type eye color allele from their fathers, and were thus phenotypically wild-type irrespective of which allele they received from their heterozygous mothers.
Homozygous white-eyed females: White-eyed females were obtained only in crosses that allowed them to inherit an X chromosome carrying the recessive white-eyed allele from each parent (for example, in a cross of a heterozygous F1 female with a white-eyed male). When a white eyed female was mated with a wild-type male, all of the male progeny were white-eyed and all of the female progeny were red eyed (figure 14.11b). The F2 generation (white eyed male crossed to heterozygous female) yielded half red eyes and half white eyes in both sexes. The hemizygous males inherited either red or white from their heterozygous mothers, and the females received either a red or a white from their mothers, always paired with a white from their fathers.
Significance: At the time of its discovery in 1910, sex linkage was the first direct experimental confirmation that inheritance was associated with specific chromosomes. This had been suspected since the discovery of the behaviour of chromosomes in meiosis a few years earlier, but no direct link had previously been forged between a physical entity and the inheritance of a specific trait. Similar results were also obtained in the original studies with two other X-linked genes, miniature wing and yellow body. In addition to verifying the chromosomal theory of inheritance, these studies also provided the basis for many new experimental approaches. For example, the first studies on genetic recombination and map distances were done with genetic loci that had already been demonstrated to be carried on the Drosophila X-chromosome (pages 446-447).
X-linked inheritance in a gynandromorph: Another interesting example is the use of X-linked markers to verify the chromosomal mechanisms involved in the formation of a gynandromorph. Female embryos that were heterozygous for white eyes and miniature wings were studied for gynandromorph formation. In cases where the X-chromosome bearing the wild-type alleles was lost, the male half of the gynandromorph that developed had white eyes and miniature wings, whereas the female half remained wild type (for an illustration, see figure 9.8 in Klug and Cummings, Concepts of Genetics, 5th Edition, on reserve in Norlin).
Pseudoautosomal inheritance: The pseudoautosomal regions of the Drosophila Y chromosome carry a few functional genes. As shown in figure 14.16, inheritance of recessive traits in the pseudoautosomal regions is much like autosomal inheritance, except that in the 3:1 phenotypic distribution in the F2 generation, all of the recessive individuals are either male or female, depending on whether or not one of the recessive alleles is carried on the Y chromosome.
Sex linkage in humans: Many human diseases, disorders and phenotypic traits have been show to be inherited as alleles carried on the X chromosome. A number of such conditions are summarized in Table 14.1 in the textbook, and several are discussed briefly below. In addition, both in humans and in other species, there are numerous traits that are not X-linked whose phenotypic expression is limited or influenced by hormonal mechanisms related to sexual differentiation. These will be discussed separately in the next lecture.
Color blindness: Half of the sons of a woman who is heterozygous for color blindness will be color blind, irrespective of the genotype of their father. If the father is color blind, half of the daughters will also be color blind. If the father has normal vision, none of the daughters will be color blind. A normal vision man and a normal vision woman who is heterozygous for color blindness will produce progeny with a 3:1 ratio of normal vision to color blind, but all of the color blindness will be in male progeny. Note that all of this is an oversimplification. There are actually various types of color blindness involving loss of sensitivity to different colors of light.
Hemophilia: This disorder of blood clotting is X-linked and is common in the males of European royal families because of frequent consanguineous matings within this limited breeding pool. Pedigrees suggest that Queen Victoria of England was heterozygous for classic hemophilia (hemophilia A), which involves a deficiency of clotting factor VIII (figure 14.12). Hemophilia B, with a deficiency of clotting factor IX, is also X-linked (Table 14.1).
Lesch-Nyhan Syndrome: This X-linked disease involves an absence of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT), which is involved in a so-called "salvage" pathway for utilization of purine bases that have become available either from dietary sources (nearly all foods contain some amount of nucleic acids) or as the result of recycling processes within the body. Loss of HGPRT results in severe mental retardation and a strange self-mutilating syndrome. Because victims of this disease die young without reproducing, it is seen primarily in males. Cells cultured from patients that lack HGPRT are unable to utilize externally supplied purines and thus cannot multiply when de novo synthesis of purines is blocked with aminopterin or similar drugs. This trait can be used to select for cells that have acquired a functional HGPRT gene by incorporation of a plasmid or by fusion with another cell type that contains a functional gene. Such cells gain the ability to utilize preformed purines and thus can be selected for on the basis of their ability to multiply when provided with purines in the presence of aminopterin. Cell fusion techniques are used in somatic cell hybridization mapping (described on pages 466-467)
Duchenne muscular dystrophy: This is another genetic disease that is rare in females because affected males do not live long enough to reproduce. The defect is in a very large protein (dystrophin) that is coded for from a huge locus consisting of over 2 million base pairs. The large size of the locus, as well as some of its structural features result in a high rate of new mutation. The relatively high frequency of this genetic disease appears to be sustained almost entirely by that high rate of mutation.
Y-linked inheritance: Except for limited pseudoautosomal regions that permit the X and Y chromosomes to pair during meiotic prophase (figure 14.15), there is little genetic similarity between the two. Because females do not have a Y chromosome, it has long been believed that the human (and mammalian) Y chromosome must not have much genetic function beyond determining maleness. Even in the determination of maleness, only the product of a single genetic locus appears to be needed to trigger a regulatory cascade involving gene products from other chromosomes. However, recent sequencing studies have revealed the presence of more genetic information on the Y chromosome than originally expected, including several genes whose products are needed for normal testicular function and several others that are involved in normal cellular "housekeeping" activities.
Genes on human Y chromosome: When "Y" is entered into the search the gene map option of OMIM, a list of 23 genes and pseudogenes appears, with links to full OMIM descriptions of each. Clicking on "map viewer" for any one of these loci brings up a more detailed map of the Y chromosome from Entrez Genome that includes a total of 50 identified loci spread over several web pages. A special report from Associated Press, published in the October 30, 2000, Denver Post, describes claims from the scientists inolved in sequencing the human Y chromosome that many unusual features will be revealed when the details are published. Many older textbooks suggested that the Y chromosome probably carried the genetic locus responsible for hairy rims of the ears, which occur on some middle-aged men of Middle-Eastern ancestry. However, most investigators now believe that this is not the case.
Alternative sex chromosome systems: In other species, there are diverse patterns of chromosomal and non-chromosomal sex determination. In birds and some reptiles, as well as moths, the male is homogametic (ZZ) and the female heterogametic (ZW). In certain types of insects, females are XX and males are XO (with O indicating absence of a second sex chromosome). In bees, females are diploid and males are haploid. The small nematode, C. elegans, which has become a popular subject for research on developmental genetics, exhibits a similar pattern, except that worms with two X chromosomes are true hermaphrodites (with male and female in the same individual), while those with only one X chromosome are true males. Other than the ZZ/ZW system, which will be discussed briefly in the next lecture, we will not have much opportunity to explore the diversity of mechanisms for sex determination, but you need to be aware that there are far more alternatives than we have covered in this course.