Textbook assignment: Chapter 14, 433 - 443; also please read pages 539-541 in chapter 17. .
Major concepts
Introduction: This lecture deals with additional aspects of sex-linked inheritance and related phenomena. Topics covered include attached X chromosomes in Drosophila, sex-linked inheritance in ZZ/WZ systems, dosage compensation in mammals and in Drosophila, sex chromosome aneuploidies in humans, sex-limited inheritance, and sex-influenced inheritance.
Attached X chromosomes in Drosophila: The X-chromosome in Drosophila is telocentric. In rare cases, two X chromosomes can become linked in the centromeric region, such that they behave like a single metacentric chromosome in meiosis. Because triple-X flies have low viability and are sterile, the only successful progeny of mating an attached X (X^X) fly with a normal male will be X^XY female progeny. When these X^XY females are mated with XY males, the progeny will be X^XY females, with the Y chromosome inherited from the father, and XY males, with the X chromosome inherited from the father and the Y from the mother. The X^XX and YY progeny will not be viable. This arrangement allows X chromosomes to be passed directly from one male to another, with no intervening heterozygous female generation. See problem 36 on page 443 (end of Chapter 14) for an example of the strange patterns of inheritance that attached X can achieve (vermillion eyes and yellow body are both X-linked).
Sex linkage in ZZ/WZ systems: In species with ZZ/ZW sex chromosomal sex determination, such as chickens, the male with two Z chromosomes is the homogametic sex and the female with one Z and one W is heterogametic. Thus, the patterns of sex-linked inheritance are exactly reversed from those of species with XX/XY sex chromosomes. Our textbook illustrates these patterns with Z-linked alleles that cause the feathers to be barred (dominant) or non-barred (recessive) as shown in figure 14.19.. The hemizygous female always exhibits the pattern dictated by her one and only Z chromosome, while the phenotype of the male is determined by the dominance relationship of the two alleles carried on his Z chromosomes.
Criscross patterns: When a hemizygous recessive (non-barrred) female is mated with a homozygous dominant (barred) male, the F1 progeny are all dominant (barred). The F2 males all receive a dominant (barred) allele from their hemizygous mother, and thus are all barred. Half of the F2 females receive a recessive (non-barred) allele from their heterozygous fathers, and the other half receive a dominant (barred) allele (figure 14.19b). Except that everything happens in the opposite sex, this is exactly what happens when a white-eyed (recessive) male fly is mated with a homozygous wild-type female (figure 14.11a). Similarly, a mating of a homozygous recessive rooster with a hemizygous dominant hen generates sex-reversed results that are otherwise comparable to those from the mating of a homozygous white-eyed female fly with a hemizygous wild-type male fly (compare figure 14.19a and figure 14.11b). Generally the best way to keep the ZZ/ZW results straight is to diagram each process that you try to analyze, at least until you learn to readjust your reflexes.
Dosage compensation in mammals: Gene dosage must be balanced quite precisely in higher organisms. An elaborate mechanism has evolved to insure that the ratio of functional X-chromosomal genes to autosomal genes remains constant despite a two-fold difference in X:A ratios between male and female mammals (including humans). Early in development, there is random inactivation of one or the other of the X chromosomes in every cell in female embryos. That inactivation is stably inherited by all of the daughter cells arising from each cell, with the possible exception of the germ cells (those destined to form future gametes). Throughout the rest of that female's lifespan, the inactivated X chromosomes remain partially condensed as heterochromatic Barr bodies in the interphase nuclei of all of her somatic cells (figure 14.20). Genes on the inactivated X chromosomes are not transcribed and replication of the chromosomes is delayed, occurring at the very end of the S period of the cell cycle. When abnormal numbers of X chromosomes are present, as in the aneuploidies described below, the number of Barr bodies is always one less than the total number of X chromosomes, leaving only one X chromosome active in each cell.
Functional hemizygosity in individual cells of female mammals: The term hemizygous refers to having just one copy of a gene or group of genes in an otherwise diploid background. As discussed in the previous lecture, the classic example is a sex-linked gene carried on the X-chromosome, which is present in only one copy in XY males. This allows a single copy of a recessive sex-linked gene to express its phenotype in males in the same manner as it does when it is homozygous in an XX female. As a result of random inactivaiton of one of the X chromosomes in every cell, a female mammal is a mosaic of two cell types, one expressing the maternal X chromosome and the other expressing the paternal X chromosome This is evident, for example, in the orange and black pigmented areas of a calico or tortiseshell cat (figure 14.21), where alternative pigmentation alleles are expressed in patches that represent the mitotic descendants of single cells with one or the other X chromosome active. Male cats with only one X chromosome do not exhibit this pattern. However, in rare cases, a cat with two X chromosomes and one Y chromosome may exhibit the calico or tortiseshell patterns. In such case, the cat has a Y chromosome to make it male, but also has two X chromosomes, and is sterile (comparable to human Kleinfelter syndrome, described below). The concept that a female mammal is a mosaic of two kinds of cells that all have their maternal or paternal X-chromosomes inactivated is often referred to as the Lyon hypothesis, named for Mary Lyon, who first proposed the concept.
X inactivation in human females: Although no pigmentation is involved, a similar body surface pattern also occurs in human females who are heterozygous for sex-linked anhydrotic ectodermal dysplasia (absence of sweat glands). In such cases, patches of skin lacking and containing sweat glands are randomly distributed over the body surface. One of the best demonstrations of random X inactivation in human females has been done with cultured cells from individuals who are heterozygous for two variants of the enzyme glucose-6-phosphate dehydrogenase that have different electrophoretic mobilities. When the mitotic descendants of single cultured cells are allowed to grow into large cultures (clones of genetically identical cells), some of the cultures exhibit one isoform of the enzyme and the rest exhibit the other. This experiment demonstrates that only one of the X-chromosome linked alleles is expressed in any individual cell, and also shows that the pattern of expression is stably inherited by all of the mitotic descendants of that cell. The inactivation tends to be highly stable and persists even in selective media that will only support growth of cells that have reactivated a previously inactivated gene. An example of this is seen in cells from individuals heterozygous for Lesch-Nyhan syndrome that have inactivated the functional HGPRT gene. When they are placed in a medium that requires them to utilize preformed purines for growth because de novo synthesis is blocked, they are unable to multiply.
Mechanism of X-chromosome inactivation: The mechanism responsible for X-chromosome inactivation remains incompletely understood. The process is controlled from a single region on the X-chromosome, called the X-inactivation center (XIC). That region contains a gene that codes for a rather large RNA that is not translated into a protein and is only transcribed from inactivated chromosomes. This gene is called XIST (for X-inactive transcript) in humans and Xist in mice. The XIST RNA appears to be directly involved in the inactivation process on each chromosome that is inactivated. There is no genetic expression in the XIC region of the chromosome that remains active, but the details of the switching mechanism remain somewhat obscure.
Dosage compensation in Drosophila: Dosage compensation between autosomal and X-linked genes also occurs in Drosophila, but with a totally different mechanism than in mammals. Transcription from the single X chromosome in male Drosophila occurs at roughly twice the rate of transcription from each of the two X-chromosomes in female Drosophila. Thus, in Drosophila, dosage compensation is achieved by adjusting the rate of transcription of genes on the X-chromosome, whereas in mammals, it is achieved by almost totally inactivating one of the X-chromosomes. Studies on female Drosophila with translocations of chromosomal segments between autosomes and the X chromosome suggest that the modification of rate of transcription occurs at the level of individual genes and remains functional in alternative locations, rather than occurring globally for the entire X-chromosome
Human chromosome number: Chapter 10 described the human karyotype and chromosome banding techniques that allow unequivocal identification of each of the human chromosome pairs. However, our textbook provides very little background on the history of attempts to determine accurately the number of human chromosomes, which is summarized briefly in the following paragraphs. It was not until 1956 that the correct number of 46 was finally established. For many years before that, the number was generally believed to be 48. The difficulty in determining the correct number arose from the fact that all of the chromosomes are packed tightly together in mitotic and meiotic cells such that in ordinary histological preparations, they cannot be clearly seen as individuals and counted.
Hypotonic swelling: The key to finally identifying the correct number of human chromosomes was a technique for mitotic arrest of the cells with colchicine (which disrupted the spindle fibers), followed by carefully controlled hypotonic swelling that was sufficient to separate the chromosomes without bursting the cells. The cells were then ruptured very gently, so that the chromosomes from each individual cell would settle into a well separated pattern on a microscope slide without losing their identity as a clearly delineated set. This allowed the chromosomes to be counted precisely and arranged in pairs as show in figures 10.18, 10.31, and 11.2 (note that the numbering in figure 10.31 is incorrect -- see the textbook errors page for details). .
Karyotype analysis: Figure 10.31 quite accurately depicts the way in which karyotype analysis (the process of sorting out of individual chromosomes and deciding whether any are missing, duplicated, or morphologically altered) was originally done, based entirely on relative sizes of the chromosomes and positions of their centromeres. The subsequent development of staining techniques that produce banded patterns, such as those in figures 10.18 and 11.2, has made the identification of individual chromosomes far easier and more precise. Notice, however, that the basic scheme for arrangement of the 22 pairs of autosomes plus the sex chromosomes has not changed.
Aneuploidy: The term euploid refers to having an exact multiple of a haploid set of unaltered normal chromosomes (including expected alternative sex chromosome patterns in species where sex is chromosomally determined). Any pattern that does not satisfy that criterion is referred to as aneuploid. Loss of one chromosome, resulting in one of the chromosomes being unpaired, is referred to as monosomy. The presence of an extra chromosome, causing one of the normal chromosomes to be present in three copies, is called trisomy. Changes in the structure of individual chromosomes that do not alter the total number of chromosomes also cause a karyotype to be considered aneuploid. We will explore various types of aneuploidy in detail in chapter 17. However, it is more convenient to deal with the short section of that chapter that describes sex chromosome aneuploidies (pages 539 - 540) at this time.
Nondisjunction: The most common cause of monosomy and trisomy is nondisjunction (figure 17.2), which was discussed briefly at the end of the lecture 20 notes. During meiosis, homologous chromosomes pair, followed by random assortment of one member from each homologous pair to each of the poles during the first division and separation of sister chromatids during the second division. This process normally generates gametes that contain precisely one haploid set of chromosomes. If disjunction fails to occur and both homologs (or sister chromatids) of one chromosome move to the same pole, the resulting gametes will lack one chromosome or have a duplicate copy of one of the chromosomes. When the abnormal gametes produced by nondisjunction fuse with normal gametes during fertilization, the resulting progeny will have 2n - 1 chromosomes (monosomy) or 2n + 1 chromosomes (trisomy).
Human sex chromosome aneuploidies: Despite their major structural differences, X and Y chromosomes contain pseudoatosomal regions that permit them to come together as "homologous pairs" during meiotic prophase and to be independently assorted to the poles during the first meiotic division in much the same manner as autosomes. Like other kinds of monosomies and trisomies, sex chromosome aneuploidies can originate either during the first or second meiotic division (Fig. 17.2)
Dosage compensation increases survival: Because dosage compensation inactivates all but one X chromosome in each cell, aneuploidies that increase or decrease the expected number of X chromosomes have relatively mild effects in humans and other mammals. However, because not all of the genes on the X-chromosome are inactivated, and because germ cells that do not contain the correct number of X-chromosomes tend to degenerate, there are definite syndromes associated with each class of X-chromosome aneuploidy, as described on pages 539 - 540 of the textbook.
Turner syndrome (45, XO): Humans with one X and no Y chromosomes (XO) develop as females who exhibit characteristic features known as Turner syndrome. Their ovaries degenerate and fail to produce the hormones needed for sexual maturation. In addition, they are short in stature and often have thickened and webbed necks and a variety of other characteristic phenotypic traits. However, their intelligence is not affected and they can lead realtively normal lives, particularly when given hormonal therapy to achieve additional growth and sexual maturation. XO females exhibit no Barr bodies because they do not have a second X chromosome to be inactivated.
Kleinfelter syndrome (47, XXY): Humans with two (or more) X chromosomes and one Y chromosome exhibit characteristic features known as Kleinfelter syndrome. They develop as males, but are sterile and often exhibit some female characteristics, such as enlarged breasts. They may also be mildly mentally retarded, particularly in cases where more than two X chromosomes are present. Kleinfelter syndrome is most easily diagnosed by the presence of one or more Barr bodies (one for each extra X chromosome) in a male.
Metafemales (47, XXX): Humans with 3X chromosomes and no Y develop as females who are phenotypically variable, ranging from fully fertile and normal appearing to sterile with amenorrhea and mild mental retardation. The XXX state is sometimes referred to as metafemale and is characterized by the presence of two Barr bodies. (Our textbook stresses normalcy, but others have reported variability in the XXX condition).
XYY males: Humans with one X and two Y chromosomes (47, XYY) develop as normal fertile males, although they are usually taller than average. At one time, it was thought that they had strong criminal tendancies, but further studies have cast serious doubt on the original conclusions. There appears to be a slight excess of XYY males in penal instutions compared to the general population, but the vast majority of XYY men lead normal lives.
Sex-limited traits: These are traits that are not genetically sex-linked, but are only expressed in one sex, mostly because of hormonal controls. The textbook cites antlers on male deer and bright coloration of certain species of male birds as examples of sex-limited traits. It is probably also reasonably safe to cite facial hair in men and breast development in women as human examples of sex-limited traits. Both of these phenomena are under the control of hormones that are relatively gender-specific. However, individuals of both sexes normally express low levels of the hormones associated primarily with the other sex, and cases can be found within the usually accepted range of normalcy where there is some degree of expression of facial hair in women or breast enlargement in men. Thus, one can argue that these traits are actually sex-influenced, rather than strictly sex-limited.
Feather patterns in roosters: Another interesting example of sex-limited traits is the difference in shapes of feathers in hens and roosters (Figure 14.23 and problem 35 at the end of the chapter). Whether or not the males in particular strains of chickens express the pattern known as cock feathering is determined by alleles at an autosomal locus. The pattern that we commonly associate with roosters is actually a recessive autosomal trait (which has obviously been selected by chicken breeders). A rooster with the dominant phenotype exhibits a pattern of feathering that is not different from that of hens. However, the recessive (hh) cock feathering phenotype occurs only in males. Females of the same genotype still express typical hen feathers.
Sex-influenced traits: These traits are expressed to some degree in both sexes, but are differentially affected by sex hormones. Examples include amount of body hair, muscle mass, and male pattern balding. In the case of pattern balding, there is an autosomal gene pair that determines a propensity to the condition. The amount of thinning of the hair or balding that is observed depends both on genotype and the amount of testosterone exposure. Females who are homozygous for the baldness allele tend to develop baldness later in life and to a lesser extent than males. In addition, the baldness allele tends to be dominant in males, such that heterozygous males also become bald, whereas heterozygous females do not.