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Chapter 5. The Chromosomal Basis of Mendelism 1. Chromosome 2. The Chromosome Theory of Heredity 3. Sex-linked Genes in Human Beings 4. Sex Chromosomes and Sex Determination 5. Dosage Compensation of X-linked Genes 1 What causes organisms to develop as males or females? Why are there only two sexual phenotypes? Is the sex of an organism determined by its genes? Male and female Drosophila. The male has white eyes because it carries a mutation on its X chromosome 2 1. Chromosomes Each species has a characteristic set of chromosomes. chromatin The complex of DNA and proteins in eukaryotic chromosomes; originally named because of the readiness with which it stains with certain dyes. euchromatin Genetic material that is not stained so intensely by certain dyes during interphase and that comprises many different kinds of genes. heterochromatin Chromatin staining darkly even during interphase, often containing repetitive DNA with few genes. 3 4 http://www.bu.edu/histology/i/20104loa.jpg Chromosome Number Within a species, the number of chromosomes is almost always an even multiple of a basic number. In human beings, for example, the basic number is 23; mature eggs and sperm have this number of chromosomes. Most other types of human cells have twice as many (46), although a few kinds, such as some liver cells, have four times (92) the basic number. 5 Chromosome Number The haploid, or basic, chromosome number (n) defines a set of chromosomes called the haploid genome. Most somatic cells contain two of each of the chromosomes in this set and are therefore diploid (2n). Cells with four of each chromosome are tetraploid (4n), those with eight of each are octaploid (8n), and so on. 6 The basic number of chromosomes varies among species. Chromosome number is unrelated to the size or biological complexity of an organism, with most species containing between 10 and 40 chromosomes in their genomes The muntjac, a tiny Asian deer, has only three chromosomes in its genome, whereas some species of ferns have many hundreds. 7 The record for minimum number of chromosomes belongs to a subspecies of the ant Myrmecia pilosula, in which females have a single pair of chromosomes. This species reproduces by a process called haplodiploidy, in which fertilized eggs (diploid) become females, while unfertilized eggs (haploid) develop into males. Hence, the males of this group of ants have, in each of their cells, a single chromosome. The record for maximum number of chromosomes is found in the fern family. Ophioglossum reticulatum. This fern has roughly 630 pairs of chromosomes or 1260 chromosomes per cell. The fact that these cells can accurately segregate these enormous numbers of chromosomes during mitosis is truly remarkable. 8 9 Sex chromosome In some animal species such as grasshoppers females have one more chromosome than males. called the X chromosome Females of these species have two X chromosomes, and males have only one (XO). 10 Sex chromosome During meiosis in the male, the solitary X chromosome moves independently of all the other chromosomes and is incorporated into half the sperm; the other half receive no X chromosome. 11 In many other animals, including human beings, males and females have the same number of chromosomes Y is much shorter than the X 12 If fertilization were to occur randomly, approximately half the zygotes would be XX and the other half would be XY, leading to a 1:1 sex ratio at conception However, in human beings, Y-bearing sperm have a fertilization advantage, and the zygotic sex ratio is about 1.3:1. During development, the excess of males is diminished by differential viability of XX and XY embryos, and at birth, males are only slightly more numerous than females (sex ratio 1.07:1). By the age of reproduction, the excess of males is essentially eliminated and the sex ratio is very close to 1:1. 13 Human X and Y chromosomes. The terminal regions are common to both sex chromosomes. The X and Y chromosomes are called sex chromosomes. All the other chromosomes in the genome are called autosomes. 14 2. The Chromosome Theory of Heredity By 1910 many biologists suspected that genes were situated on chromosomes, but they did not have definitive proof. Thomas H. Morgan discovered a particular eye color mutation in the fruit fly reproduced quickly and prolifically and was inexpensive to rear in the laboratory. Only four pairs of chromosome. The X and Y chromosomes were morphologically distinguishable from each other and from each of the autosomes. 15 Experimental evidence linking the inheritance of genes to chromosomes Morgan's experiments commenced with his discovery of a mutant male fly that had white eyes instead of the red eyes of wild-type flies. When this male was crossed to wild-type females, all the progeny had red eyes, indicating that white was recessive to red. When these progeny were intercrossed with each other, Morgan observed a peculiar segregation pattern 16 Experimental evidence linking the inheritance of genes to chromosomes The transmission of the mutant condition in association with sex suggested that the gene for eye color was present on the X chromosome but not on the Y chromosome. 17 Hemizygote : an organism that has only one copy of a gene Morgan carried out additional experiments to confirm the elements of his hypothesis. Cross between a heterozygous female and a hemizygous mutant male. 18 he crossed white-eyed females to red-eyed males. This time, all the daughters had red eyes, and all the sons had white eyes. When he intercrossed these progeny, Morgan observed the expected segregation: half the progeny of each sex had white eyes, and the other half had red eyes. 19 Chromosomes as Arrays of Genes Morgan and his students soon identified other Xlinked genes in Drosophila. In each case, simple breeding experiments demonstrated that recessive mutations of these genes were transmitted along with the X chromosome. Morgan's research group also identified genes that were not on the X chromosome. These genes followed the Mendelian Principle of Segregation, but they did not segregate with sex, as the gene for eye color did. 20 Morgan's students were able to show that genes were indeed situated at different sites, or loci (from the Latin word for “place”; singular; locus), on a linear structure. all genes were located on chromosomes and Mendel's principles could be explained by the transmissional properties of chromosomes during reproduction. This idea, called the Chromosome Theory of Heredity, 21 Nondisjunction as proof of the chromosome theory Bridges performed one of Morgan's experiments on a larger scale. He crossed white-eyed female Drosophila to red-eyed males and examined many F1 progeny. Although as expected, nearly all the F1 flies were either red-eyed females or white-eyed males, Bridges found a few exceptional flies—white-eyed females and red-eyed males. 22 Nondisjunction as proof of the chromosome theory white-eyed females and red-eyed males. The exceptional males all proved to be sterile; however, the exceptional females were fertile 23 Nondisjunction as proof of the chromosome theory Bridges explained these results by proposing that the exceptional F1 flies were the result of abnormal X chromosome behavior during meiosis in the females of the P generation. Ordinarily, the X chromosomes in these females should disjoin, or separate from each other, during meiosis. Occasionally, however, they might fail to separate, producing an egg with two X chromosomes or an egg with no X chromosome at all. 24 Nondisjunction as proof of the chromosome theory nondisjunction Failure of disjunction or separation of homologous chromosomes in mitosis or meiosis, resulting in too many chromosomes in some daughter cells and too few in others. Examples: In meiosis, both members of a pair of chromosomes go to one pole so that the other pole does not receive either of them; in mitosis, both sister chromatids go to the same pole. 25 The chromosomal basis of Mendel’s principles of segregation and independent assortment Mendel established two principles of genetic transmission: (1) the alleles of a gene segregate from each other (2) the alleles of different genes assort independently. The finding that genes are located on chromosomes made it possible to explain these principles (as well as exceptions to them) in terms of the meiotic behavior of chromosomes. 26 The Principle of Segregation 27 The Principle of Independent Assortment 28 The Principle of Independent Assortment 29 3. Sex-Linked Genes in Human Beings • Because males only need to inherit one X chromosome to exhibit an X-linked trait, there are a preponderance of males who are afflicted with recessive sex-linked disorders. Some X-linked diseases are: • Hemophilia characterized by excessive bleeding because of a lack of a critical bloodclotting factor. -female?? • Color blindness caused by faulty red-green perception through red or green color receptors in the retina. 30 Sex-linked gene in human beings Hemophilia, an x-linked blood-clotting disorder 31 Color blindness, an X-linked vision disorder 32 • Mental retardation due to fragile X syndrome, associated with a constriction in the long arm of the X chromosome; this anomaly is caused by a long section of DNA containing repeats of a short nucleotide sequence. 1/2000 33 Genes on the human Y chromosome - 250 genes - more than people expected why? Several of the genes on the human Y chromosome seem to be required for male fertility. Obviously, a mutation in such a gene will interfere with a man's ability to reproduce. By comparison, it has identified more than 1000 genes on the human X chromosome. 34 Genes on both the X and Y chromosomes - mostly near the ends of the short arms - pseudoautosomal genes 35 4. Sex Chromosomes & Sex Determination In the animal kingdom, sex is perhaps the most conspicuous phenotype. Animals with distinct males and females are sexually dimorphic. Sometimes this dimorphism is established by environmental factors. In one species of turtles, for example, sex is determined by temperature. Eggs that have been incubated above 30°C hatch into females, whereas eggs that have been incubated at a lower temperature hatch into males. 36 Sex determination in human beings The discovery that human females are XX and that human males are XY suggested that sex might be determined by the number of X chromosomes or by the presence or absence of a Y chromosome. As we now know, the second hypothesis is correct. In humans and other placental mammals, maleness is due to a dominant effect of the Y chromosome 37 Sex determination in human beings The evidence for this fact comes from the study of individuals with an abnormal number of sex chromosomes. XO animals develop as females, and XXY animals develop as males. The dominant effect of the Y chromosome is manifested early in development, when it directs the primordial gonads to develop into testes. Once the testes have formed, they secrete testosterone, a hormone that stimulates the development of male secondary sexual characteristics. 38 39 Researchers have shown that the testis-determining factor (TDF) is the product of a gene called SRY (for s ex-determining r egion Y ), which is located just outside the pseudoautosomal region in the short arm of the Y chromosome. The discovery of SRY was made possible by the identification of unusual individuals whose sex was inconsistent with their chromosome constitution—XX males and XY females 40 1/20000 41 Testosterone is a hormone that binds to receptors in many kinds of cells. Once bound, the hormone–receptor complex transmits a signal to the nucleus, instructing the cell in how to differentiate. If the testosterone signaling system fails, these characteristics do not appear and the individual develops as a female. One reason for failure is an inability to make the testosterone receptor 42 Testicular feminization 43 Testicular feminization 44 Sex determination in Drosophila The Y chromosome in Drosophila—unlike that in humans—plays no role in sex determination. Instead, the sex of the fly is determined by the ratio of X chromosomes to autosomes. Normal diploid flies have three pairs of autosomes + XX or XY, Three pairs of autosomes: AA A: represents one haploid set of autosomes. Y chromosome for male fertility. 45 Sex determination in Drosophila -the ratio of X’s to A’s: 1.0 ~ greater, female 0.5~1.0, both sexes 0.5 or less, male 46 Sex determination in other animals In both Drosophila and human beings, males produce two kinds of gametes, X-bearing and Y-bearing. For this reason, they are referred to as the heterogametic sex; in these species females are the homogametic sex. In birds, butterflies, and some reptiles, this situation is reversed. Males are homogametic (usually denoted ZZ) and females are heterogametic (ZW). 47 Sex determination in other animals 48 In a haplo-diplo system of sex determination, eggs are produced through meiosis in the queen, and sperm are produced through mitosis in the male. 49 Hermaphrodites Hermaphrodites have both male and female sex organs. Many species of fish are hermaphroditic. Some start out as one sex and then, in response to stimuli in their environment, switch to the other. Other species have both testes and ovaries at the same time (but seldom fertilize themselves). Like those reptiles and fishes whose sex is determined by incubation temperature, hermaphroditic fishes have no sex chromosomes. 50 5. Dosage Compensation of X-Linked Genes Animal development is usually sensitive to an imbalance in the number of genes. Normally, each gene is present in two copies. Departures from this condition, either up or down, can cause abnormal phenotypes, and sometimes even death. Females with two X chromosomes and males with only one. In these species, how is the numerical difference of X-linked genes accommodated? 51 Dosage Compensation of X-Linked Genes three mechanisms may compensate for this difference: (1) each X-linked gene could work twice as hard in males as it does in females, or (2) one copy of each X-linked gene could be inactivated in females, or (3) each X-linked gene could work half as hard in females as it does in males. Extensive research has shown that all three mechanisms are utilized, the first in Drosophila, the second in mammals, and the third in the nematode (see Chapter21) 52 Hyperactivation of X-linked Genes in Male Drosophila In Drosophila, dosage compensation of X-linked genes is achieved by an increase in the activity of these genes in males. This phenomenon, called hyperactivation, involves a complex of different proteins that binds to many sites on the X chromosome in males and triggers a doubling of gene activity When this protein complex does not bind, as is the case in females, hyperactivation of X-linked genes does not occur. In this way, total X-linked gene activity in males and females is approximately equalized. 53 Inactivation of X-linked Genes in Female Mammals In placental mammals, dosage compensation of X-linked genes is achieved by the inactivation of one of the female's X chromosomes the inactivation event occurs when the mouse embryo consists of a few thousand cells. At this time, each cell makes an independent decision to silence one of its X chromosomes. The chromosome to be inactivated is chosen at random; once chosen, however, it remains inactivated in all the descendants of that cell. 54 Thus, female mammals are genetic mosaics containing two types of cell lineages; the maternally inherited X chromosome is inactivated in roughly half of these cells, and the paternally inherited X is inactivated in the other half. A female that is heterozygous for an X-linked gene is therefore able to show two different phenotypes. 55 Inactivation of X-linked Genes in Female Mammals An X chromosome that has been inactivated does not look or act like other chromosomes. Chemical analyses show that its DNA is modified by the addition of numerous methyl groups. In addition, it condenses into a darkly staining structure called a Barr body This structure becomes attached to the inner surface of the nuclear membrane, where it replicates out of step with the other chromosomes in the cell. 56 Inactivation of X-linked Genes in Female Mammals The inactivated X chromosome remains in this altered state in all the somatic tissues. In the germ tissues it is reactivated, perhaps because two copies of some X-linked genes are needed for the successful completion of oogenesis. 57 Mechanism of x chromosome inactivation 58 59 Inactivation of X-linked Genes in Female Mammals Cytological studies have identified human beings with more than two X chromosomes (see Chapter 6). For the most part, these people are phenotypically normal females, apparently because all but one of their X chromosomes is inactivated. Often all the inactivated X's congeal into a single Barr body. These observations suggest that cells may have a limited amount of some factor needed to prevent Xinactivation. Once this factor has been used to keep one X chromosome active, all the others quietly succumb to the 60 inactivation process.