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Chapter 12 Chromosomal Basis of Inheritance (Meiosis) Copyright © 2010 Pearson Education Inc. Meiosis is two successive divisions of a diploid nucleus after only one DNA replication cycle. The result is haploid gametes (animals) or meiospores (plants). The two rounds of division are meiosis I and meiosis II, each with a series of stages Cytokinesis usually accompanies meiosis, producing four haploid cells from a single diploid cell. Meiosis I is when the chromosome information is reduced from diploid to haploid. It has five stages. 1. Prophase I is very similar to prophase of mitosis, except that homologous chromosomes pair and undergo crossingover. ◦ i. Leptonema is when chromosomes begin to coil, committing the cell to the meiotic process. ◦ ii. In zygonema, chromosomes continue to condense, and synapsis, a tight association between homologous chromosomes, occurs. Telomeres are important in synapsis. ◦ iii. Pachynema occurs when synapsis is reached. The fourchromatid synaptonemal tetrad facilitates crossing-over. Crossing-over is reciprocal exchange of chromosome segments between homologous chromosomes. If the homologs are not identical, new gene combinations (recombinant chromosomes) can result, but usually no genetic material is added or lost. ◦ v. Diplonema is the period when chromosomes begin to move apart, and chiasmata (singular is chiasma) become visible. (1) Human oocytes arrest in diplonema in the seventh month of fetal development (2) Preparation for ovulation takes the oocyte through meiosis I. (3) Fertilization causes meiosis II to occur, allowing fusion with the sperm nucleus to form a zygote. ◦ vi.Diakinesis involves chromosomes condensing even more, and at this stage they are most easily counted. Prometaphase I: breakdown of the nucleoli and nuclear envelope and entry of the meiotic spindle into the former nuclear area. Kinetochore microtubules attach to the chromosomes. Metaphase I: has kinetochore microtubules aligning tetrads on the metaphase plate. ◦ Difference from metaphase of mitosis: pairs of homologous chromosomes align together to form tetrads. Anaphase I: tetrads separate, with chromosomes of each homologous pair disjoining. Resulting dyads migrate toward opposite poles. This migration assumes that: ◦ i. Centromeres derived from each parent will migrate randomly toward each pole. ◦ ii. Each pole will receive a haploid complement of replicated centromeres with associated chromosomes. ◦ iii. Sister chromatids will remain attached to each other (the major difference from mitosis). Telophase I has dyads completing migration to the poles, and usually a nuclear envelope forms around each haploid grouping. Cytokinesis follows in most species, forming two haploid cells. Meiosis II is very similar to mitotic division. ◦ a. Prophase II: chromosomes condense and spindle forms. ◦ b. Prometaphase II: nuclear envelopes (if any) break down, spindle organizes with kinetochore microtubules from opposite poles attached to kinetochores of each chromosome. ◦ c. Metaphase II: chromosomes line up on metaphase plate. ◦ d. Anaphase II: centromeres separate, and sister chromatids are pulled to opposite poles. ◦ e. Telophase II: nuclear envelope forms around each set of chromosomes. ◦ f. Cytokinesis usually takes place, and chromosomes become elongated and invisible with light microscopy. After both rounds of meiotic division, four haploid cells (gametes in animals) are usually produced. Each has one chromosome from each homologous pair, but these are not exact copies due to crossing-over. Meiosis has three significant results: a. Haploid cells are produced: b. Alignment of paternally and maternally derived chromosomes is random in metaphase I. ◦ i. The number of possible chromosome ◦ ◦ arrangements at the metaphase I plate is 2n-1 (n is the number of chromosome pairs). ii. The number of possible chromosome combinations in nuclei produced by meiosis is 2n. (23 chromosomes= > 4million combinations) iii. Due to differences between paternally and maternally derived chromosomes, many possibilities exist. Nuclei produced by meiosis will be genetically distinct from parental cells and from one another. c. Crossing-over between maternal and paternal chromatid pairs during meiosis I provides still more variation, making the number of possible progeny nuclei extremely large. In diploid animals, the only haploid cells are gametes produced by meiosis and used in sexual reproduction. Gametes are produced by specialized cells. ◦ i. In males, spermatogenesis produces spermatozoa within the testes. (1) Primordial germ cells (primary spermatogonia) undergo mitosis to produce secondary spermatogonia. (2) Secondary spermatogonia transform into primary spermatocytes (meiocytes), which undergo meiosis I, giving rise to two secondary spermatocytes. (3) Each secondary spermatocyte undergoes meiosis II, producing haploid spermatids that differentiate into spermatozoa. ii. In females, oogenesis produces eggs (oocytes) in the ovary. (1) Primordial germ cells (primary oogonia) undergo mitosis to produce secondary oogonia. (2) Secondary oogonia transform into primary oocytes, which grow until the end of oogenesis. (3) Primary oocytes undergo meiosis I and unequal cytokinesis, producing large secondary oocyte and a small cell called first polar body. (4) The secondary oocyte produces two haploid cells in meiosis II. One very small cell, the second apolar body, the other rapidly matures into an ovum. (5) The first polar body may or may not divide during meiosis I. Polar bodies have no, so a round of meiosis produces only one viable gamete, the ovum. Human oocytes form in the fetus, completing meiosis only after fertilization. Sexually reproducing plants typically have two phases: gametophyte (haploid), in which gametes are produced, and sporophyte (diploid), in which meiosis produces haploid spores. ◦ i. Angiosperms (flowering plants) contain stamens (male) and pistils (female) in either the same or different flowers. (1) Stamens consist of a stalk (filament) and anther. Pollen grains are immature gametophytes (gamete-producing structures). (2) The pistil consists of a stigma (the surface to which pollen sticks); a style, down which the pollen tube grows; and an ovary at the base that contains the ovules. Each ovule contains a female gametophyte (embryo sac) with a single egg cell. After fertilization, the ovule develops into a seed. ii. Plants are unique among living organisms in producing gametes from gametophytes. The two distinct reproductive phases are called alternation of generations, with meiosis and fertilization the transition points between stages. ◦ (1) Meiosis creates haploid spores that produce the haploid gametophyte generation. In angiosperms, the spores become the pollen and embryo sac that are used in fertilization. ◦ (2) Fertilization begins the diploid sporophyte generation, producing a plant that will ultimately make spores by meiosis, completing the cycle. Chromosome number is constant in all cells of a species but varies widely between species. The chromosome theory of inheritance states that Mendelian factors (genes) are located on chromosomes. Behavior of sex chromosomes offers support for the chromosomal theory. In many animals sex chromosome composition relates to sex, while autosomes are constant. McClung, Stevens, and Wilson indicated that chromosomes are different in male and female insects. ◦ a. Stevens named the extra chromosome found in females “X.” ◦ b. In grasshoppers, all eggs have an X; and half of the sperm produced have an X, and the other half do not. After fertilization, an unpaired X produces a male, while paired X chromosomes produce a female. Other insects have a partner for the X chromosome. Stevens named it “Y.” In mealworms, for example, XX individuals are female, and XY are male. In both humans and fruit flies (Drosophila melanogaster) females have two X chromosomes, while males have X and Y. ◦ a. Males produce two kinds of gametes with respect to sex chromosomes (X or Y) heterogametic sex. ◦ b. Females produce gametes with only one kind of sex chromosome (X) homogametic sex. ◦ c. In some species the situation is reversed, with heterogametic females and homogametic males. Random fusion of gametes produces an F1 that is 1⁄2 female (XX) and 1⁄2 male (XY). Morgan (1910) found a mutant whiteeyed male fly and used it in experiments that showed a gene for eye color located on the X chromosome. ◦ a. First cross the white-eyed male with a wild-type (red-eyed) female. All F1 flies are red eyes. The white-eyed trait is recessive. ◦ b. Next, F1 were interbred. They produced an F2 with: i. 3,470 red-eyed flies. ii. 782 white-eyed flies. ◦ c. The recessive number is too small to fit Mendelian ratios (the explanation, discovered later, is that white-eyed flies have lower viability). ◦ d. All of the F2 white-eyed flies were male. This eye color gene is located on the X chromosome. ◦ i. Males are hemizygous, no homologous gene on the Y. Mutant male’s genotype was w/Y (hemizygous with the recessive allele). ◦ ii. Females may be homozygous or heterozygous. The wild-type female in the original cross was w+/w+ (homozygous for red eyes). ◦ iii. The F1 flies w+/w (females), w+/Y (males) (females all heterozygous, males hemizygous dominant). ◦ iv. The F2 data complete a crisscross inheritance pattern, with transmission from the mutant fly through his daughter (who is heterozygous) to his grandson. The F2 were: 1 w+/w+; 1 w/w+; 1w+/Y; 1 w/Y. Confirmed by an experiment reciprocal to the original cross. A white-eyed female (w/w) was crossed with a wildtype male (w+/Y). Results of the reciprocal cross: ◦ (1) All F1 females had red eyes (w+/w). ◦ (2) All F1 males had white eyes (w/Y). These F1 results are different from those in the original cross, where all the F1 had red eyes. When the F1 from the reciprocal cross interbred, the F2 were: 1/4 w+/w; 1/4 w+/Y; 1/4 w/w; 1/4 w/Y Morgan’s discovery of X-linked inheritance showed that when results of reciprocal crosses are different, and ratios differ between progeny of different sexes, the gene involved is likely to be X-linked (sex-linked). This was strong evidence that genes are located on chromosomes. Morgan received the 1933 Nobel Prize for Physiology or Medicine for this work. Bridges, found that about 1 in 2,000 of the offspring was an exception from the crossing a white-eyed female (w/w) with a red-eyed male (w+/Y) that produces an F1 of whiteeyed males (w/Y) and red-eyed females (w+/w). Either a white-eyed female or red-eyed male. Bridges’s hypothesis was that chromatids failed to separate normally during anaphase of meiosis I or II, resulting in nondisjunction. Nondisjunction can involve either autosomes or sex chromosomes. For the eye color trait, X chromosome nondisjunction was the relevant event. Nondisjunction in an individual with a normal set of chromosomes is called primary nondisjunction. Nondisjunction, a rare event, in a w/w female would result in eggs with two X chromosomes (XX) and those with none (O). If these are fertilized with normal sperm from a wild-type male (w+/Y), the results are: ◦ i. YO, which die due to lack of an X chromosome. ◦ ii. XXX, which die, presumably due to the extra dose of X genes. ◦ iii. Red-eyed Xw+O sterile males who received Xw+ from the father and no sex chromosome from the mother. ◦ iv. White-eyed XwXwY females that received two Xw chromosomes from the mother and Y from the father. Bridges crossed the white-eyed female (XwXwY) with wild-type males (Xw+Y). The progeny were: ◦ i. XwXw+ and XwXw+Y females with red eyes, which received the Xw+ chromosome from the father, and Xw or XwY from the mother. ◦ ii. Rarely, males with red eyes. ◦ iii. Rarely, females with white eyes. Secondary nondisjunction had occurred, producing eggs with either XwXw or Y. Secondary nondisjunction had occurred, producing eggs with either XwXw or Y. When these eggs are fertilized by normal sperm, XXX and YY won’t survive, but an XwXw egg united with a Y-bearing sperm becomes a white-eyed female, while a Y-bearing egg united with an Xw+-bearing sperm produces a red-eyed male. The odd inheritance pattern matches specific aneuploid types (XO and XXY), clearly associating a specific phenotype with a specific chromosome complement. Thus, gene segregation mirrors chromosome behavior in meiosis. Mendel’s principles of segregation and independent assortment of genes correlate with the movement of chromosomes during meiosis. Some mechanisms of sex determination include: ◦ a. Genotypic sex determination, in which sex is governed by genotype. ◦ b.Genic sex determination, in which sex chromosomes are not involved. Sex Determination in Mammals ◦ Mammals use the Y-chromosome mechanism of sex-determination, in which the Y chromosome determines sex by conferring maleness. ◦ Sex of mammals is determined by a gene on the Y chromosome, testis-determining factor. In the absence of this gene, gonads develop into ovaries. ◦ XO individuals, sterile females exhibiting Turner syndrome. Most XO fetuses die before birth. Surviving Turner syndrome individuals become noticeable at puberty, when secondary sexual characteristics fail to develop and: i. Below-average height. ii. Weblike necks. iii. Poorly developed breasts. iv. Immature internal sexual organs. v. Reduced ability to interpret spatial relationships. XXY individuals, who are male and have Klinefelter syndrome Other traits include: ◦ i. Above-average height. ◦ ii. Breast development in about 50% of XXY individuals. ◦ Iii. Subnormal intelligence in some cases. Gene dosage varies between the sexes in mammals. Females have two copies of X while males have one. Early in development, gene expression from the X chromosome must be equalized to avoid death. Different dosage compensation systems have evolved in different organisms. Female somatic cell nuclei contain a Barr body (highly condensed chromatin) while male nuclei do not. The Lyon hypothesis explains the phenomenon: ◦ a. A Barr body is a condensed and (mostly) inactivated X chromosome. Lyonization of one chromosome leaves one transcriptionally active X, equalizing gene dose between the sexes. ◦ b. An X is randomly chosen in each cell for inactivation early in development (in humans, day 16 postfertilization). ◦ c. Descendants of that cell will have the same X inactivated, making female mammals genetic mosaics. Examples are: i. Calico cats, in which differing descendant cells produce patches of different color on the animal. ii. Women heterozygous for an X-linked allele responsible for sweat glands; these women have a mosaic of normal skin and patches lacking sweat glands (anhidrotic ectodermal displasia). Lyonization allows extra sex chromosomes to be tolerated well. No such mechanism exists for autosomes and so an extra autosome is usually lethal. The number of Barr bodies is the number of X chromosomes minus one. X inactivation involves three steps: ◦ i. Chromosome counting (determining number of Xs in the cell). ◦ ii. Selection of an X for inactivation. ◦ iii. Inactivation itself. Selection of an X for inactivation is made by the Xcontrolling element (Xce) in the Xic region. There are different alleles of Xce, and each allele has a different probability that the X chromosome carrying it will be inactivated. ◦ i. The gene Xist is required for X inactivation. Uniquely, it is expressed from the inactive X. ◦ ii. The Xist gene transcript is 17 kb. Although it has no ORFs, it receives splicing and a poly(A) tail. ◦ iii. During X inactivation, this RNA coats the chromosome to be inactivated and silences most of its genes. ◦ iv. Inactivation itself is not well understood, but it is known that it is initiated at the Xic and moves in both directions, ultimately resulting in heterochromatin. An X chromosome–autosome balance system is used. Sex is determined by the ratio between the number of X chromosomes and the number of sets of autosomes. Drosophila has three pairs of autosomes and one pair of sex chromosomes. Like humans, XX is female and XY is male. Unlike humans, Y does not determine sex, but it is required for male fertility. An XXY fly is female, and an XO fly is male. The sex of the fly results from the ratio of the number of X chromosomes (X) to the number of sets of autosomes (A): ◦ i. In a normal (diploid) female Drosophila, A=2 and X=2. The X:A ratio is 1.0. ◦ ii. In a normal (diploid) male Drosophila, A=2 and X=1. The X:A ratio is 0.5. ◦ iii. In cases of aneuploidy (abnormal chromosome numbers): (1) When the X:A ratio is ≥1.0, the fly is female. (2) When the X:A ratio is =0.5, the fly is male. (3) A ratio between 0.5 and 1.0 results in a sterile intersex fly with mixed male and female traits. Dosage compensation in Drosophila results in more expression of X-linked genes in males, so the level of transcription equals that from a female’s two X chromosomes Sex chromosome composition in birds, butterflies, moths, and some fish is opposite that of mammals, with the male the homogametic sex (ZZ) and the female heterogametic (ZW). ◦ a. Z-linked genes behave like X-linked genes in mammals, but the sexes are reversed. ◦ b. The genes on the Z and W chromosomes are very different from those on X and Y, indicating that these sex chromosomes evolved independently, from different pairs of autosomes. In plants, the arrangement of sex organs varies: ◦ a. Dioecious species (e.g., ginkgo) have plants of separate sexes, one with male parts, the other with female. ◦ b. Monoecious species have male and female parts on the same plant. i. Perfect flowers (e.g., rose, buttercup) have both types of parts in the same flower. ii. Imperfect flowers (e.g., corn) have male and female parts in different flowers on the same plant. Some dioecious plants have sex chromosomes and use an X chromosome–autosome balance system, but many other sex determination systems also occur in dioecious plants. Other eukaryotes use a genic system instead of entire sex chromosomes. A single allele determines the mating type (e.g., MATa and MATα in Saccharomyces cerevisiae). Yeast mating types have identical morphologies, but are able to fertilize gametes only from the opposite mating type. X-linked traits, like autosomal ones, can be analyzed using pedigrees. Human pedigree analysis, however, is complicated by several factors: ◦ a. Data collection often relies on family recollections. ◦ b.If the trait is rare and the family small, there may not be enough affected individuals to establish a mechanism of inheritance. ◦ c. Expression of the trait may vary, resulting in affected individuals being classified as normal. ◦ d.More than one mutation may result in the same phenotype, and comparison of different pedigrees may show different inheritance for the “same” trait. Human traits involving recessive alleles on the X chromosome are Xlinked recessive traits. A famous example is hemophilia A among Queen Victoria’s descendants. X-linked recessive traits occur much more frequently among males, who are hemizygous. A female would express a recessive X-linked trait only if she were homozygous recessive at that locus. Affected fathers transmit the recessive allele to all daughters (who are therefore carriers) and to none of their sons. Father-to-son transmission of X-linked alleles generally does not occur. Many more males than females exhibit the trait. All sons of affected (homozygous recessive) mothers are expected to show the trait. With a carrier mother, about 1⁄2 of her sons will show the trait and 1⁄2 will be free of the allele. A carrier female crossed with a normal male will have 1⁄2 carrier and 1⁄2 normal daughters. Only a few X-linked dominants are known. ◦ a. Hereditary enamel hypoplasia. ◦ b. Webbing to the tips of the toes. ◦ c. Constitutional thrombopathy (severe bleeding due to lack of blood platelets). Patterns of inheritance are the same as X-linked recessives, except that heterozygous females show the trait (although often in a milder form). Y-linked (holandric) traits, except for maleness itself (resulting from SRY on the Y chromosome), have not been confirmed, but many genes on the Y chromosome have been identified. The hairy ears trait may be Y linked, but it is a complex phenotype that might also be the result of autosomal gene(s) and/or effects of testosterone.