Peter J. Russell A molecular Approach 2 nd Edition

CHAPTER 12 Chromosomal Basis of Inheritance, Sex Linkage, and Sex Determination

edited by Yue-Wen Wang Ph. D.

Dept. of Agronomy, NTU 台大農藝系 遺傳學 601 20000 Chapter 11 slide 1

Chromosomes and Cellular Reproduction

1. Cytology and genetics together were used to determine the association of genes and chromosomes.

2. Eukaryotic chromosomes are transmitted during cell division by mitosis and during reproduction by meiosis.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 2

Eukaryotic Chromosomes

1. Eukaryotes have multiple linear chromosomes in a number characteristic of the species. Most have two versions of each chromosome, and so are diploid (2N).

a. Diploid cells are produced by haploid (N) gametes that fuse to form a zygote. The zygote then undergoes development, forming a new individual.

b. Examples of diploid organisms are humans (23 pairs) and

Drosophila melanogaster

(4 pairs). The yeast

Saccharomyces cerevisiae

is haploid (16 chromosomes).

台大農藝系 遺傳學 601 20000 Chapter 11 slide 3

Eukaryotic Chromosomes

2. Chromosome pairs in diploid organisms are homologous chromosomes. One member of each pair (homolog) is inherited from each parent. Chromosomes that have different genes and do not pair are nonhomologous chromosomes (Figure 12.1).

台大農藝系 遺傳學 601 20000 Chapter 11 slide 4

Eukaryotic Chromosomes

3. Animals and some plants have male and female cells with distinct chromosome sets, due to sex chromosomes. One sex has a matched pair (e.g., human females with XX) and the other has an unmatched pair (human male with XY). Autosomes are chromosomes other than sex chromosomes.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 5

Eukaryotic Chromosomes

4. Chromosomes differ in size and morphology. Each has a constriction called a centromere that is used in segregation during mitosis and meiosis. The centromere location is useful for identifying chromosomes (Figure 12.2).

台大農藝系 遺傳學 601 20000 Chapter 11 slide 6

Eukaryotic Chromosomes

a. Metacentric means the centromere is approximately in the center of the chromosome, producing two equal arms.

b. Submetacentric means one arm is somewhat longer than the other.

c. Acrocentric chromosomes have one long arm and a short stalk and often a bulb (satellite) as the other arm.

d. Telocentric chromosomes have only one arm, because the centromere is at the end.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 7

Eukaryotic Chromosomes

5. A karyotype shows the complete set of chromosomes in a cell. Metaphase chromosomes are used because they are easiest to see under the microscope after staining. The karyotype is species-specific.

a. The karyotype for a normal human male has 22 pairs of autosomes, and 1 each of X and Y (Figure 12.3).

b. Human chromosomes are numbered from largest (1) to smallest (although 21 is actually smaller than 22).

c. Human chromosomes with similar morphologies are grouped (A through G).

台大農藝系 遺傳學 601 20000 Chapter 11 slide 8

台大農藝系 遺傳學 601 20000 Chapter 11 slide 9

Eukaryotic Chromosomes

d. Staining produces bands on the chromosomes, allowing easier identification. G banding is an example.

i. Chromosomes are partially digested with proteolytic enzymes or treated with mild heat, and then stained with Giemsa stain. The dark bands produced are G bands.

ii. In humans, metaphase chromosomes show about 300 G bands, while about 2,000 can be distinguished in prophase.

iii. Drawings (ideograms) show the G banding pattern of human chromosomes.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 10

Eukaryotic Chromosomes

iv. Standard nomenclature is used to reference specific regions of the chromosomes.

(1) The two arms are separated by the centromere, with the smaller one designated p and the larger q.

(2) Regions and subregions are numbered from the centromere outward (1 is closest).

(3) An example is the BRCA1 (breast cancer susceptibility) gene at 17q21 (long arm of chromosome 17 in region 21).

(4) If a gene spans subregions, both are given. For example, the human cystic fibrosis gene is at 7q31.2-q31.3, spanning both subregions 2 and 3 on the long arm of chromosome 7.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 11

Mitosis

• Mitosis animation 台大農藝系 遺傳學 601 20000 Chapter 11 slide 12

Mitosis

1. Both unicellular and multicellular eukaryotes show a cell cycle, with growth, mitosis and cell division

.

a. The cycle of somatic cells consists of: i. Mitosis.

ii. Interphase, composed of: (1) Gap 1 (G1) when the cell prepares for chromosome replication.

(2) Synthesis (S) when DNA replicates and new chromosomes are formed.

(3) Gap 2 (G2) when the cell prepares for mitosis and cell division.

b. Relative time in each phase varies among cell types, with duration of G1 generally the deciding factor. Some cells exit G1 and enter a nondividing state called G0.

c. Interphase chromosomes are elongated and hard to see with light microscopy. Sister chromatids are held together by replicated but unseparated centromeres. The chromatids become visible in prophase and metaphase of mitosis. When the centromeres separate, they become daughter chromosomes.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 13

Mitosis

2. Mitosis is a continuous process, but geneticists divide it into 4 cytologically distinguishable stages (Figures 12.5 and 12.6): 台大農藝系 遺傳學 601 20000 Chapter 11 slide 14

台大農藝系 遺傳學 601 20000 Chapter 11 slide 15

台大農藝系 遺傳學 601 20000 Chapter 11 slide 16

Prophase

is characterized by chromosomes condensing to a form visible by light microscopy.

i. The mitotic spindle, composed of microtubules made of tubulins, begins to form.

ii. In animal cells, the centrioles replicate and become the focus for the aster (radial array of microtubules). During prophase, asters move from near each other and the nuclear envelope to the poles of the cell, spanned by the mitotic spindle.

iii. The nucleoli in the nucleus cease to be discrete areas.

iv. The nuclear envelope breaks down.

v. Kinetochores form on the centromeres and become attached to kinetochore microtubules.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 17

Metaphase

begins when the nuclear envelope has completely disappeared.

i. The kinetochore microtubules orient the chromosomes with their centromeres in a plane between the spindle poles, the metaphase plate.

ii. A protein scaffold causes the chromosomes to reach a highly condensed state (Figure 12.17).

台大農藝系 遺傳學 601 20000 Chapter 11 slide 18

Anaphase

begins when the centromeres of the sister chromatids separate.

i. The chromatids separate (disjunction) and daughter chromosomes move toward opposite poles by kinetochore microtubules.

ii. Shape of the chromosomes moving toward the poles is defined by their centromere locations.

iii. Cytokinesis usually begins near the end of anaphase.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 19

Telophase

is when migration of daughter chromosomes is completed.

i. Chromosomes begin to uncoil and form interphase chromosomes.

ii. Nuclear envelope forms around each chromosome group.

iii. Spindle microtubules disappear.

iv. Nucleoli reform.

v. Nuclear division is complete.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 20

Cytokinesis

Cytokinesis is division of the cytoplasm, compartmentalizing the new nuclei into separate daughter cells (Figure 12.18).

a. In animal cells, cytokinesis begins with a constriction in the center of the cell, which develops until two new cells are produced.

b. Most plant cells form a cell plate (membrane and wall) between the two nuclei, resulting in two progeny cells

Mitosis

Gene segregation in mitosis is highly ordered, so that each new cell receives a complete set of chromosomes (pairs in a diploid cell, and one of each type in a haploid cell).

台大農藝系 遺傳學 601 20000 Chapter 11 slide 22

Meiosis

Meiosis animation 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 in meiosis are meiosis I and meiosis II, each with a series of stages(Figure 12.9). Cytokinesis usually accompanies meiosis, producing four haploid cells from a single diploid cell.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 23

台大農藝系 遺傳學 601 20000 Chapter 11 slide 24

Meiosis I

is when the chromosome information is reduced from diploid to haploid. It has four stages: Prophase I Leptonema Zygonema Pachynema Diplonema diakinesis Metaphase I Anaphase I Telophase I 台大農藝系 遺傳學 601 20000 Chapter 11 slide 25

Meiosis I Prophase I - leptonema

Prophase I is very similar to prophase of mitosis, except that homologous chromosomes pair and undergo crossing-over.

i. Leptonema is when chromosomes begin to coil, committing the cell to the meiotic process. Homologous chromosomes pair during the leptomene stage.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 26

Meiosis I Prophase I - zygonema

ii. 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.

iii. In zygonema, synapsis occurs. Synapsis is a tight association between homologous chromosomes. The synaptonemal complex consists of a tetrad of the four chromatids at maximum condensation.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 27

Meiosis I Prophase I - pachynema

iv. Pachynema follows, when the synaptonemal complex is disassembled and chromosomes start to elongate.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 28

Meiosis I Prophase I - diplonema

v. Diplonema is when chromosomes begin to move apart, and chiasmata (singular is chiasma) formed by crossing-over become visible (Figure 12.10).

(1) Human oocytes arrest in diplonema in the 7th month of fetal development, and remain there until an oocyte is activated to prepare for ovulation.

(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.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 29

Meiosis I Prophase I - diakinesis

vi. Diakinesis involves breakdown of the nucleoli and nuclear envelope, and assembly of the spindle. This is the phase where chromosomes are most easily counted.

vii. Sex chromosomes are not homologous, but behave as if they were due to a pseudoautosomal region shared between X and Y.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 30

Meiosis I metaphase I, anaphase I, telophase I

b. Metaphase I starts with the nuclear envelope completely broken down, bivalents (pairs of homologs) aligned at the equatorial plane, the spindle completely formed, and microtubules attached to kinetochores. It is distinguishable from metaphase of mitosis because independent alignment of homologous chromosomes does not occur.

c. Anaphase I is when bivalents separate, with chromosomes of each homologous pair disjoining. Resulting dyads migrate toward opposite poles, where new nuclei will form. 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).

d. Telophase I has dyads completing migration to the poles, and usually formation of a nuclear envelope around each haploid grouping. Cytokinesis follows in most species, forming two haploid cells.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 31

Meiosis II

is very similar to mitotic division.

a. Prophase II involves chromosome condensation.

b. Metaphase II includes spindle formation, with centromeres lining up on the equator.

c. Anaphase II involves splitting of the centromeres, with chromosomes pulled to opposite poles.

d. Telophase II takes place as a nuclear envelope forms around each set of chromosomes.

e. Cytokinesis usually takes place, and chromosomes become elongated and invisible with light microscopy.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 32

Meiosis v.s. mitosis

4. 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. Figure 12.11 compares mitosis and meiosis.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 33

Meiosis has three significant results

a. Haploid cells are produced because two rounds of division follow only one round of chromosome replication. Fusion of haploid cells restores the diploid number, maintaining a constant chromosome number through generations in sexually reproducing organisms.

b. Alignment of paternally and maternally derived chromosomes is random in metaphase I, resulting in random combinations of chromosomes in each nucleus generated (Figure 12.12).

i. The number of possible chromosome arrangements at the meiosis I metaphase plate is 2 n-1 (n is the number of chromosome pairs).

ii. The number of possible chromosome combinations in nuclei produced by meiosis is 2n.

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.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 34

Meiosis in animals and plants is somewhat distinct - animal

a. In diploid animals, the only haploid cells are gametes produced by meiosis and used in sexual reproduction. Gametes are produced by specialized cells (Figure 1.26).

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 a large secondary oocyte, and a small cell called the first polar body.

(4) The secondary oocyte produces two haploid cells in meiosis II. One is a very small cell, the second polar body, and the other rapidly matures into an ovum.

(5) The first polar body may or may not divide during meiosis I. Polar bodies have no function in most species and degenerate, so that a round of meiosis produces only one fertilization.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 35

Meiosis in animals and plants is somewhat distinct - plant

b. 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, which releases pollen grains. Pollen grains are immature gametophytes (gamete-producing structures).

(2) The pistil contains female gametophytes, and consists of a stigma (the surface to which pollen sticks), a style, down which the pollen tube grows, and an ovary at the base which 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 (Figure 12.15).

(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.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 36

Chromosome Theory of Inheritance

1. By the beginning of the 20 th century, cytologists had observed that chromosome number is constant in all cells of a species, but varies widely between species.

2. Sutton and Boveri (1902) independently realized the parallel between Mendelian inheritance and chromosome transmission, and proposed the chromosome theory of inheritance, which states that Mendelian factors (genes) are located on chromosomes.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 37

Sex Chromosomes

1. Behavior of sex chromosomes offers support for the chromosomal theory. In many animals sex chromosome composition relates to sex, while autosomes are constant.

2. Independent work of 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.

3. 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.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 38

4. In both humans and fruit flies (

Drosophila melanogaster

) females have two X chromosomes, while males have X and Y (Figure 12.16).

a. Males produce two kinds of gametes with respect to sex chromosomes (X or Y), and are called the heterogametic sex.

b. Females produce gametes with only one kind of sex chromosome (X) and are called the homogametic sex.

c. In some species the situation is reversed, with heterogametic females and homogametic males.

5. Random fusion of gametes (Figure 12.17) produces an F1 that is 1⁄2 female (XX) and 1⁄2 male (XY).

台大農藝系 遺傳學 601 20000 Chapter 11 slide 39

Fig. 12.16 Drosophila melanogaster (fruit fly), an organism used extensively in genetics experiments Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 40

Fig. 11.17 Inheritance pattern of X and Y chromosomes in organisms where the female is XX and the male is XY: Production of the F 1 generation Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 41

Sex Linkage

Animation: X-Linked Inheritance 1. Morgan (1910) found a mutant white-eyed male fly, and used it in a series of experiments that showed a gene for eye color located on the X chromosome.

a. First, he crossed the white-eyed male with a wild-type (red-eyed) female. All F 1 is recessive.

flies had red eyes. Therefore, the white-eyed trait b. Next, F 1 were interbred. They produced an F 2 with: i. 3,470 red-eyed flies.

ii. 782 white-eyed flies.

c. The recessive number is too small to fit Mendelian ratios (explanation discovered later is that white-eyed flies have lower viability).

d. All of the F 2 white-eyed flies were male.

e. Cross is diagramed in Figure 12.18, and Drosophila symbolism is explained in Box 12.1.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 42

Fig. 12.18 X-linked inheritance of white eyes in Drosophila: Red-eyed female  white-eyed male Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 43

f.

Morgan’s hypothesis was that this eye color gene is located on the X chromosome. If so, i. Males are hemizygous, because there is no homologous gene on the Y. The original 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 F 1 flies were w + /w (females) and w + /Y (males) (females all heterozygous, males hemizygous dominant).

iv. The F 2 data complete a crisscross inheritance pattern, with transmission from the mutant fly through his daughter (who is heterozygous) to his grandson. The F 2 were: w + Y w + w w + / w + Red-eyed females w + / w Red-eyed females w + / Y Red-eyed males w/ Y 601 20000 Chapter 11 slide 44

v. Morgan’s hypothesis was confirmed by an experiment reciprocal to the original cross(Figure 12.19). A white eyed female (w/w) was crossed with a wild-type male (w + /Y). Results of the reciprocal cross: (1) All F 1 females had red eyes (w + /w).

(2) All F 1 males had white eyes (w/Y).

vi. These F 1 results are different from those in the original cross, where all the F 1 had red eyes. When the F 1 from the reciprocal cross interbred, the F 2 were: w + w w w + / w Red-eyed females w/ w White-eyed females Y w + / Y Red-eyed males w/ Y White-eyed males 台大農藝系 遺傳學 601 20000 Chapter 11 slide 45

Fig. 12.19a Reciprocal cross of that shown in Figure 11.3: Homozygous white-eyed female  red-eyed ( wild-type) male Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 46

Fig. 12.19b Reciprocal cross of that shown in Figure 11.3: The F 1 produce the F 2 s flies are interbred to Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 47

2.

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).

3.This was strong evidence that genes are located on chromosomes. Morgan received the 1933 Nobel Prize for Physiology or Medicine for this work.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 48

Non-Disjunction of X Chromosomes

Animation: Non-disjunction 1.

Morgan’s work showed that crossing a white-eyed female (w/w) with a red-eyed male (w + /Y) produces an F 1 of white-eyed males (w/Y) and red-eyed females (w + /w). His student, Bridges, found that about 1 in 2,000 of the offspring was an exception, either a white-eyed female or red-eyed male.

2.

Bridges’ hypothesis was that chromatids failed to separate normally during anaphase of meiosis I or II, resulting in non disjunction.

3. Non-disjunction can involve either autosomes or sex chromosomes. For the eye-color trait, X chromosome non disjunction was the relevant event. Non-disjunction in an individual with a normal set of chromosomes is called primary non-disjunction (Figure 12.20).

台大農藝系 遺傳學 601 20000 Chapter 11 slide 49

Fig. 12.20 Nondisjunction in meiosis involving the X chromosome Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 50

4. Non disjunction explains Bridges’ findings: a. Non-disjunction, a rare event, in a w/w female would result in eggs with two X chromosomes (XX), and those with none (O) (Figure 12.21).

b. 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 X w+ O sterile males who received X w+ from the father and no sex chromosome from the mother.

iv. White-eyed X w X w Y females that received 2 X w chromosomes from the mother and Y from the father.

c. Chromosomes of the exceptional flies matched the prediction: white-eyed females were XXY, and red-eyed males XO. They show aneuploidy, meaning that 1 or more chromosomes of a normal set are missing or present in unusual number.

d. Bridges crossed the white-eyed female (X w X w Y) with wild-type males (X w+ Y). The progeny were: i. X w X w+ and X w X w+ Y females with red eyes, that received the X w+ from the father, and X w or X w Y from the mother.

chromosome ii. Rarely, males with red eyes.

iii. Rarely, females with white eyes.

e. He proposed that secondary non-disjunction had occurred, producing eggs with either X w X w or Y(Figure 12.22). When these eggs are fertilized by normal sperm, XXX and YY won’t survive, but an X w X w egg united with a Y-bearing sperm becomes a white eyed female, while a Y-bearing egg united with an X w+ -bearing sperm produces a red 台大農藝系 遺傳學 601 20000 Chapter 11 slide 51 eyed male.

Fig. 12.22 a Rare primary nondisjunction during meiosis in a white-eyed female Drosophila and results of a cross with a normal red-eyed male Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 52

Fig. 12.22b Results of a cross between the exceptional white-eyed XXY female of Figure 12.22a with a normal red-eyed XY male Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 53

5.The odd inheritance pattern matches specific aneuploid types (XO and XXY), clearly associating a specific phenotype with a specific chromosome complement.

6.Thus, gene segregation mirrors chromosome behavior in meiosis(Figure 12.23). Mendel’s principles of segregation and independent assortment of genes correlate with the movement of chromosomes during meiosis.

Animation: Gene and Chromosome Segregation in Meiosis 台大農藝系 遺傳學 601 20000 Chapter 11 slide 54

Fig. 12.23 The parallel behavior between Mendelian genes and chromosomes in meiosis Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 55

Sex Determination

1. Some mechanisms of sex determination include: a.

b.

Genotypic sex determination, in which sex is governed by genotype.

Genic sex determination, in which sex chromosomes are not involved.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 56

Genotypic Sex Determination Systems

1. Genotypic sex determination may occur two different ways: a. In the Y-chromosome mechanism of sex-determination (e.g., in mammals), the Y chromosome determines sex, conferring maleness.

b. In the X chromosome-autosome balance system (e.g.,

Drosophila, Caenorhabditis elegans

) the ratio between number of X chromosomes and number of sets of autosomes determines sex. Y is required for male fertility, but does not determine sex.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 57

Sex Determination in Mammals

1. Mammals use the Y-chromosome mechanism of sex-determination, in which the Y chromosome determines sex by conferring maleness.

2. 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.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 58

Evidence for the Y Chromosome Mechanism of 1.

Sex Determination Understanding of the Y chromosome mechanism of sex determination came from the study of individuals with unusual chromosome complements. In humans these aneuploidies include: a. XO individuals, who are 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. Other traits include: i. Below average height.

ii. Weblike necks.

iii. Poorly developed breasts.

iv. Immature internal sexual organs.

v. Reduced ability to interpret spatial relationships.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 59

b.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.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 60

c. XYY individuals are male, and tend to be taller than average. Fertility is sometimes affected.

d. XXX individuals are usually normal women, although they may be slightly less fertile and a few have below average intelligence.

e. Higher numbers of X and/or Y chromosomes are sometimes found, including XXXY, XXXXY, and XXYY. The effects are similar to Klinefelter syndrome. Consequences of sex chromosome aneuploidy in humans are summarized in Table 12.2.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 61

Dosage Compensation Mechanism for X Linked Genes in Mammals

1. Gene dosage varies between the sexes in mammals, because 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.

2. In mammals, female somatic cell nuclei contain a Barr body (highly condensed chromatin) while male nuclei do not(Figure 12.26). The Lyon hypothesis explains the phenomenon: 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).

台大農藝系 遺傳學 601 20000 Chapter 11 slide 62

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 (Figure 12.27).

ii. Women heterozygous for an X-linked allele responsible for sweat glands, who have a mosaic of normal skin and patches lacking sweat glands (anhidrotic ectodermal displasia).

d. Lyonization allows extra sex chromosomes to be tolerated well. No such mechanism exists for autosomes, and so an extra autosome is usually lethal.

e. The number of Barr bodies is the number of X chromosomes minus one (Table 12.2).

台大農藝系 遺傳學 601 20000 Chapter 11 slide 63

f.

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.

g. Counting the chromosomes involves the X-inactivation center (

XIC

in humans, mice). Experiments in transgenic mice show that:

Xic

in i. Inactivation requires the presence of at least two chromosome.

Xic

sequences, one on each X ii. Autosomes with an

Xic

inserted are randomly inactivated, showing that

Xic

sufficient for chromosome counting and initiation of lyonization.

is h. Selection of an X for inactivation is made by the X-controlling 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.

i. The

Xist

gene transcript is 17-kb. Although it has no ORFs, it receives splicing and a poly(A) tail.

ii. During X inactivation, this RNA coats the chromosome to be inactivated and silences most of its genes.

iii. Inactivation itself is not well understood, but it is known that it initiates at the

Xic

and moves in both directions, ultimately resulting in heterochromatin.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 64

Sex Determination in

Drosophila

1. An X-chromosome-autosome balance system is used.

2. 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.

3. 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): a. In a normal (diploid) female Drosophila, A=2 and X=2. The X:A ratio is 1.0.

b. In a normal (diploid) male Drosophila, A=2 and X=1. The X:A ratio is 0.5.

c. In cases of aneuploidy (abnormal chromosome numbers): i. When the X:A ratio is ≧ 1.0, the fly is female.

ii. When the X:A ratio is ≦ 0.5, the fly is male.

iii. A ratio between 0.5 and 1.0 results in a sterile intersex fly with mixed male and female traits.

4. 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.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 65

Sex Determination in

Caenorhabditis

1.

C. elegans

, the nematode, also uses the X-chromosome autosome balance system to produce its two sexes, hermaphrodites and males.

a. Self-fertilization in a hermaphrodite generally produces more hermaphrodites; only 0.2% of the offspring are male.

b. Cross-fertilization between a hermaphrodite and a male produces approximately equal numbers of hermaphrodites and males.

2. Both hermaphrodites and males have five pairs of autosomes, so hermaphrodites (XX) have an X-chromosome-autosome ratio of 1.0, while males (XO) have a ratio of 0.5.

3. Dosage compensation limits transcription from each X chromosome of the hermaphrodite to 1⁄2 the level transcribed from the single X chromosome in the male.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 66

Sex Chromosomes in Other Organisms

1. 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). Z-linked genes behave like X linked genes in mammals, but the sexes are reversed.

2. 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.

3. 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.

4. Other eukaryotes use a genic system instead of entire sex chromosomes. A single allele determines the mating type (e.g.,

MATa

and

MAT α

in

Saccharomyces cerevisiae

).

601 20000 Chapter 11 slide 67

Genic Sex Determination

1. Other eukaryotes use a genic system instead of entire sex chromosomes. A single allele determines the mating type (e.g.,

MAT

a

and

MAT

a in

Saccharomyces cerevisiae

).

2. Yeast mating types have identical morphologies, but are able to fertilize gametes only from the opposite mating type.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 68

Environmental Sex Determination Systems

1. A few species use environmental sex determination systems, in which environmental factors affect the sex of progeny.

2. Some types of turtles are an example. Eggs incubated above 32 ° develop into females, while those below 28 ° become males. Eggs between these temperatures produce a mix of the two sexes. Details will vary with each species using this system.

3. In this system, the environment triggers a developmental pathway which is under genetic control.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 69

Analysis of Sex-Linked Traits in Humans

iActivity: It Runs in the Family 1. 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.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 70

X-Linked Recessive Inheritance

1. Human traits involving recessive alleles on the X chromosome are X-linked recessive traits. A famous example is hemophilia A among Queen Victoria’s descendants (Figure 12.28).

2. 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.

3. Some characteristics of X-linked recessive inheritance: a. Affected fathers transmit the recessive allele to all daughters (who are therefore carriers), and to none of their sons.

b. Father-to-son transmission of X-linked alleles generally does not occur.

c. Many more males than females exhibit the trait.

d. All sons of affected (homozygous recessive) mothers are expected to show the trait.

e.

f.

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.

4. Other X-linked recessive traits are Duchenne muscular dystrophy and two forms of color blindness.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 71

Fig. 12.28 Pedigree of Queen Victoria (III-2) and her descendants, showing the X linked recessive inheritance of hemophilia Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 72

X-Linked Dominant Inheritance

1. Only a few X-linked dominants are known.

2. Examples include: a. Hereditary enamel hypoplasia (faulty and discolored tooth enamel) b. Webbing to the tips of toes.

c. Constitutional thrombopathy (severe bleeding due to lack of blood platelets).

3. Patterns of inheritance are the same as X-linked recessives, except that heterozygous females show the trait (although often in a milder form).

台大農藝系 遺傳學 601 20000 Chapter 11 slide 73

Fig. 11.14b Pedigree showing the transmission of the X-linked dominant trait of faulty tooth enamel Peter J. Russell, iGenetics: Copyright © Pearson Education, Inc., publishing as Benjamin Cummings.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 74

Y-Linked Inheritance

1.Y-linked (holandric) traits, except for maleness itself (resulting from SRY on the Y chromosome), have not been confirmed.

2.The hairy ears trait may be Y-linked, but it is a complex phenotype, and might also be the result of autosomal gene(s) and/or effects of testosterone.

台大農藝系 遺傳學 601 20000 Chapter 11 slide 75