The Philadelphia Story

1. The first abnormal chromosome to be associated with cancer was named the Philadelphia chromosome after the city in which it was discovered.
   
   
   1. Karyotyping revealed that the abnormal chromosome is number nine to which a piece of number twenty-two is attached.
   
   
   
   2. The altered genes specify an abnormal protein that stimulates unrestrained division of white blood cells--leukemia.


2. The modern study of genetics began with the rediscovery of Mendel's work in 1884.
   
   
   1. By 1882, Flemming observed threadlike chromosomes in the nuclei of dividing cells.
   
   
   
   2. By 1887, Weismann suggested that meiosis halves the number of chromosomes when gametes are made.
   
   
   
   3. By 1900, Mendel's work was finally appreciated--namely, his view that diploid cells have two units for each trait and the units segregate during gamete formation.

12.1   Chromosomes and Inheritance

1. Genes and Their Chromosome Locations
   
   
   1. Genes are units of information about heritable traits.
   
   
   
   2. Diploid organisms possess pairs of homologous chromosomes, which are alike in length, shape, and gene sequence.
   
   
   
   3. Alleles are slightly different molecular forms of the same gene, which are shuffled during meiosis.
   
   
   
   4. Crossing over between homologous chromosomes results in genetic recombination.
   
   
   
   5. Independent assortment refers to the random alignment of each pair of homologous chromosomes at metaphase I of mitosis, which results in new combinations of genes in offspring.
   
   
   
   6. A chromosome's structure may change during mitosis or meiosis.


2. Autosomes and Sex Chromosomes
   
   
   1. Sex chromosomes determine gender.
      
      
      1. Human females have two X chromosomes.
      
      
      
      2. Males have one X and one Y.
   
   
   2. Most of the chromosomes are of the same quantity and type in both sexes and are called autosomes (44 in humans).

12.2   Focus on Science: Karyotyping Made Easy

12.3   Sex Determination in Humans

1. Each human egg will contain twenty-two autosomes plus one X; but sperm will carry twenty-two autosomes plus either an X or a Y.
   
   
   1. X-bearing egg plus X-bearing sperm produces female offspring.
   
   
   
   2. X-bearing egg plus Y-bearing sperm produces male offspring.


2. The X chromosome obviously codes for sexual traits, but it also carries many genes for nonsexual traits.
   
   
   1. The Y chromosome carries a male-determining (SRY) gene which leads to formation of the testes.
   
   
   
   2. Absence of the male gene in females results in formation of ovaries.

12.4   What Mendel Didn't Know: Crossovers and Recombinations

1. Linked genes on specific chromosomes are referred to as linkage groups.
   
   
   1. In his experiments using fruit flies, Thomas Hunt Morgan confirmed that each gene has a specific location on a chromosome.
   
   
   
   2. Some of the most intriguing linkages are those of X-linked and Y-linked genes.


2. Linkage is the tendency of genes located on the same chromosome to be transmitted together in inheritance.
   
   
   1. Linkage can be disrupted by crossing over--the exchange of parts of homologous chromosomes.
      
      
      1. Certain alleles that are linked on the same chromosome tend to remain together during meiosis because they are positioned closer together on the chromosome.
      
      
      
      2. This eventually led to the generalization that the probability that a cross over will disrupt the linkage of two genes is proportional to the distance that separates them.
   
   
   2. The careful analysis of recombination patterns in experimental crosses has resulted in linkage mapping of gene locations.

12.5   Human Genetic Analysis

1. Human genetics is difficult to study.
   
   
   1. We live under variable conditions in diverse environments.
   
   
   
   2. Humans mate by chance and may, or may not, choose to reproduce.
   
   
   
   3. Humans live as long as those who study them.
   
   
   
   4. The small family size characteristic of human beings is not sufficient for meaningful statistical analysis.


2. Constructing Pedigrees
   
   
   1. A pedigree is a chart that shows genetic connections among individuals.
   
   
   
   2. The analysis of family pedigrees provides data on inheritance patterns through several generations.
   
   
   
   3. Knowledge of probability and Mendelian inheritance patterns is used in analysis of pedigrees to yield clues to a trait's genetic basis.


3. Regarding Human Genetic Disorders
   
   
   1. Genetic abnormality is a term applied to a genetic condition that is a deviation from the usual, or average, and is not life-threatening.
   
   
   
   2. Genetic disorder is more appropriately used to describe conditions that cause medical problems.
   
   
   
   3. Genetic disease is applied to those instances where a person's genes increase susceptibility to infection or weakens the response to it.

12.6   Examples of Inheritance Patterns

1. Autosomal Recessive Inheritance
   
   
   1. The characteristics of this condition are:
      
      
      1. Either parent can carry the recessive allele on an autosome.
      
      
      
      2. Heterozygotes are symptom-free; homozygotes are affected.
      
      
      
      3. Two heterozygous parents have a 50 percent chance of producing heterozygous children and a 25 percent chance of producing a homozygous recessive child. When both parents are homozygous, all children can be affected.
   
   
   2. Galactosemia (the inability to metabolize lactose) is an example of autosomal recessive inheritance in which a single gene mutation prevents manufacture of an enzyme needed in the conversion pathway.


2. Autosomal Dominant Inheritance
   
   
   1. The dominant allele is nearly always expressed and if it reduces the chance of surviving or reproducing, its frequency should decrease; mutations, nonreproductive effects, and postreproductive onset work against this hypothesis.
   
   
   
   2. If one parent is heterozygous and other homozygous recessive, there is a 50 percent chance that any child will be heterozygous.
   
   
   
   3. Huntington disease is serious degeneration of the nervous system with an onset from age 40 onward, by which time the gene has (usually) been passed to offspring unknowingly.
   
   
   
   4. Achondroplasia (dwarfism) is a benign abnormality which does not affect persons to the point that reproduction is impossible so the gene is passed on.


3. X-Linked Recessive Inheritance
   
   
   1. The characteristics of this condition are:
      
      
      1. The mutated gene occurs only on the X chromosome.
      
      
      
      2. Heterozygous females are phenotypically normal; males are more often affected because the single recessive allele (on the X chromosome) is not masked by a dominant gene.
      
      
      
      3. A normal male mated with a female heterozygote have a 50 percent chance of producing carrier daughters and a 50 percent chance of producing affected sons. In the case of a homozygous recessive female and a normal male, all daughters will be carriers and all sons affected.
   
   
   2. A serious X-linked recessive condition is hemophilia A, (affecting 1/7,000 males), which is the inability of the blood to clot because the genes do not code for the necessary clotting agent(s).
   
   
   
   3. Males with fragile X syndrome have a defective X chromosome that produces a faulty protein that results in retarded brain development.

12.7   Focus on Health: Progeria--Too Young to Be Old

12.8   Changes in Chromosome Structure

1. Major Categories of Structural Change
   
   
   1. Duplication occurs when a gene sequence is in excess of the normal amount; apparently this is true of chromosome regions that code for polypeptides of hemoglobin and is not harmful.
   
   
   
   2. An inversion alters the position and sequence of the genes so that gene order is reversed.
   
   
   
   3. A translocation occurs when a part of one chromosome is transferred to a nonhomologous chromosome as in form of leukemia in which a segment of chromosome 9 is attached to chromosome 22.
   
   
   
   4. A deletion is the loss of a chromosome segment as when a terminal segment is lost, or when viruses, chemicals, or irradiation cause breaks in a chromosome region; an example is the loss of a portion of chromosome 5 causing a disorder called cri-du-chat with its symptoms of crying and mental retardation.


2. Does Chromosome Structure Evolve?
   
   
   1. Changes in chromosome structure tend to be selected against rather than conserved over evolutionary time.
   
   
   
   2. However, gene regions for the polypeptide chains of hemoglobin have duplicated to produce different hemoglobins with different oxygen transporting efficiencies.

12.9   Changes in Chromosome Number

1. Categories and Mechanisms of Change
   
   
   1. Aneuploidy is a condition in which the gametes or cells of an affected individual end up with one extra or one less chromosome than is normal.
   
   
   
   2. Polyploidy is the presence of three or more of each type of chromosome in gametes or cells. It is common in plants but fatal in humans.
      
      
      1. A chromosome number can change during mitotic or meiotic cell division or during the fertilization process.
      
      
      
      2. Tetraploid germ cells can result if cytoplasmic division does not follow normal DNA replication and mitosis.
   
   
   3. Nondisjunction at anaphase I or anaphase II frequently results in a change in chromosome number.
      
      
      1. If a gamete with an extra chromosome (n + 1) joins a normal gamete at fertilization, the diploid cell will be 2n + 1; this condition is called trisomy.
      
      
      
      2. If an abnormal gamete is missing a chromosome, the zygote will be 2n - 1--monosomy.


2. Case Study: Down Syndrome
   
   
   1. Down syndrome results from trisomy 21; 1 in 1,100 liveborns in North America are affected.
   
   
   
   2. Most children with Down syndrome show mental retardation, and 40 percent have heart defects.
   
   
   
   3. Down syndrome occurs more frequently in children born to women over age 35.

12.10   Case Studies: Changes in the Number of Sex Chromosomes

1. Female Sex Chromosome Abnormalities
   
   
   1. Turner Syndrome
      
      
      1. Turner syndrome involves females whose cells have only one X chromosome (designated XO).
      
      
      
      2. Affected individuals (1/2,500 to 10,000 girls) are infertile and have other phenotypic problems such as premature aging and shorter life expectancy.
      
      
      
      3. About 75 percent of the cases are due to nondisjunction in the father; furthermore, about 98 percent of all XO zygotes spontaneously abort.
   
   
   2. XXX Syndrome
      
      
      1. About 1 in 1,000 females inherits 3, 4, or 5 X chromosomes.
      
      
      
      2. Most of these girls are taller and slimmer than average, but are fertile and fall within the normal range of appearance and social behavior.


2. Male Sex Chromosome Abnormalities
   
   
   1. Klinefelter Syndrome
      
      
      1. Nondisjunction results in an extra X chromosome in the cells (XXY) of these affected males (1/500 to 2,000 liveborn males).
      
      
      
      2. About 67 percent of these result from nondisjunction in the mother, 33 percent in the father.
      
      
      
      3. Sterility, slight mental retardation, and body feminization are symptoms.
   
   
   2. XYY Condition
      
      
      1. The extra Y chromosome in these males (1/1,000) does not affect fertility, but they are taller than average and are slightly mentally retarded.
      
      
      
      2. Erroneous correlations have linked these persons with predisposition to crime.

12.11   Focus on Bioethics: Prospects in Human Genetics

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