The Chromosomal Basis of Inheritance Chapter 15

New knowledge confirms Mendel’s principles… 1890: Cell biologists understand process of meiosis. 1902: Confirmed that chromosomes are paired in diploid cells, and that they separate in meiosis. Biologists develop the chromosome theory of inheritance: • Mendel’s “factors”, now “genes” are located on chromosomes. • Chromosomes segregate and independently assort during gamete formation. Important work started in 1910 by Thomas Hunt Morgan from Columbia University who performed experiments with the fruit fly Drosophila melanogaster; These flies: Are easily cultured in the laboratory (live in small jars; can be anesthetized). Are prolific breeders (100’s of eggs laid). Have a short generation time (10 days). Have only four pairs of chromosomes which are easily seen with a microscope.

An exception to Mendel’s rule… Linked genes -- Genes located on the same chromosome, which do not indepedently assort and tend to be inherited together. B = normal body color b = black body W = normal wing shape w = vestigial wing BbWw x bbww  1 norm/norm : 1 norm/vest : 1 black/norm : 1 black/vest (expected) BbWw x bbww  5 norm/norm : 1 norm/vest : 1 black/norm : 5 black/vest (observed) Sturtevant hypothesized that probability of crossing over between two genes is directly proportional to the distance between them. He used recombination frequencies between genes to assign them a linear position on a chromosome map. One map unit = 1% recombination frequency; genes farthest apart have highest recombination frequency.

Discovery of a Sex-Linked Gene Sex-linked genes -- Genes located on sex chromosomes, commonly applied only to genes on the X chromosome. Morgan discovered a male fly with white eyes instead of the wild-type red eyes. Morgan mated this mutant white-eyed male with a red-eyed female. w = white-eye allele w+ = red-eye or wild-type allele P generation: Xw+ Xw+ x Xw Y F1 generation: Xw+ Xw and Xw+ Y (all red-eyed) F2 generation: Xw+ Xw+ and Xw+ Xw (all females red-eyed) Xw+ Y and Xw Y (half males red; half males white) Morgan’s conclusions: If eye color is located only on the X chromosome, then females (XX) carry two copies of the gene, while males (XY) have only one. Since the mutant allele is recessive, a white-eyed female must have that allele on both X chromosomes (impossible in this case). A white-eyed male has no wild-type allele to mask the recessive mutant allele, so a single copy results in white eyes.

Sex-Linked Disorders in Humans Color blindness, Duchenne muscular dystrophy, hemophilia. Human X-chromosome is much larger than the Y; more genes on the X, many without a homologous loci on the Y. Fathers pass X-linked alleles to only and all of their daughters. Males receive their X chromosome only from their mothers. Fathers cannot pass X-linked traits to their sons. Mothers can pass X-linked alleles to both sons and daughters. A female that is heterozygous for the trait can be a carrier, but not show the recessive trait herself; far more males than females have sex-linked disorders. Males are said to be hemizygous (having only one copy of a gene in a diploid organism).

Sex-Limited/Sex-Influenced Traits Autosomal traits which affect one gender more than the other. A dominant gene causes a rare type of uterine cancer, but only affects women. A form of baldness also caused by a dominant gene usually only affects men because of hormone levels.

X Inactivation in Females In female mammals, most diploid cells have only one fully functional X chromosome; one of the 2 chromosomes is inactivated during embryonic development. Inactive X chromosome condenses into an object called a Barr body; most Barr body genes are not expressed. Barr bodies are highly methylated compared to active DNA; Methyl groups (-CH3) attach to cytosine. Female mammals are a mosaic of two types of cells, one with an active X from the father and one with an active X from the mother; inactivation appears to happen randomly. Examples of this type of mosaicism are coloration in calico cats.

Humans: Fragile X, muscular dystrophies, patchy skin discoloration

Genetic Disorders: Alterations of Chromosome Number Aneuploidy -- having an abnormal number of certain chromosomes. Three copies of a chromosome is called “trisomy” (Down’s Syndrome, or Trisomy 21); missing a chromosome is called “monosomy” (Turner’s Syndrome). Polyploidy -- more than two complete chromosome sets. Triploidy means three haploid chromosome sets (3N); may be produced by fertilization of an abnormal diploid egg. Tetraploidy means four haploid chromosome sets (4N); may result by mitosis without cytokinesis. Polyploidy is common in plants, but occurs rarely in animals. Nondisjunction -- error in meiosis when homologous chromosomes or sister chromatids fail to separate into different gametes.

Genetic Disorders: Alterations of Chromosome Number(cont) Aneuploidy usually prevents normal embryonic development and often results in spontaneous abortion. Some types cause less severe problems. Down syndrome (1 in 700 live births in U.S.); characteristic facial features, short stature, heart defects, mental retardation. Correlates with maternal age; time lag prior to completion of meiosis at ovulation? Rarer disorders are Patau syndrome (trisomy 13) and Edwards syndrome (trisomy 18); incompatable with life. Sex chromosome aneuploidy: Klinefelter Syndrome (usually XXY); sterile males with feminine body characteristics. Extra Y (or “super-male” , XYY); taller males with higher testosterone production. Turner Syndrome (XO); only known viable human monosomy; short stature; sexual characteristics fail to develop; sterile.

Genetic Disorders: Alterations of Chromosome Structure Chromosome breakage can alter chromosome structure in four ways: 1. Deletion: loss of a fragment of chromosome. 2. Duplication: lost fragment attaches to a homologous chromosome, repeating a sequence. 3. Translocation: lost fragment joins to a nonhomologous chromosome. 4. Inversion: lost fragment reattaches to the original chromosome in reverse. These errors usually happen during crossing-over.

Genetic Disorders: Alterations of Chromosome Structure(cont) Cri du chat syndrome; deletion on chromosome; mental retardation, unusual facial features, and cat’s cry. Chronic myelogenous leukemia (CML); portion of chromosome 22 switches places with fragment from chromosome 9. Some cases of Down syndrome: the third chromosome 21 translocates to chromosome 15. Prader-Willi syndrome; deletion from the paternal chromosome 15; mental retardation, obesity, short stature. Angelman syndrome; same deletion from the maternal chromosome 15; uncontrollable spontaneous laughter, jerky movements, and other mental symptoms. Genomic imprinting -- changes in chromosomes inherited from males and females; certain genes expressed differently depending upon whether inherited from the ovum or from the sperm cell.

Genetic Disorders: Alterations of Chromosome Structure(cont) Fragile X syndrome (1 in 1500 males; 1 in 2500 females); most common genetic cause of mental retardation. Caused by triplet repeat (CGG); repeated up to 50 times on the tip of a normal X chromosome; repeated more than 200 times in a fragile X chromosome. Syndrome more likely to appear if the abnormal X chromosome is inherited from the mother; chromosomes in ova are more likely to acquire new CGG triplets than chromosomes in sperm. Maternal imprinting explains why fragile-X disorder is more common in males. Males (XY) inherit the fragile X chromosome only from their mothers. Heterozygous carrier females are usually only mildly retarded.