The Chromosomal Basis of Inheritance

1. The Chromosomal Basis of Inheritance Chapter 15

2. 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.

3. 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.

4. 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.

6. 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).

8. 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.

9. X Inactivation in Females • In female mammals, most diploid cells have only one fully functional Xchromosome; 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 mosaicof 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.

10. Humans: Fragile X, muscular dystrophies, patchy skin discoloration

11. 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.

13. 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.

14. 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.

17. 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.

19. 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.