Chromosomal Basis of Inheritance: Mendel's Laws on Chromosomes

1. Chapter 15 The Chromosomal Basis of Inheritance What you learned already • Chapter 13 : Meiosis and sexual life cycles • Chapter 14 : Mendel and the gene idea

2. Overview: Locating Genes on Chromosomes ☞Genes ( passengers) and chromosomes ( wagon) • Mendel’s “hereditary factors” were genes, though this wasn’t known at the time • Today we can show that genes are located on chromosomes • Q: How to visualize that? • The location of a particular gene can be seen by tagging isolated chromosomes with a fluorescent dye that highlights the gene  Chromosomes: a physical basis for the principles of heredity (=Mendel’s laws of segregation and independent assortment) • This chapter’s aim: Is to study the chromosomal basis for the transmission of genes from parents to offspring

3. Concept 15.1: Mendelian inheritance has its physical basis in the behavior of chromosomes • Mitosis and meiosis were first described in the late 1800s • The chromosome theory of inheritance states: • Mendelian genes have specific loci (positions) on chromosomes • Chromosomes undergo segregation and independent assortment • The behavior of chromosomes during meiosis can account for Mendel’s laws of segregation and independent assortment

4. 1 3 1 2 3 2 Figure 15.2 P Generation Yellow-roundseeds (YYRR) Green-wrinkledseeds (yyrr) y Y r  R r R Y y Meiosis Fertilization r y Y R Gametes All F1 plants produceyellow-round seeds (YyRr). F1 Generation R R y y r r Y Y Meiosis LAW OF SEGREGATIONThe two alleles for eachgene separate duringgamete formation. LAW OF INDEPENDENTASSORTMENT Alleles of geneson nonhomologous chromosomesassort independently duringgamete formation. r R r R Metaphase I Y y Y y R R r r Anaphase I Y Y y y r R R r y Metaphase II Y y Y y Y Y Y y Y y y Gametes r R r R r r R R 1/4 1/4 1/4 1/4 yr yR YR Yr F2 Generation An F1  F1 cross-fertilization Fertilization results in the 9:3:3:1 phenotypic ratioin the F2 generation. Fertilization recombinesthe R and r alleles at random. : 3 : 3 : 1 9

5. 1 2 1 2 Figure 15.2b All F1 plants produceyellow-round seeds (YyRr). F1 Generation R R y y r r Y Y LAW OF INDEPENDENTASSORTMENT Alleles of genes on nonhomologous chromosomes assort independently during gamete formation. Meiosis LAW OF SEGREGATIONThe two alleles for eachgene separate duringgamete formation. r R r R Metaphase I y Y Y y R r R r Anaphase I Y Y y y r R r R Metaphase II y Y y Y y Y Y y Y y Y y Gametes r R R r r r R R 1/4 1/4 1/4 1/4 yr yR YR Yr

6. 3 3 Figure 15.2c LAW OF INDEPENDENTASSORTMENT LAW OF SEGREGATION F2 Generation An F1  F1 cross-fertilization Fertilization recombines the R and r alleles at random. Fertilization results in the 9:3:3:1 phenotypic ratio in the F2 generation. : 3 : 3 : 1 9

7. Summary for the chromosomal basis of Mendel’s laws • Law of segregation: • Two alleles for each gene segregate during gamete formation and end up in different gametes •  Each gamete gets only one of the two alleles •  In terms of chromosomes, this segregation corresponds to the distribution of homologous chromosomes to different gamete (R or r allele; Y or y allele) • Law of independent assortment: • Alleles of genes on nonhomologous chromosomes assort independently during gamete formation •  Each gamete gets one of four allele combinations (YR:Yr:yR:yr = 1:1:1:1) depending on the alternative arrangements of homologous chromosome pairs in metaphase I

8. Morgan’s Experimental Evidence for chromosomal theory: Scientific Inquiry • Thomas Hunt Morgan (Embryologist at Columbia Univ. early in the 20th century) • Provided the first solid evidence associating a specific gene with a specific chromosome • Namely, provided convincing evidence that chromosomes are the location of Mendel’s heritable factors Morgan’s Choice of Experimental Organism • Several characteristics make fruit flies a convenient organism for genetic studies: • They breed at a high rate • A generation can be bred every two weeks • They have only four pairs of chromosomes

9. Morgan first observed and noted : Wild type, or normal, phenotypes that were common in the fly populations • Traits alternative to the wild type: Are called mutant phenotypes • Morgan first invented a notation for symbolizing alleles in Drosophila (still widely used) • The allele for white eyes in flies is symbolized by w (indicated as a mutant allele) • A superscript + identifies the allele for the wild-type trait: w+ for the allele for red eyes

10. How to Correlate Behavior of a Gene’s Alleles with Behavior of a Chromosome Pair • In one experiment, Morgan mated male flies with white eyes (mutant) with female flies with red eyes (wild type) • The F1 generation all had red eyes • The F2 generation showed the 3:1red:white eye ratio, but only males had white eyes • Morgan determined that the white-eyed mutant allele must be located on the X chromosome • Morgan’s finding supported the chromosome theory of inheritance

11. Morgan’s discovery that transmission of the X chromosome in fruit flies correlates with inheritance of the eye-color trait • Was the first solid evidence indicating that a specific gene is associated with a specific chromosome

12. 성염색체 연관 유전자의 유전현상의 특징 • Concept 15.2: Sex-linked genes exhibit unique patterns of inheritance What will you examine here • We consider the role of sex chromosome in heritance • First step: reviewing the chromosomal basis of sex determination in humans and some other animals The Chromosomal Basis of Sex (성결정과 염색체) How to determine sex in an organism? • An organism’s sex • Is an inherited phenotypic character determined by the presence or absence of certain chromosomes (sex chromosomes)

13. In humans and other mammals, there are two varieties of sex chromosomes: a larger X chromosome and a smaller Y chromosome • Only the ends of the Y chromosome have regions that are homologous with the X chromosome • The SRY gene on the Y chromosome codes for the development of testes

14. 22 + XX 22 + X (b) The X–0 system 76 + ZZ 76 + ZW (c) The Z–W system 16 (Haploid) 16 (Diploid) (d) The haplo-diploid system • Different systems of sex determination • Are found in other organisms In grasshoppers, cockroaches, there is only one type of sex chromosome (the X) In birds, some fishes, and some insects, the sex chromosome present in the egg (not the sperm) determines the sex of offspring (Z and W) In most species of bees and ants, there are no sex chromosomes. Female develop from fertilized eggs and are thus diploid. Males develop from unfertilized eggs and haploid (no fathers) 32 Figure 15.6b–d

15. Inheritance of Sex-Linked Genes Key points to keep in mind • The sex chromosomes have genes for many characters unrelated to sex • A gene located on either sex chromosome is called a sex-linked gene • In humans, sex-linked usually refers to a gene on the larger X chromosome Sex-linked trait by recessive allele on X chromosome • Female: has two X chromosomes • Homozygous recessive alleles : expression of phenotype • Heterozygous: no expression of phenotype (called carrier) • Male: has only one X chromosome • You don’t use the terms homozygous and heterozygous: use “hemizygous” • Any male receiving the recessive allele from his mother will express the trait  far more males than females have sex-linked recessive disorders (The freq. of sex-linked recessive disorders in male is higher than that in female)

16. What kinds of X-lined disorders are found? • Some recessive alleles found on the X chromosome in humans cause certain types of disorders • Color blindness: • Duchenne muscular dystrophy : 1/3500 males born in US; progressive weakening of the muscles; the absence of a key muscle protein called dystrophin • Hemophilia: shows delayed blood clotting due to the absence of one or more of the proteins required for blood clotting; treated with intravenous injections of the missing protein

17. How do sex-lined recessive traits transmit to offspring? XAXa A father with the disorder will transmit the mutant allele to all daughters but to no sons. When the mother is a dominant homozygote, the daughters will have the normal phenotype but will be carriers of the mutation. (a) Figure 15.7a–c

18. The transmission of sex-linked recessive traits XaXA If a carrier female mates with a male of normal phenotype, there is a 50% chance that each daughter will be a carrier like her mother, and a 50% chance that each son will have the disorder. (b) Figure 15.7a–c

19. The transmission of sex-linked recessive traits XaXa If a carrier mates with a male who has the disorder, there is a 50% chance that each child born to them will have the disorder, regardless of sex. Daughters who do not have the disorder will be carriers, where as males without the disorder will be completely free of the recessive allele. (c) Figure 15.7a–c

20. X inactivation in Female Mammals • In mammalian females, one of the two X chromosomes in each cell is randomly inactivated during embryonic development • The inactive X condenses into a Barr body • If a female is heterozygous for a particular gene located on the X chromosome, she will be a mosaic for that character Mystery of the presence or absence of sweat glands in female skin • In humans, mosaicism can be observed in a recessive X-linked mutation that prevents the development of sweat glands • A woman who is heterozygous for this trait has patches of normal skin and patches of skin lacking sweat glands

21. Concept 15.3: Linked genes tend to be inherited together because they are located near each other on the same chromosome Each chromosome has hundreds or thousands of genes Location of some genes on the same chromosome is expected The genes tend to be inherited together in genetic crosses: are said to be linked genes The linked genes do not always follow Mendel’s law of independent assortment

22. How Linkage Affects Inheritance • Morgan did other experiments with fruit flies to see how linkage affects inheritance of two characters • Morgan crossed flies that differed in traits of body color and wing size

23. However, nonparental phenotypes were also produced • The production of a small number of offspring with nonparental phenotypes indicated that some mechanism occasionally breaks the linkage between genes on the same chromosome • Understanding this result involves exploring genetic recombination, the production of offspring with combinations of traits differing from either parent

24. Genetic Recombination and Linkage What you learned in the Chapter 13 Meiosis and random fertilization generate genetic variation among offspring of sexually reproducing organisms • The genetic findings of Mendel and Morgan relate to the chromosomal basis of recombination What will you examine next What is the chromosomal basis of recombination in relation to the genetic findings of Mendel and Morgan?

25. Recombination of Unlinked Genes: Independent Assortment of Chromosomes • Mendel observed that combinations of traits in some offspring differ from either parent • Offspring with a phenotype matching one of the parental phenotypes are called parental types • Offspring with nonparental phenotypes (new combinations of traits) are called recombinant types, or recombinants • A 50% frequency of recombination is observed for any two genes on different chromosomes

26. Recombination of Linked Genes: Crossing Over • Morgan discovered that genes can be linked, but the linkage was incomplete, because some recombinant phenotypes were observed • He proposed that some process must occasionally break the physical connection between genes on the same chromosome • That mechanism was the crossing over of homologous chromosomes

27. Figure 15.10 Black body, vestigial wings(double mutant) Gray body, normal wings(F1 dihybrid) Testcrossparents bvg bvg Chromosomal basis for recombination of linked genes: Linked genes exhibit RF less than 50% bvg bvg Replicationof chromosomes Replicationof chromosomes bvg bvg bvg bvg bvg bvg bvg bvg Meiosis I bvg Meiosis I and II bvg bvg bvg Meiosis II Recombinantchromosomes bvg bvg bvg bvg Eggs 206Gray-vestigial 965Wild type(gray-normal) 944Black-vestigial 185Black-normal Testcrossoffspring bvg bvg bvg bvg bvg bvg bvg bvg bvg Sperm Recombinant offspring Parental-type offspring 391 recombinants2,300 total offspring Recombinationfrequency   100  17%

28. Figure 15.10a Gray body, normal wings(F1 dihybrid) Black body, vestigial wings(double mutant) Testcrossparents bvg bvg bvg bvg Replicationof chromosomes Replicationof chromosomes bvg bvg bvg bvg bvg bvg Meiosis I:Crossing over between b and vg loci produces new allele combinations. bvg bvg bvg Meiosis I and II: Even if crossing over occurs, no new allele combinations are produced. bvg Meiosis II: Segregation of chromatids produces recombinant gametes with the new allele combinations. bvg bvg Recombinantchromosomes bvg bvg bvg bvg bvg Eggs Sperm

29. Figure 15.10b Recombinantchromosomes bvg bvg bvg bvg Eggs 206Gray-vestigial 944Black-vestigial 185Black-normal 965Wild type(gray-normal) Testcrossoffspring bvg bvg bvg bvg bvg bvg bvg bvg bvg Sperm Parental-type offspring Recombinant offspring 391 recombinants2,300 total offspring Recombinationfrequency  100  17%  RF: the percentage of recombinants in the total offspring

30. Mapping the Distance Between Genes Using Recombination Data: Scientific Inquiry • Alfred Sturtevant, one of Morgan’s students, constructed a genetic map, an ordered list of the genetic loci along a particular chromosome • Sturtevant predicted that the farther apart two genes are, the higher the probability that a crossover will occur between them and therefore the higher the recombination frequency • A linkage map is a genetic map of a chromosome based on recombination frequencies • Distances between genes can be expressed as map units; one map unit, or centimorgan, represents a 1% recombination frequency • Map units indicate relative distance and order, not precise locations of genes

31. How to construct a linkage map Example • Consider three genes: the body-color (b), wing-size (vg), and cinnabar eyes (cn) [brighter red than wt eye color] • The observed recombination frequencies between three Drosophila gene pairs : b–cn 9%, cn–vg 9.5%, and b–vg 17% • Make a linear order : cn is positioned about halfway between the other two genes: Recombinationfrequencies RESULTS 9% 9.5% Chromosome 17% b, black body color vg, vestigial wing cn, cinnabar eyes b cn vg 1st cross-over 2nd CO Figure 15.11

32. How to construct a linkage map (continued) Example Inquiry: The b–vg recombination frequency (17%) is slightly less than the sum (18.5%) of the b–cn and cn–vg frequencies. Why? • Because double crossovers are fairly likely to occur between b and vg in matings tracking these two genes. • A second crossover would “cancel out” the effect of the first crossover and thus reduce the observed b–vg RF.

33. Canceling out of the effect of the 1st crossover by 2nd cross-over

34. Genes that are far apart on the same chromosome can have a recombination frequency near 50% • Such genes are physically linked, but genetically unlinked, and behave as if found on different chromosomes • Sturtevant used recombination frequencies to make linkage maps of fruit fly genes • Using methods like chromosomal banding, geneticists can develop cytogenetic maps of chromosomes • Cytogenetic maps indicate the positions of genes with respect to chromosomal features

35. Concept 15.4: Alterations of chromosome number or structure cause some genetic disorders • Large-scale chromosomal alterations in humans and other mammals often lead to spontaneous abortions (miscarriages) or cause a variety of developmental disorders • Plants tolerate such genetic changes better than animals do

36. Abnormal Chromosome Number • In nondisjunction, pairs of homologous chromosomes do not separate normally during meiosis • As a result, one gamete receives two of the same type of chromosome, and another gamete receives no copy

37. The consequences of nondisjunction after fertilization? • Polyploidy is a condition in which an organism has more than two complete sets of chromosomes • Triploidy (3n) is three sets of chromosomes • Tetraploidy (4n) is four sets of chromosomes • Polyploidy is common in plants, but not animals • Polyploids are more normal in appearance than aneuploids • Aneuploidy • Results from the fertilization of aberrant gametes (nondisjunction occurred) with a normal one • Is a condition in which offspring have an abnormal number of a particular chromosome • Chromosome number of haploid (gamete): n • Chromosome number of normal zygote: 2n • If a zygote is trisomic (2n+1 chromosomes) • It has three copies of a particular chromosome • If a zygote is monosomic (2n-1 chromosomes) • It has only one copy of a particular chromosome

38. Alterations of Chromosome Structure • Breakage of a chromosome can lead to four types of changes in chromosome structure • Deletion removes a chromosomal segment • Duplication repeats a segment • Inversion reverses orientation of a segment within a chromosome • Translocation moves a segment from one chromosome to another

39. Human Disorders Due to Chromosomal Alterations • Alterations of chromosome number and structure are associated with some serious disorders • Some types of aneuploidy appear to upset the genetic balance less than others, resulting in individuals surviving to birth and beyond • These surviving individuals have a set of symptoms, or syndrome, characteristic of the type of aneuploidy Down Syndrome (Trisomy 21) • Down syndrome is an aneuploid condition that results from three copies of chromosome 21 • It affects about one out of every 700 children born in the United States • The frequency of Down syndrome increases with the age of the mother, a correlation that has not been explained

40. Aneuploidy of Sex Chromosomes • Nondisjunction of sex chromosomes produces a variety of aneuploid conditions • Klinefelter syndromeis the result of an extra chromosome in a male, producing XXY individuals • Monosomy X, called Turner syndrome, produces X0 females, who are sterile; it is the only known viable monosomy in humans

41. Disorders Caused by Structurally Altered Chromosomes • The syndrome cri du chat (“cry of the cat”), results from a specific deletion in chromosome 5 • A child born with this syndrome is mentally retarded and has a catlike cry; individuals usually die in infancy or early childhood • Certain cancers, including chronic myelogenous leukemia (CML), are caused by translocations of chromosomes

42. Concept 15.5: Some inheritance patterns are exceptions to the standard chromosome theory • There are two normal exceptions to Mendelian genetics • One exception involves genes located in the nucleus, and the other exception involves genes located outside the nucleus • In both cases, the sex of the parent contributing an allele is a factor in the pattern of inheritance Genomic Imprinting • For a few mammalian traits, the phenotype depends on which parent passed along the alleles for those traits • Such variation in phenotype is called genomic imprinting (Monoallelic expression) • Genomic imprinting involves the silencing of certain genes that are “stamped” with an imprint during gamete production

43. Genomic imprinting Involves the silencing of certain genes that are “stamped” with an imprint during gamete production A zygote expresses only one allele of an imprinted gene (either from the mother or the father)  The imprints are transmitted to all the body cells during development A gene imprinted for maternal allele expression is always imprinted for maternal allele expression, generation to generation

44. Figure 15.17a Genomic imprinting of the mouse Igf2 gene.

45. Inheritance of Organelle Genes • Extranuclear genes (or cytoplasmicgenes)are found in organelles in the cytoplasm • Mitochondria, chloroplasts, and other plant plastids carry small circular DNA molecules • Extranuclear genes are inherited maternally because the zygote’s cytoplasm comes from the egg • The first evidence of extranuclear genes came from studies on the inheritance of yellow or white patches on leaves of an otherwise green plant (see next slide)