The Chromosomal Basis of Inheritance: Genes on Chromosomes and Sex-Linked Inheritance

1. Chapter 15 The Chromosomal Basis of Inheritance Updated November 2008

2. Figure 15.1 Overview: Locating Genes on Chromosomes • Genes • Are located on chromosomes • Can be visualized using certain techniques

3. Concept 15.1: Mendelian inheritance has its physical basis in the behavior of chromosomes • Several researchers proposed in the early 1900s that genes are located on chromosomes • The behavior of chromosomes during meiosis was said to account for Mendel’s laws of segregation and independent assortment

4. The chromosome theory of inheritance states that • Mendelian genes have specific loci on chromosomes • During meiosis chromosomes undergo: • Segregation • Independent assortment

5. Meiosis • Homologous chromosomes during meiosis account for the segregation of alleles at each locus to different gametes • Nonhomologous chromosomes account for independent assortment of alleles

6. All F1 plants produce yellow-round seeds (YyRr) 0.5 mm F1 Generation R R y y r r Y Y LAW OF SEGREGATION The two alleles for each gene separate during gamete formation. LAW OF INDEPENDENT ASSORTMENT Alleles of genes on nonhomologous chromosomes assort independently during gamete formation. Meiosis r r R R Metaphase I Y y Y y 1 1 r R r R Anaphase I Y Y y y Metaphase II r R R r 2 2 y Y y Y y Y Y y Y y Y y Gametes r R r R r r R R yr yR 4 4 YR 4 Yr 4 1 1 1 1 3 3

7. Morgan’s Experimental Evidence: Scientific Inquiry • Thomas Hunt Morgan • In early 20th century, first geneticist to associate a specific gene with a specific chromosome • Provided convincing evidence that chromosomes are the location of Mendel’s heritable factors

8. Morgan’s Choice of Experimental Organism • Morgan worked with fruit flies • Because they breed at a high rate • A new generation can be bred every two weeks • They have only four pairs of chromosomes (3 pairs of autosomes & 1 pair of sex chromosomes) • And they are cheap and easy to get!

9. Figure 15.3 Morgan’s Flies • Morgan first observed and noted • Wild type (normal) phenotypes that were common in the fly populations • Traits alternative to the wild type • Are called mutant phenotypes

10. Correlating 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 3:1 red:white eye ratio, but only males had white eyes • Morgan determined that the white-eyed mutant allele must be located on the X chromosome

11. Fig. 15-4c CONCLUSION + w w P X X  Generation Y X + w w Sperm Eggs + + F1 w w + w Generation w + w Sperm Eggs + + w w + w F2 Generation w w w + w

12. 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 • (Morgan and his lab did a lot of fascinating fly research. He won a Nobel Prize in 1933.)

13. Concept 15.2: Sex-linked genes exhibit unique patterns of inheritance • In humans and some other animals, there is a chromosomal basis of sex determination

14. The Chromosomal Basis of Sex • 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

15. SRY gene • The sex determining gene on the Y chromosome • Individuals with the SRY gene develop the generic embryonic gonads into testes • The SRY triggers a cascade of biochemical, physiological and anatomical features • Key in developmental biology

16. Females are XX, and males are XY • Each ovum contains an X chromosome, while a sperm may contain either an X or a Y chromosome • Other animals have different methods of sex determination

17. Fig. 15-6a 44 + XY 44 + XX Parents 22 + X 22 + X 22 + Y or + Sperm Egg 44 + XX 44 + XY or Zygotes (offspring) (a) The X-Y system

18. 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 Figure 15.9b–d Different systems of sex determination are found in other organisms

19. Inheritance of Sex-Linked Genes • 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

20. Sex-linked genes follow specific patterns of inheritance • For a recessive sex-linked trait to be expressed • A female needs two copies of the allele • A male needs only one copy of the allele • Sex-linked recessive disorders are much more common in males than in females

21. Fig. 15-7 XnY XnY XNXN XNXn  XNY XNXn   Sperm Sperm Sperm Xn Y XN Xn Y Y Eggs Eggs XNXN Eggs XNXn XNY XN XNY XN XNXn XNY XN XnXn XnY XNXn XNY XnXN XnY Xn Xn XN (a) (b) (c)

22. Some disorders caused by recessive alleles on the X chromosome in humans: • Color blindness • Duchenne muscular dystrophy • Hemophilia

23. 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

24. Fig. 15-8 X chromosomes Allele for orange fur Early embryo: Allele for black fur Cell division and X chromosome inactivation Two cell populations in adult cat: Active X Inactive X Active X Black fur Orange fur

25. X inactivation • Involves modification of the DNA by attachment of methyl (-CH3) groups to cytosine nucleotides on the X chromosome that will become Barr body • Discovered a gene XIST (X-inactive specific transcript) which is only active on the Barr body chromosome

26. Concept 15.2: 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 • Genes located on the same chromosome that tend to be inherited together are called linked genes

27. How Linkage Affects Inheritance: Scientific Inquiry • Morgan did other experiments with fruit flies • To see how linkage affects the inheritance of two different characters • Morgan crossed flies • That differed in traits of two different characters

28. Fig. 15-9-4 EXPERIMENT P Generation (homozygous) Wild type (gray body, normal wings) Double mutant (black body, vestigial wings) According to independent assortment, this should produce 4 phenotypes in a 1:1:1:1 ratio  b b vg vg b+ b+ vg+ vg+ F1 dihybrid (wild type) Double mutant TESTCROSS  b+ b vg+ vg b b vg vg Testcross offspring b+ vg+ b vg b+ vg b vg+ Eggs Black- normal Wild type (gray-normal) Black- vestigial Gray- vestigial b vg Sperm b b vg+ vg b+ b vg+ vg b b vg vg b+ b vg vg PREDICTED RATIOS 1 If genes are located on different chromosomes: 1 : : : 1 1 If genes are located on the same chromosome and parental alleles are always inherited together: 1 0 : 1 : 0 : 965 : : 185 : 944 206 RESULTS

29. b+ vg+ bvg X Parents in testcross b vg b vg bvg b+ vg+ Most offspring or b vg b vg Morgan determined that • Body color and wing shape are usually inherited together because the genes are on the same chromosomes • Genes that are close together on the same chromosome are linked and do not assort independently

30. Genetic Recombination and Linkage • Unlinked genes are either on separate chromosomes or are far apart on the same chromosome and assort independently • Genetic recombination is the production of offspring with new combinations of traits • Parental types – phenotype matches one of the parents • Recombinant types (or recombinants)

31. Gametes from yellow-round heterozygous parent (YyRr) yR YR Yr yr Gametes from green- wrinkled homozygous recessive parent (yyrr) yr YyRr yyrr Yyrr yyRr Parental- type offspring Recombinant offspring Recombination of Unlinked Genes: Independent Assortment of Chromosomes • When Mendel followed the inheritance of two characters • He observed that some offspring have combinations of traits that do not match either parent in the P generation

32. Linked? Dependent? • Recombinant offspring • Are those that show new combinations of the parental traits • When 50% of all offspring are recombinants • Geneticists say that there is a 50% frequency of recombination • The two genes are on different nonhomologous chromosomes

33. Independent and not linked • Unlinked genes randomly assort at metaphase I of meiosis • They follow the independent probability rules • And is multiplication • Or is addition • If these rules don’t seem to apply, the genes are probably linked

34. Recombination of Linked Genes: Crossing Over • Morgan discovered that genes can be linked • But due to the appearance of recombinant phenotypes, the linkage appeared incomplete • They tend to move together through meiosis and fertilization • But not completely or we would see the ratio 1:1:0:0

35. Morgan proposed that • Some process must occasionally break the physical connection between genes on the same chromosome • Crossing over of homologous chromosomes was the mechanism • Linked genesexhibit recombination frequencies less than 50% Animation: Crossing Over

36. Linkage Mapping: Using Recombination Data: Scientific Inquiry • A genetic map • Is an ordered list of the genetic loci along a particular chromosome • Can be developed using recombination frequencies • A linkage map • Is the actual map of a chromosome based on recombination frequencies

37. Fig. 15-10a Testcross parents Black body, vestigial wings (double mutant) Gray body, normal wings (F1 dihybrid) bvg b+vg+ b vg bvg Replication of chromo- somes Replication of chromo- somes b+vg+ bvg b+vg+ bvg bvg bvg bvg bvg Meiosis I b+vg+ Meiosis I and II b+vg bvg+ bvg Meiosis II Recombinant chromosomes bvg+ b+vg bvg bvg b+vg+ Sperm Eggs

38. Fig. 15-10b Recombinant chromosomes b+vg+ b+vg bvg+ bvg Eggs 944 Black- vestigial 965 Wild type (gray-normal) 185 Black- normal 206 Gray- vestigial Testcross offspring bvg b+vg+ bvg bvg+ b+vg bvg bvg bvg bvg Sperm Recombinant offspring Parental-type offspring 391 recombinants Recombination frequency  100 = 17% = 2,300 total offspring

39. Linkage Maps • The farther 2 genes are, the higher the probability that a crossover will occur between them • Therefore, the higher the recombination frequency • The relative distance is expressed as map units called centimorgans

40. Distances between genes can be expressed as map units; one map unit, or centimorgan, represents a 1% recombination frequency Recombination frequencies RESULTS 9% 9.5% Chromosome 17% b cn vg

41. Multiple crossing over • The recombination frequencies in our mapping example are not quite additive: 9% (b-cn) + 9.5% (cn-vg) > 17% (b-vg). • This results from multiple crossing-over events. • A second crossing over “cancels out” the first and reduces the observed number of recombinant offspring. • Genes father apart (for example, b-vg) are more likely to experience multiple crossing-over events.

42. Realistically... • Some genes on a chromosome are so far apart that a crossover between them is virtually certain • If genes are far enough apart, they appear to be on different chromosomes • So what’s the recombination frequency? • In fact, Mendel’s pea seed color & flower color were on the same chromosome

43. Genes located far apart on a chromosome are mapped by adding the recombination frequencies between the distant genes and the intervening genes. • 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

44. I IV X Y III II Mutant phenotypes Short aristae Black body Cinnabar eyes Vestigial wings Brown eyes 0 48.5 57.5 67.0 104.5 Long aristae (appendages on head) Red eyes Gray body Normal wings Red eyes Wild-type phenotypes Figure 15.8 • Cytogenetic maps indicate the positions of genes with respect to chromosomal features

45. Concept 15.4: Alterations of chromosome number or structure cause some genetic disorders • Large-scale chromosomal alterations • Often lead to spontaneous abortions or cause a variety of developmental disorders • When nondisjunction occurs • Pairs of homologous chromosomes do not separate normally during meiosis • Gametes contain two copies or no copies of a particular chromosome

46. Fig. 15-13-3 Meiosis I Nondisjunction Meiosis II Nondisjunction Gametes n – 1 n + 1 n – 1 n n n + 1 n + 1 n – 1 Number of chromosomes (b) Nondisjunction of sister chromatids in meiosis II (a) Nondisjunction of homologous chromosomes in meiosis I

47. Aneuploidy • Results from the fertilization of gametes in which nondisjunction occurred • Is a condition in which offspring have an abnormal number of a particular chromosome

48. Types of aneuploidy • If a zygote is trisomic • It has three copies of a particular chromosome (2n + 1) • If a zygote is monosomic • It has only one copy of a particular chromosome (2n – 1) • If the organism survives, usually leads to a distinct phenotype

49. Figure 15.13 Polyploidy • Is a condition in which there are more than two complete sets of chromosomes in an organism

50. Polyploidy • Common in the plant kingdom • Plays a large role in the evolution of plants • Less common in animals, but more common in fish and amphibians • Triploid (3n), tetraploid (4n), etc. • Polyploids are more nearly normal than aneuploids