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LECTURE 5: LINKAGE

LECTURE 5: LINKAGE. Linked genes, recombination, and chromosomal mapping. Mendel's Law of Independent Assortment is a consequence of the fact that chromosomes segregate independently in meiosis. Take two individuals One heterozygous and one homozygous. AaBb x aabb. ab. AaBb. AB. 25%.

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LECTURE 5: LINKAGE

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  1. LECTURE 5: LINKAGE

  2. Linked genes, recombination, and chromosomal mapping Mendel's Law of Independent Assortment is a consequence of the fact that chromosomes segregate independently in meiosis Take two individuals One heterozygous and one homozygous AaBb x aabb ab AaBb AB 25% aB aaBb 25% Aabb 25% Ab aabb 25% ab

  3. Chromosome alignment in MeiosisI These results are readily explained by the two alternative ways the chromosomes can line up on the metaphase plate during meiosis I: a A a A OR B b b B AB ab Ab aB Because the A and B genes assort independently, AaBb dihybrids constructed from different parental genotypes will behave the same. AABBxaabb AAbbxaaBB

  4. a a A A B b B b AAbb x aaBB AABB x aabb AaBb OR Test Cross AaBb x aabb AaBb x aabb ab ab AaBb AaBb AB AB 25% 25% aB aB aaBb aaBb 25% 25% Aabb Aabb 25% 25% Ab Ab aabb aabb 25% 25% ab ab

  5. Why 50:50Why not 25:25:25:25 A hypothetical dihybrid cross involving the genes A and C produced the following results: · A= Tall a= short · C= Cream c = white Cross I: Cross II: Tall, Cream x short, white Tall, white x short, Cream AACC aacc AAcc aaCC Tall, Cream AaCc Tall, Cream AaCc X X short, white aacc short, white aacc 50% Tall, Cream 50% Tall, white 50% short, white 50% short, Cream Why 50:50? Why not 25:25:25:25?

  6. In these crosses, independent assortment is not occurring. For example in the first cross, the alleles Tall and Cream behave as if they are linked to one another. Similarly in the second cross the alleles Tall and white appear as if they are linked to one another. These results are readily explained if the genes A and C lie next to one another on the same chromosome:

  7. Cross I: a-c a-c a-c A-C a-c A-C a-c a-c A-C X a-c Short white A-C Tall cream a-c A-C X a-c a-c Tall cream Short white A= Tall a= short C= Cream c = white

  8. Cross II: a-c a-C a-c A-c a-C A-c a-c a-C A-c X a-C Short cream A-c Tall white a-c A-c X a-C a-c Tall white Short cream A= Tall a= short C= Cream c = white

  9. Purple vestigial Morgan performed the following experiments in Drosophila to determine if the genes pr and vg were linked. PR+ = normal red eyes pr = purple eyes VG+ = normal wings vg = vestigial wings P PR+PR+ VG+VG+ x prpr vgvg F1 PR+pr VG+vg x prpr vgvg If they are on different chromosomes they should assort independently If they are next to one another on the same chromosome they should not assort independently pr vg pr vg PR+ VG+ pr vg PR+ VG+ pr vg PR+ VG+ 25% PR+ VG+ ~50% PR+ vg pr vg PR+ vg pr vg 25% ~0% PR+ vg PR+ vg pr VG+ pr vg pr VG+ pr vg 25% ~0% pr VG+ pr VG+ pr vg pr vg pr vg pr vg pr vg 25% pr vg ~50%

  10. When Morgan performed this cross, he obtained the following result: pr vg PR+ VG+ pr vg PR+ VG+ ~44% 1005 PR+ vg pr vg ~6% 153 PR+ vg Pr VG+ pr vg ~6% 143 Pr VG+ pr vg pr vg pr vg ~44% 968 Although the non- parental classes are present, their frequencies are dramatically reduced from that expected from independent assortment. The two loci are linked !!! How do we explain the presence of non-parental classes?

  11. Morgan suggested that when homologous chromosomes pair during meiosis I, the chromosomes occasionally exchange parts PR+ VG+ pr vg P PR+ VG+ pr vg pr vg pr vg F1 PR+ VG+ PR+ VG+ pr vg pr VG+ Crossover chromosome PR+ vg PR+ VG+ The chromosomes that have gone through this crossover are known as crossover products or recombinants. The original chromosomes and those that have not undergone a crossover are known as parental. Evidence for the model that chromosomes physically exchange during meiosis is found in meiotic structures known as chiasmata. During meiosisI when homologs pair, non-sister chromatids appear to cross with each other. The resulting cross-shaped structure is known as a chiasmata.

  12. Crossing-over through the microscope Duplicated homologous chromosomes Synapsis in meiosis I Crossing over between Non-sister chromatids Anaphase in meiosisI Segregation of homologous chromosomes Haploid gametes in meiosis II

  13. Answer: How does one determine whether two genes reside on different chromosomes or reside on the same chromosome as linked genes? To explain this we need to define the terms parental and recombinant: Parents: AB/AB x ab/ab Gametes: AB ab F1: AB/ab Meiosis produces the following gametes: AB Ab aB ab Recombinant gametes are those with different allelic combinations than those gametes of the previous generation.

  14. Coupling/repulsion Genes located on the same pair of homologous chromosomes are called LINKED GENES Therefore when the A and C alleles are introduced from one parent they are physically located on the same chromosome and they do not assort independently. We say that they are linked. In the above cross we say that the A and C genes are linked. Therefore when we write the genotype of a dihybrid for two linked genes, there are two possible conformations: AaCc

  15. Coupling/repulsion- PHASE • Results like these led Morgan to suggest that the A and C genes are located on the same pair of homologous chromosomes. • Therefore when the A and C alleles are introduced from one parent they are physically located on the same chromosome and they do not assort independently. We say that they are linked. • In the above cross we say that the A and C genes are linked. • Therefore when we write the genotype of a dihybrid for two linked genes, there are two possible conformations: • AaCc • ----A----C------o----- • ----a----c------o----- Coupling conformation • (linkage of two dominant • or two recessive alleles) • ---A----c-------o----- • ---a----C-------o----- Repulsion conformation • (linkage of a dominant and recessive allele)

  16. If genes A and B are on different chromosomes: B b A a P b B a A B A b a Gamete b B a A F1 diploid b a b a (tester) B A 25% Parental b a b a 25% Parental b a Test cross progeny b A 25% Recombinant b a B a 25% Recombinant b a

  17. Genes A and B are linked on the same chromosome A-B a-b P A-B a-b A-B a-b Gamete A-B a-b F1 diploid a-b a-b (tester) A-B > 25% Parental a-b a-b > 25% Parental a-b Test cross progeny A-b < 25% Recombinant a-b a-B < 25% Recombinant a-b

  18. Recombination frequency A B parental A B A B recombinant A b a b a B recombinant a b parental a b IF a crossover occurred between linked genes each time homologs paired, the recombinant frequency would be 50% This is because crossing-over involves only two of the four chromatids on the metaphase pair (each of the paired homologs consists of two sister chromatids). For example, the frequency of recombinant gametes between linked genes A and B is 50% if crossing-over occurred each time the homologs paired.

  19. However there are many instances in which the homologs pair and crossing over does not occur between genes A and B. It occurs somewhere else Consequently the overall frequency of recombinants is significantly reduced from 50% A B A B parental parental A B A B a b a b parental a b parental a b

  20. A B A B a b a b A B A B a b a b A B A b a B a b A B A B A B A B a b a b a b a b A B A B a b a b

  21. Distance The larger the distance between two genes residing on the same chromosome, the higher the probability there is that a crossover event will occur between them. That is for any chromosome, there is a fixed probability per given distance on the chromosome that a crossover event will event. Sturtevant realized that this property could be used to map genes with respect to one another. For each pair of genes on a chromosome a recombination frequency can be determined. By determining the recombination frequency between many pairs of genes on a chromosome, the relative distance between genes and the order of the genes on the chromosome can be determined.

  22. Distance The larger the distance between two genes residing on the same chromosome, the higher the probability there is that a crossover event will occur between them. That is for any chromosome, there is a fixed probability per a given distance on the chromosome that a crossover event will event. Sturtevant realized that this property could be used to map genes with respect to one another. For each pair of genes on a chromosome a recombination frequency can be determined. By determining the recombination frequency between many pairs of genes on a chromosome, the relative distance between genes and the relative order of the genes on the chromosome can be determined. On average a car breaks down every 40 miles Santa Cruz to San Francisco is 80 miles= 2 breakdowns Santa Cruz to Monterrey is 45 miles = 1 breakdown There is greater probability that your car will break down between Santa Cruz and San Francisco. If crossing-over occurs once every 50 kb of DNA, then there is greater probability of a crossover between two genes 100 kb apart than two genes 50 kb apart.

  23. For example Sturtevant identified three recessive mutations that reside on the X chromosome of Drosophila W+ red eyes w- white eyes CV+ normal wings cv- crossveinless SN+ normal bristle sn- singed bristle cv w sn Cen Tel X chromosome By calculating recombination frequencies between each pair of genes we can begin to establish where these three genes reside on the X chromosome with respect to one another

  24. To determine the distance between the w gene and the sn gene P w sn/w sn x W+ SN+/Y F1 w sn/W+ SN+ x w sn/Y F2 y w sn Red eye Normal bristle 96 Red eye Normal bristle 102 W+ SN+ Parental White eye Singed bristle 92 White eye Singed bristle 88 w sn White eye Normal bristle 24 White eye Normal bristle 23 w SN+ Recomb Red eye Singed bristle 24 Red eye Singed bristle 23 W+ sn Fill out the phenotypes- recombinants can be determined by phenotype analysis

  25. Recombination frequency equals the number of recombinants over total number of progeny white eye red eye # recombinant progeny = normal bristle + singed bristle # total progeny # total progeny = 24+24+23+23=94/472 1 map unit (m.u.) = 1% recombination frequency Therefore _19.92% or ~20cM or ~20 m.u. separate the W+ and SN+ genes. This is a relative distance- depends upon recombination between two genes. Not an absolute distance like bp In the above cross, we could have determined recombination frequency by counting only males (or only females)

  26. w -------20--------sn The next issue is where does cv map with respect to w and sn: By crosses similar to those described above, we find that there are 7 m.u. between cv and sn This means cv can map to either one of two positions: w ____________14?______________cv_________7___ sn OR B) w______________20____________ sn_________7____ cv These models can be distinguished by determining the map distance between w and cv. Recombination analysis indicates 14 m.u. between w and cv. By determining the map distance between w and cv and the map distance between cv and sn, we can determine the distances and order of all three genes. Which map is consistent with this distance? Internal inconsistency- 14+7=21 not 20 Map gives you order of genes but not PRECISE distance

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