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Chapter 8 Linkage and Chromosome Mapping in Eukaryotes

Chapter 8 Linkage and Chromosome Mapping in Eukaryotes. genes close together on a chromosome do not assort independently at meiosis Recombination 重组 genotypes with new combinations of parental alleles homologous chromosomes can exchange segments by crossing-over

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Chapter 8 Linkage and Chromosome Mapping in Eukaryotes

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  1. Chapter 8 Linkage and Chromosome Mapping in Eukaryotes • genes close together on a chromosome do not assort independently at meiosis • Recombination重组 genotypes with new combinations of parental alleles • homologous chromosomes can exchange segments by crossing-over • recombination results from either independent assortment or crossing-over

  2. genes can be mapped by measuring frequencies of recombinants produced by crossing-over • interlocus map distances based on recombination measurements are ~ additive • one crossover can influence the occurrence of a second one in an adjacent region

  3. Linkage Versus Independent Assortment • Incomplete Linkage,Crossing over, and Chromosome Mapping • Mapping In Drosophila and Maize • The Accuracy of Mapping Experiment • The Genetic Map of Drosophila • Somatic Cell Hybridization and Human Gene mapping • Haploid Organisms in Linkage and mapping Studies • Other aspects of Genetic exchange • Did Mendel Encounter linkage

  4. 8.1 LINKAGE versus INDEPENT ASSORTMENT • observe deviations from • 9 : 3 : 3 : 1 ratios derived from dihybrid crosses • 1 : 1 : 1 : 1 ratios derived from test crosses • 1906年 香豌豆杂交： 实验1、P 紫花长形花粉 X 红花圆形花粉 F1 紫花长形花粉 ⊕ F2 紫长 紫圆 红长 红圆 P-L- P-ll ppL- ppll

  5. Bateson 和Punnett发现非自由组合现象： 互引相（coupling phase）：AB/ab 互斥相（repulsion phase）：Ab/aB

  6. Mendel’s principle of independent assortment states that: In a cross involving more than one gene, the different genes assort independently of each other.

  7. Independent assortment is true for: Genes on separate chromosomes. Genes on the same chromosome (linked genes) if they are far apart.

  8. unlinked genes, different chromosomes • write as ... Aa; Bb or A/a; B/b • illustrate as ... • segregate and assort independently • test cross to a/a; b/b  4 progeny types ... 1 AB : 1 Ab : 1 aB : 1 ab

  9. linked genes, same chromosomes • write as ... Aa Bb or AB/ab or Ab/aB • 2 possible dihybrids, illustrate as ... • segregate and assort dependently ~ distance • test cross to ab/ab  4 progeny types ... in CIS: < 1 AB : > 0 Ab : > 0 aB : < 1 ab in TRANS: > 0 AB : < 1 Ab : < 1 aB : > 0 ab

  10. A simplified overview of the major theme of this chapter is given in Figure 8-1, which contrasts the meiotic consequences of (a) independent assortment, (b) linkage without crossing over, and (c) linkage wish crossing over. In Figure 8-l(a)

  11. Independent assortment(genes on different chromosomes or very far apart on one chromosome):

  12. compare these results with what occurs if the same genes are linked on the same chromosome. If no crossing over occurs between the two genes [Figure 8-1 (b)], only two genetically different gametes are formed. Each gamete receives the alleles present on one homolog or the other, which transmits intact as the result of segregation. This case demonstrates complete linkage, which produces only parental or noncrossover gametes

  13. Complete linkage(genes too close on the chromosome for crossing-over to occur):

  14. exchange generates two new allele combinations, called recombinant or crossover gametes.

  15. Incomplete linkage: More than 50% of offspring with parental arrangement of genes and fewer than 50% with alleles recombined.

  16. The LINKAGE ratio连锁比 • Complete linkage exists between two genes because of their close proximity, and organisms heterozygous at both loci are mated, an F2 phenotypic ratio results that is unique, which we designate the linkage ratio.

  17. 8.2 Incomplete Linkage,Crossing over, and Chromosome Mapping • It is highly improbable that two randomly selected genes linked on the same chromosome will be so close to one another along the same chromosome that they demonstrate complete linkage. Instead, crosses involving two such genes almost always produce a percentage of offspring resulting from recombinant gametes. This percentage is variable and depends on the distance between the two genes along the chromosome. This phenomenon was first explained in 1911 by two Drosophila geneticists, Thomas H. Morgan and his undergraduate student, Alfred H. Sturtevant.

  18. Morgan and Crossing Over FIGURE 8-3 In cross A, 1.3 percent of the F2 flies (males and females) demonstrate recombinant phenotypes, which express either white or yellow. In cross B, 37.2 percent of the F2 flies (males and females) demonstrate recombinant phenotypes, which express either miniature or white.

  19. For recombination to occur between two linked genes, a crossover must occur between them. • The probability that a crossover will occur between two linked genes is directly proportional to the distance between them. • Therefore, the frequency of recombination can be used as an indicator of the distance between genes.

  20. Single Crossovers Why should the relative distance between two loci influence the amount of recombination and crossing over observed between them? During meiosis, a limited number of crossover events occurs in each tetrad. These recombinant events occur randomly along the length of the tetrad. Therefore, the closer two loci reside along the axis of the chromosome, the less likely any single crossover event will occur between them.

  21. The same reasoning suggests that the farther apart two linked loci, the more likely a random crossover event will occur between them. In Figure 8-5(a), a single crossover occurs between two nonsister chromatids, but not between the two loci; there the crossover goes undetected because no recombinant gametes are produced. In Figure 8-5(b). where two loci are quite far apart, the crossover occurs between them, yielding recombinant gametes.

  22. When a single crossover occurs between two nonsister chromatids, the other two chromatids of the tetrad are not involved in this exchange and enter the gamete unchanged. Even if asingle crossover occurs 100 percent of the time between two linked genes, recombination is subsequently observed in only 50 percent of the potential gametes formed. This concept is diagrammed in Figure 8-6.

  23. Sturtevant and Mapping Morgan's student, Alfred H. Sturtevant, was the first to realize that his mentor's proposal could be used to map the sequence of, as well as the distance between, linked genes. Sturtevant compiled further data on recombination between the genes represented by the yellow, white, and miniature mutants initially studied by Morgan. Frequencies of crossing over between each pair of these three genes were observed in separate crosses to be (1) yellow, white0.5%(2) white, miniature 34.5%(3) yellow, miniature 35.4%

  24. Recombination Analysis Recombination analysis is a technique used to determine how frequently a crossover occurs between two genes during meiosis and, therefore, how far apart the genes are on the chromosome.

  25. two-point testcross • To do recombination analysis, • you need: • A heterozygote for two genes known to be on the same chromosome. • A homozygous recessive to test cross it to (so that every genotype will have a unique phenotype). • Enough offspring for accurate counts of non-crossover and crossover progeny.

  26. Recombination Analysis AABB × aabb Line indicates alleles are on the same chromosome. [coupling (cis) linkage] AAbb × aaBB [repulsion (trans) linkage]

  27. What is the distance betweentwo X-linked genes in Drosophila? w = white eyes; w+ = red eyes m = miniature wings; m+ = normal wings Inbred stock #1 white eyes, miniature wings Inbred stock #2 red eyes, normal wings (wildtype) + +

  28. Make an F1 hybrid • Testcross it.

  29. Testcross: Gametes: F2 Phenotypes: Calculate the percentage of offspring that result from crossing over = 217 + 230 / 1190 x 100.

  30. Recombinant Frequency (RF)

  31. miniature wings white eye X chromosome 37.6% recombinant frequency (RF) 37.6 map units 37.6 centiMorgans (cM)

  32. Another mapping experiment: pr = purple eyes, pr+= red eyes vg = vestigial wings, vg+ = normal wings Inbred stock #1 (Wildtype) Inbred stock #2 (Purple eyes, vestigial wings)

  33. Make an F1 hybrid • Testcross it. • List the gametes each testcross parent will produce: (Wildtype phenotype)

  34. Total CO frequency (RF) = 11.5% (20 + 22 /382 x 100)

  35. vestigial wings purple eye 11.5% recombinant frequency 11.5 map units 11.5 centiMorgans (cM)

  36. 交换机制? • 1.交换的机制 在同一染色体上相互连锁的基因为什么会出现一定频率的重组？换言之，在两对基因连锁遗传时，形成亲代所没有的新组合的机制是什么？ • Janssens（1909）根据两栖类和直翅目昆虫的减数分裂的观察，在摩尔根等人确立遗传的染色体学说之前，就提出了一种交叉型假设（chiasmatype hypothesis），其要点是： • （1）在减数分裂期，尤其是双线期，配对的染色体不是简单的平行的，而是在某些位点上出现交叉缠绕，在这些交叉缠绕的点上是同源染色体发生交换的地方。 • （2）相互连锁在同一染色体上的基因之间如果发生交换，就可导致两个基因的重组（recombination)

  37. 连锁交换定律: 处在同一染色体上的两个或多个基因联合在一起传入子代的频率大于重新组合的频率. 重组类型的产生是由于配子形成时，同源染色体的非姊妹染色单体间发生了局部交换的结果。

  38. 三大遗传定律的关系 • 分离定律是自由组合定律和连锁交换定律的基础 • 自由组合定律和连锁交换定律是变异的主要机制 • 自由组合是染色体间重组（分配）(interchromosomal recombination) • 交换则是染色体内重组(intrachromosomal recombiation)

  39. 连锁群 通过连锁遗传研究，得出两条基本规则： （1）如果A基因与B基因连锁，B与C连锁，A与C也连锁 （2）如果A基因与B基因连锁，B与C不连锁，A与C也不连锁。 基因位于染色体上，那么同一条染色体的不同基因就组成了一个连锁群。理论上讲，每种生物有多少对染色体，就有多少个连锁群。

  40. A b A B a B a b A B a b A B A B A b a b a B a b 交换发生在染色体复制之后 A b 交换 复制 a B A b 复制 交换 a B A b a B

  41. 基因定位与染色体作图染色体图（chromosome ma）称基因连锁图（linkage map）或遗传图（genetic map）1. 两点测交(two-point testcross) bi-w: 5.3cM w-y: 1.1 cM (1) w-y-bi (2) y-w-bi y-bi: 5.5 cM bi w 5.3cM w y 1.1 cM (1) w y bi 1.1 cM 4.2cM (2) y w bi 1.1 cM 5.3cM y-bi: 5.5 cM 依据基因之间的交换值（或重组值），确定连锁基因在染色体上的相对位置而绘制的一种简单线性示意图。

  42. 三点测验与基因定位 • Morgan1911曾提出，重组值的大小可能由基因在染色体上的距离决定。这个设想可以用实验的方法来验证.例如a.b.c三个基因相互连锁，可用两两间a-b、b-c、a-c间的重组值确立三者之间的关系。但这样做很烦琐。 • Morgan与他的学生Sturtevant提出了一个包括三个基因的一次性交配测定三者关系的方法。既三杂合体abc/+++或ab+/++c,与三隐性个体abc/abc测交。这种测验称三点测验。一次测验等于三次两点测验。其优点： • （1）一次测验得到三个重组值，在同一基因型背景同一环境。 • （2）可得到两点测验得不到的数据——双交换值。 • 看一下黑腹果蝇中三点测验的例子：

  43. 2. 三点测交(three-point testcross): 由摩尔根的学生Sturtevant创立 三杂合体(abc/+ + +) × 三隐性纯合体(abc/abc) w,y,bi/+ + + × w,y,bi/w,y,bi 例如: ec + +/+ sc cv × ec sc cv/y棘眼、缺胸刚毛、缺横脉 表型 个体数目 比例 交换发生在 ec + + 810 + sc cv 828 ec sc + 62 + + cv 88 + sc + 89 ec + cv 103 RF ec-sc=7.6 cM RF ec-cv=9.7 cM RF sc-cv=17.3 cM 82.7% 亲本类型,无交换 7.6% sc-ec, sc-cv之间发生交换 9.7% ec-cv, sc-cv之间交换 Sc ec cv 7.6 9.7 17.3

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