BIS101

Lecture 4 - Gene Linkage, Linkage maps

Reading Assignment: Text book, Chapter 5: pp 141-162.

Practice Problems: Fixsen & Lavett Solutions Manual:. Chp 5: 1-3, 6, 7, 9-11, 17,19-21, 28, 34, 39, 46.

Suggested additional activity: Visit "Linkage and Recombination" in the Electronic Companion of Genetics CD.

What do you need to know?

Summary

Gene Linkage Concept:

Loci of two genes close together on the same chromosome do not assort independently at meiosis.

Morgan proposed the term gene linkage following the segregation of two mutants in Drosophila flies: purple eye color (pr) and vestigial wing (vg).

He observed that test-crosses deviated from the expected 1:1:1:1 ratio for independent assortment:

  1. The largest classes were those corresponding to gametes contributed by the original parents of the dihybrid F1.
  1. Approximately a 1:1 ratio existed between the two parental classes and also between the two non-parental classes.

Furthermore, Morgan suggested that when chromosomes pair in meiotic prophase, they occasionally exchange parts during the process called crossing-over. He arrived at this conclusion after learning of the existence of chiasmata (chiasma, singular) in meiosis, points where non-sister chromatid exchange or cross-overs take place in meiotic prophase. Chiasmata are the visible manifestation of crossing over.

The original gene arrangement is called parental combination.

The new gene combination is called crossover products or recombinants.

Genes can be linked in two different phases:

  1. Coupling: Both recessive or dominant alleles are on the same homologue chromosome. This phase is also called cis.


For example: A     B  or  a     b

  1. Repulsion: Association of dominant with recessive alleles on the same homologue. This phase is also called trans.


For example: a     B   or   A     b

A testcross is used to determine phase of a genotype, by crossing the double heterozygote to the double recessive.


Independent assortment results in inter chromosomal recombination. Recombinant classes make 50% of the progeny. Each meiosis will produce 50% recombinant gametes.

Crossing over between two genes on the same chromosome produces intra chromosomal recombination.

When two genes are close together on a chromosome, they will tend to pass together to the resulting gametes after meiosis. The frequency of recombination depends of the distance separating the genes. Therefore, the linked genes will recombine only when there is a cross-over between non-sister chromatids in the space between them in a meiosis. Since recombination will not take place in all the cells undergoing meiosis, a total count will yield less than 50% recombinant progeny.

Crossing over generates two reciprocal products, which explains why reciprocal recombinant classes are generally in equal frequency.
 

Linkage maps:

Gene loci on a chromosome can be mapped by measuring the frequency of recombinants produced by crossing-over.


It was evident from the early work of Morgan that recombination frequencies were not always the same for two different genes, so it was suspected that it depended on the distance of the genes on the chromosome.

Morgan's student, Alfred Sturtevant, an undergraduate at the time in 1911, devised a system to determine relationships between genes, producing the first linkage map.

We still use this technique today to plot genes on chromosomes.
Sturtevant's system is based on the use of the percentage of recombinants as a quantitative index of linear distance between two genes on a linkage map.
 

Genetic map unit

It is the distance between two genes, for which one product of meiosis out of 100 is recombinant. In other words, a recombination frequency of 1%, is defined as a map unit. A map unit is also called centiMorgan in honor of the discoverer of gene linkage.


Map distances are additive.

Additivety allows the combination of distances for various genes for assembling maps or linear order of gene loci on chromosomes. Linkage maps are purely based on genetic analysis, not physical distances, which are not always related to genetic distances.

For example, in certain regions of the chromosomes, such as centromere and telomeres, there is suppression of recombination resulting in short genetic distances for long physical distances.

Map distance  between two genes is directly proportional to the crossover frequency , but only up to approximately 7 units. This is because in two given genes, an even number of crossing-overs will not be detected, and an odd number of cross-overs will yield the same number of recombinants as a single exchange.

Therefore larger physical gene intervals underestimate observed recombination. Mathematical functions for correcting distances have been developed such as Haldane's function and Kosambi's function The best gene mapping approach is the three-point testcross, which uses three genes instead of two for calculating genetic distances. The addition of a third gene allows detection of double recombinants.
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Three-point testcross

The standard approach used for linkage analysis is based on trihybrid testcross: Crossing of a triple heterozygote by a triple homozygote recessive.


This is illustrated by a Three Point Mapping Problem  (pdf)   Key (.doc)  (pdf).
 

Interference

Often a crossover in a chromosomal region affects the likelihood of a 2nd crossover in the adjacent region due to mechanical inhibition, or interference in the chromatids. If the crossovers in two regions are independent, according to the product rule, the frequency of double recombinants would be equal to the product of the recombinant frequency of the adjacent regions.


Formula to calculate interference:

I = 1 - c, where c= coefficient of coincidence

Coincidence between observed and expected double cross over (dco) classes.

c = observed dco/ expected dco

Interference estimates the percentage of double crossover that failed to materialize in a cross due to mechanical inhibition.

The X2 test is used in order to determine whether deviations from independent assortment segregation in a progeny are due to chance or to linkage.

 

Haplotype: Modern term used to specify specific combination of linked alleles in a group of related genes.

Visit related site on Gene Linkage

Applications:

Mapping genes and linkage maps have important applications for medical screening. For example the muscular dystrophy gene DS is linked by 10 map units to the S locus, coding for an specific antigen that can be detected immunologicaly.
These genetic tools are also quite useful for indirect selection of desirable traits, for example disease resistance, on the basis or linked markers in practical breeding.
Maps are also used for evolutionary inferences among related species and for other fundamental research programs. The new field of Genomics started with the gene mapping work of T. Morgan.

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Last Modified: October 2003