Tuesday, May 27, 2014

What are linkage maps?


Linkage and Crossing Over

When Gregor Mendel
examined inheritance of two traits at a time, he found that the dihybrid parent (Aa or Bb) produced offspring with the four possible combinations of these alleles at equal frequencies:¼ABAb, ¼aB, and¼ab. He called this pattern “independent assortment.” The discovery of meiosis explained the basis of independent assortment. If the A locus and the B locus are on nonhomologous chromosomes, then segregation of the alleles of one locus (A and a) will be independent of the segregation of the alleles of the other (B and b).










Even simple plants, animals, fungi, and protists have thousands of genes. The number of human genes is unknown, but with the completion of the human genome in 2003 it appeared that the actual number of protein-coding genes was only about 21,000. Human beings have forty-six chromosomes in each cell (twenty-three from the mother and twenty-three from the father): twenty-two pairs of autosomal chromosomes plus two sex chromosomes (two X chromosomes in females and an X and a Y chromosome in males). Since humans have only twenty-four kinds of chromosomes, there must be less than a few thousand genes on the average human chromosome.


If two loci fail to show independent assortment, they are said to be linked and are therefore near one another on the same chromosome. For example, if the alleles A and B are on one chromosome and a and b are on the homologue of that chromosome, then the dihybrid (AB/ab) would form gametes with the combinations AB and ab more often than Ab and aB. How much more often? At one extreme, if there is no crossover between these two loci on the two homologous chromosomes, then ½ of the gametes would be AB and ½ would be ab. At the other extreme, if the two genes are so far apart on a large chromosome that crossover occurs between the loci almost every time meiosis occurs, they would assort independently, thus behaving like two loci on different nonhomologous chromosomes. When two genes are on
the same chromosome but show no linkage, they are said to be “syntenic.”


In the first stage of meiosis, homologous chromosomes pair tightly with one another (synapsis). At this stage of meiosis, each homologous chromosome is composed of two chromatids called sister chromatids, so there are four complete DNA molecules (a tetrad) present in the paired homologous chromosomes. A reciprocal exchange of pieces of two paired homologous chromosomes can produce new combinations of alleles between two linked loci if a crossover occurs in the right region. Chromosomes that display a new arrangement of alleles due to crossover are called recombinants. For example, a crossover in a dihybrid with AB on one chromosome and ab on its homologue could form Ab and aB recombinants. The average number of crossovers during a meiotic division differs from species to species and sometimes between the sexes of a single species. For example, crossover does not occur in male fruit flies (Drosophila melanogaster), and it may occur slightly less often in human males than in females. Nevertheless, within a single sex of a single species, the number of crossovers during a meiotic division is fairly constant and many crossovers typically occur along the length of each pair of chromosomes.




Constructing the Maps

If two loci are very close together on the same chromosome, crossover between them will be rare, and thus recombinant gametes will also be rare. Conversely, crossover will occur more frequently between two loci that are farther apart on the same chromosome. This is true because the location for any particular crossover is random. This fact has been used to construct linkage maps (also called crossover maps or genetic maps) of the chromosomes of many species. The distances between loci on linkage maps are expressed as percent crossover. A crossover of 1 percent is equal to one centiMorgan (cM). If two loci are 12 cM apart on a linkage map, a dihybrid will form approximately twelve recombinant gametes for every eighty-eight nonrecombinant gametes. Linkage maps are made by combining data from many different controlled crosses or matings. For instance, suppose that a cross between a dihybrid AB/ab individual and a homozygous
ab/ab
individual produced 81 AB/ab + 83 ab/ab progeny (noncrossover types) and 20 Ab/ab + 16 aB/ab progeny (crossover types). The map distance between these loci would be 100(20 + 16)/(81 + 83 + 20 + 16) = 18 cM.


The table shows the frequency of recombinant gametes from test crosses of three different dihybrids, including the one already described:


It is clear that the C locus must be between the other two loci on the linkage map. The absolute order, ACB or BCA, is arbitrarily defined by the first person who constructs a linkage map of a species.


In this example, the linkage map is exactly additive. In real experiments, linkage map distances are seldom exactly additive, because the longer the distance between two loci, the greater chance there will be for double crossovers to occur. Double crossovers give the same result as no crossover, and are therefore not detected. Thus, the greater the distance between two loci, the more the distance will be underestimated.


Once a large number of genes on the same chromosome have been mapped, the linkage map is redrawn with map positions rather than map distances. For example, if many other experiments provided more information about linked genes, the following linkage map might emerge:


The A and C loci are still 7 cM apart (21 - 14 = 7), and the other distances on the first map are also still the same.


Very detailed linkage maps have been constructed for some plants, animals, fungi, and protists that are of particular value to medicine, agriculture, industry, or scientific research. Among them are Zea mays
(maize), Drosophila melanogaster (fruit fly), and Saccharomyces cerevisiae
(baker’s yeast). The linkage map of Homo sapiens (humans) is not very detailed because it is unethical and socially impossible to arrange all of the desired crosses that would be necessary to construct one. Other techniques have allowed the construction of very detailed physical maps of human chromosomes.




Genetic Linkage Maps and the Structure of Chromosomes

It should be emphasized that the linkage map is not a scale model of the physical chromosome. It is generally true that the relative order of genes on the linkage map and the physical chromosome map are the same. However, the relative distances between genes on the linkage map may not be proportionately the same on the physical map. Consider three loci (A, B, and C) that are arranged in that order on the chromosome. Suppose that the AB distance on the physical map is exactly the same as the BC distance. If the crossover frequency between A and B is higher than between B and C, then the AB linkage map distance will be larger than the BC linkage map distance. It is common to find small discrepancies between linkage maps and physical maps all along the chromosome. Large discrepancies are usually limited to loci close to centromeres. Crossover frequencies are generally very low near centromeres, apparently due to the structural characteristics of centromeres. If two loci are on opposite sides of a centromere, they will appear farther apart on the physical map and much closer on the linkage map.




Key terms



alleles

:

different forms of the same gene locus; in diploids there are two alleles at each locus




crossing over

:

an event early in meiosis in which homologous chromosomes exchange homologous regions




dihybrid

:

an organism that is heterozygous for both of two different gene loci




homologous chromosomes

:

chromosomes that are structurally the same and contain the same loci, although the loci may each have different alleles




locus (

:

pl. loci) The specific region of a chromosome that contains a specific gene




meiosis

:

cell division that reduces the chromosome number from two sets (diploid) to one set (haploid), ultimately resulting in the formation of gametes (eggs or sperm) or spores





Bibliography


Griffiths, Anthony J. F., Susan R. Wessler, Sean B. Carroll, and John Doebley. Introduction to Genetic Analysis. 10th ed. New York: Freeman, 2010. Print.



Liu, Ben-Hui. Statistical Genomics: Linkage, Mapping, and QTL Analysis. Boca Raton: CRC, 1998. Print.



Neale, Benjamin M. et al, ed. Statistical Genetics: Gene Mapping Through Linkage and Association. New York: Taylor, 2008. Print.



Ott, Jurg. Analysis of Human Genetic Linkage. 3rd ed. Baltimore: Johns Hopkins UP, 1999. Print.



Smith, Douglas. “The First Genetic Linkage Map.” Caltech. Caltech, 21 Mar. 2013. Web. 31 July 2014.



Terwilliger, Joseph Douglas, and Jurg Ott. Handbook of Human Genetic Linkage. Baltimore: Johns Hopkins UP, 1994. Print.



“What Is a Linkage Map?” Vegetable Genetic Improvement Network. U of Warwick, 5 Apr. 2013. Web. 31 July 2014.



Wu, Rongling, Chang-Xing Ma, and George Casella. “Linkage Analysis and Map Construction.” Statistical Genetics of Quantitative Traits: Linkage, Maps, and QTL. New York: Springer, 2007. Print.

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