Basis for Linkage Analysis and Association

Figure 10-1 The effect of recombination on the origin of various portions of a chromosome. Because of crossing over in meiosis, the copy of the chromosome the boy (generation III) inherited from his mother is a mosaic of segments of all four of his grandparents’ copies of that chromosome.

Although any two homologous chromosomes generally look identical under the microscope, they differ substantially at the DNA sequence level. As discussed in Chapter 4, these differences at the same position (locus) on a pair of homologous chromosomes are alleles. Alleles that are common (generally considered to be those carried by approximately 2% or more of the population) constitute a polymorphism, and linkage analysis in families (as we will explore later in the chapter) requires following the inheritance of specific alleles as they are passed down in a family. Allelic variants on homologous chromosomes allow geneticists to trace each segment of a chromosome inherited by a particular child to determine if and where recombination events have occurred along the homologous chromosomes. Several tens of millions of genetic markers are available to serve as genetic markers for this purpose. It is a truism now in human genetics to say that it is essentially always possible to determine with confidence, through a series of analyses outlined in this chapter, whether a given allele or segment of the genome in a patient has been inherited from his or her father or mother. This advance—a singular product of the Human Genome Project—is an essential feature of genetic analysis to determine the precise genetic basis of disease.

Alleles at Loci on Different Chromosomes Assort Independently


Figure 10-2 Independent assortment of alleles at two loci, 1 and 2, when they are located on different chromosomes. Assume that alleles A and B were inherited from one parent, a and b from the other. The two chromosomes can line up on the metaphase plate in meiosis I in one of two equally likely combinations, resulting in independent assortment of the alleles on these two chromosomes.

Alleles at Loci on the Same Chromosome Assort Independently If at Least One Crossover between Them Always Occurs


Figure 10-3 Crossing over between homologous chromosomes (black horizontal lines) in meiosis is shown between chromatids of two homologous chromosomes on the left. Crossovers result in new combinations of maternally and paternally derived alleles on the recombinant chromosomes present in gametes, shown on the right. If no crossing over occurs in the interval between loci 1 and 2, only parental (nonrecombinant) allele combinations, AB and ab, occur in the offspring. If one or two crossovers occur in the interval between the loci, half the gametes will contain a nonrecombinant combination of alleles and half the recombinant combination. The same is true if more than two crossovers occur between the loci (not illustrated here). NR, Nonrecombinant; R, recombinant.

How will these alleles behave during meiosis? We know that between one and four crossovers occur between homologous chromosomes during meiosis I when there are two chromatids per homologous chromosome. If no crossing over occurs within the segment of the chromatids between the loci 1 and 2 (and ignoring whatever happens in segments outside the interval between these loci), then the chromosomes we see in the gametes will be AB and ab, which are the same as the original parental chromosomes; a parental chromosome is therefore a nonrecombinant chromosome. If crossing over occurs at least once in the segment between the loci, the resulting chromatids may be either nonrecombinant or Ab and aB, which are not the same as the parental chromosomes; such a nonparental chromosome is therefore a recombinant chromosome (shown in Fig. 10-3). One, two, or more recombinations occurring between two loci at the four-chromatid stage result in gametes that are 50% nonrecombinant (parental) and 50% recombinant (nonparental), which is precisely the same proportions one sees with independent assortment of alleles at loci on different chromosomes. Thus, if two syntenic loci are sufficiently far apart on the same chromosome to ensure that there is going to be at least one crossover between them in every meiosis, the ratio of recombinant to nonrecombinant genotypes will be, on average, 1 : 1, just as if the loci were on separate chromosomes and assorting independently.

Recombination Frequency and Map Distance

Frequency of Recombination as a Measure of Distance between Loci


Figure 10-4 Assortment of alleles at two loci, 1 and 2, when they are located on the same chromosome. A, The loci are far apart and at least one crossover between them is likely to occur in every meiosis. B, The loci are so close together that crossing over between them is not observed, regardless of the presence of crossovers elsewhere on the chromosome. C, The loci are close together on the same chromosome but far enough apart that crossing over occurs in the interval between the two loci only in some meioses but not in most others.

Detecting Recombination Events Requires Heterozygosity and Knowledge of Phase


Figure 10-5 Possible phases of alleles A and a and alleles B and b.

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Nov 27, 2016 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on Basis for Linkage Analysis and Association

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