cells of the mother (germline mosaicism) may increase the apparent risk. The situation can only be resolved on the basis of previous ob- servations of the disease in question. References Griffiths, A.J.F., et al.: An Introduction to Genetic Analysis. 7th ed. W.H. Freeman & Co., New York, 2000. Harper, P.S. : Practical Genetic Counselling. 5th ed. Butterworth-Heinemann, Oxford, 1998. Vogel, F., Motulsky, A.G.: HumanGenetics. Prob- lems and Approaches. 3rd ed. Springer Ver- lag, Heidelberg\u2013New York, 1997. Fundamentals Passarge, Color Atlas of Genetics © 2001 Thieme All rights reserved. Usage subject to terms and conditions of license. 143Monogenic Inheritance Passarge, Color Atlas of Genetics © 2001 Thieme All rights reserved. Usage subject to terms and conditions of license. 144 Linkage and Recombination Linkage refers to two or more genes being in- herited together as a result of their location on the same chromosome. This depends on the distance between their loci. The closer they lie next to each other, the more frequently they will be inherited together (linked). Recombina- tion due to crossing-over between the loci (breakage and reunion during meiosis, see p. 116) leads to the formation of a new combina- tion of linked genes. When the loci are very close together, recombination is rare; when they lie farther apart, recombination is more frequent. In fact, the frequency of recombina- tion can be used as a measure of the distance between gene loci. Linkage relates to gene loci, not to specific alleles. Alleles at closely linked gene loci that are inherited together are called a haplotype. If this occurs more frequently or less frequently than expected by the individual frequencies of the alleles involved, it is referred to as linkage disequilibrium (p. 158). A. Recombination by crossing-over Whether neighboring genes on the same paren- tal chromosome remain together or become separated depends on the cytological events (1) during meiosis. If there is no crossing-over be- tween the two gene loci A and B, having the re- spective alleles A, a and B, b, then they remain together on the same chromosome (linked). The gamete chromosomes formed duringmeiosis in this case are not recombinant and correspond to the parental chromosomes. However, if crossing-over occurs between the two gene loci, then the gametes formed are recombinant with reference to these two gene loci. The cytological events (1) are reflected in the genetic result (2). For two neighboring gene loci A and B on the same chromosome, the genetic result is one of two possibilities: not recombinant (gametes correspond to parental genotype) or recombi- nant (new combination). The two possibilities can be differentiated only when the parental genotype is informative for both gene loci (Aa and Bb). B. Linkage of a gene locus with an autosomal dominant mutation (B) to a marker locus (A) The segregation of two linked gene loci in a family is shown here. There are two possibili- ties: 1, no recombination and 2, recombination. One locus (B) represents an autosomal domi- nant mutation that leads to a certain pheno- type, e.g., that of an autosomal dominant in- herited disorder. The father and three children (red symbols in the pedigree) are affected. The other locus (A) is a neighboring marker locus. All three affected children have inherited the mutant allele B as well as the marker allele A from their father. The three unaffected in- dividuals have inherited the normal allele b and the marker allele a from their father. The pater- nal allele a indicates absence of the mutation (i.e., B not present). Recombination has not oc- curred (1). In situation 2, recombination has occurred in two (indicated) persons: An affected individual has inherited alleles a and B from the father, in- stead of A and B. An unaffected individual has inherited allele A and allele b. The precondition for differentiating the pater- nal genotypes is heterozygosity at the father\u2019s loci. In the case presented, the alleles A and B lie on one of the father\u2019s chromosomes, and the al- leles a and b on the other (in cis position). It would also be possible that alleleA in the father would lie on one chromosome and allele B on the other (in trans position). These two possi- bilities represent two different linkage phases. The recognition of recombination as opposed to nonrecombination assumes knowledge of the parental linkage phase. Segregation analysis of linked genes is very im- portant in medical genetics because the pres- ence or absence of a disease-causing mutation can be determined without directly knowing the type of mutation (indirect gene analysis). In order to reduce the probability of recombina- tion, closely linked, flanking markers (DNA polymorphisms, see p. 72) are used. Fundamentals Passarge, Color Atlas of Genetics © 2001 Thieme All rights reserved. Usage subject to terms and conditions of license. 145Linkage and Recombination Passarge, Color Atlas of Genetics © 2001 Thieme All rights reserved. Usage subject to terms and conditions of license. 146 Genetic Distance between Two Gene Loci and Recombination Frequency The closer together two gene loci are located, themore frequently they are inherited together (genetic linkage); the farther apart, the more frequently they become separated by recombi- nation. The highest possible frequency of re- combination is 50% (0.50), because this corre- sponds to the frequency of segregation of genes on different chromosomes. Thus, the frequency of recombination reflects the distance between two loci (genetic distance). This distance can be expressed as the frequency of genetic recombi- nation (as opposed to the physical distance, which is given as the number of DNA base pairs lying between the two loci, see p. 240). Synteny (H. J. Renwick, 1971) refers to gene loci being located on the same chromosome, whether or not they are linked. Thus the term synteny also includes unlinked, widely sepa- rated loci on the same chromosome. A. Recombination frequency as a consequence of the distance between two loci Two neighboring gene loci A and B in the parents may either become recombinant or re- main nonrecombinant (see p. 144). If one of the parents is heterozygous for two alleles Aa and Bb, but the other homozygous for both, then ho- mozygosity at only locusA (1) or only locusB (2) in the offspring will be the result of recombina- tion. The observed recombination frequency between locus A and locus B (3%) results from the distance between them. These two loci are said to be 0.03 recombination units (3 cM) apart. One recombination unit is a centimorgan (cM), and 1 cM corresponds to a recombination frequency of 1% (0.01). In mammals, recombi- nation occurs more often in female meiosis than in male meiosis, so that the genetic dis- tance in females is about 1.5 times greater than in males (see p. 240). The term morgan is derived from the name of the American geneti- cist who in 1911 first described recombination in Drosophila. At that time, the observation of linkage and recombination was an important argument for genes being linearly arranged along the chromosomes. B. Determination of the order of three gene loci and their relative distances from each other by measuring recombination frequency Not only the relative distances between gene loci but also their order can be determined by comparing recombination frequencies. In the example presented, the order of three gene loci, A, B, and C of unknown distance from each other is to be determined (1). In plants and ani- mals, the distance between any two of the loci (locusA from locusB, locusB from locusC, locus A from locus C) can be established. In traditional experimental genetics, such hy- bridization experiments were used for this pur- pose.