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150 Part IV: Molecular and Cellular Hematology Chapter 10: Genetic Principles and Molecular Biology 151

of factor VIII or factor IX, but autosomal recessive inheritance should interaction with other genes, and the likelihood that certain individuals
suggest to the physician a deficiency of other clotting factors, such as will develop a genetic disease.
factor X, XI, or V. Careful analysis of the family history not only will Mendel’s second law, the principle of independent assortment,
make possible more appropriate genetic counseling to the patient and states that an individual’s genes will be transmitted to the next genera-
family, but also will shorten the road to a correct diagnosis. tion independently of one another. This law is only partly true, however,
because genes located close together on the same chromosome do tend
to be transmitted together to the offspring. Thus Mendel’s principle of
EPIGENETICS AND GENOMIC independent assortment holds true for most pairs of genes but not those
IMPRINTING that occupy the same region of a chromosome. Such loci demonstrate
linkage and are said to be linked.
Although this chapter focuses on DNA sequence variation and its con- During the first meiotic stage, the arms of homologous chromo-
sequence for disease, there is increasing evidence that the same DNA some pairs intertwine and sometimes exchange portions of their DNA
sequence can produce dramatically different phenotypes because of (Fig. 10–5) in a process known as crossover. During crossover, new com-
chemical modifications that alter the expression of genes (these modi- binations of alleles can be formed. For example, two loci on a chromo-
fications are collectively termed epigenetic; Chap. 12). Epigenetic altera- some have alleles A and a and alleles B and b. Alleles A and B are located
tion of gene activity can have important disease consequences. For together on one member of a chromosome pair, and alleles a and b are
example, a major cause of one form of inherited colon cancer (termed located on the other member. The genotype of this individual is denoted
hereditary nonpolyposis colorectal cancer [HNPCC]) is the methylation as AB/ab.
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of a gene whose protein product repairs damaged DNA. When this As Fig. 10–5A shows, the allele pairs AB and ab would be trans-
gene becomes inactive, damaged DNA accumulates eventually resulting mitted together when no crossover occurs. However, when crossover
in colon tumors. 36 occurs (Fig. 10–5B), all four possible pairs of alleles can be transmit-
ted to the offspring: AB, aB, Ab, and ab. The process of forming such
new arrangements of alleles is called recombination. Crossover does not
LINKAGE ANALYSIS AND GENE necessarily lead to recombination, however, because double crossover
IDENTIFICATION between two loci can result in no actual recombination of the alleles at
the loci (Fig. 10–5).
Locating genes on specific regions of chromosomes has been one of The analysis of recombination in families is used to determine
37
the most important goals of human genetics. The location and iden- the locations of disease-causing genes. Millions of SNPs have been
tification of a gene can tell much about the function of the gene, its identified in the human genome, and their chromosome locations

A 1 B 1
A B
1 1
A 1 B 1
A B
1 1
A 2 B 2
A B
2 2
A 2 B 2
A B
2 2
A
A 1 B 1 A 1 B 1
A B
1 1
A 1 B 1 A 2 B 1
A B
2 1
A 2 B 2 A 1 B 2
A B
1 2
A 2 B 2 A 2 B 2
A B
2 2
B Crossover
A 1 B 1 A 1 B 1
A B
1 1
A 1 B 1 A 2 B 1
A B
1 1
A 2 B 2 A 1 B 2
A B
2 2
A 2 B 2 A 2 B 2
A B
2 2
C
Double crossover
Figure 10–5. Genetic results of crossing over. A. No crossing over. B. Crossing over with recombination. C. Double crossing over, resulting in no
recombination. (Reproduced with permission from McCance KL, Huether SE, Brashers VL, et al: Pathophysiology: The biologic basis for disease in adults and
children, 6th edition. St. Louis, MO:Mosby/Elsevier, 2010.)

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