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The ability to analyze data obtained from the entire human genome (genomics) is having a significant impact on hematology and on medicine in general. This chapter provides a basic description of microarray technology and how this technology can be used to study disease-associated genetic variation, copy number variation, gene expression, and patterns of epigenetic modification. In addition, the principles of epigenetics, in which the expression of genes is altered by chemical modifications such as methylation, are reviewed. Several disease examples are given in which epigenetic modifications have significant clinical effects.

Acronyms and Abbreviations

Acronyms and abbreviations that occur in this chapter include: DMR, differentially methylated region; IGF2, insulin-like growth factor 2; mRNA, messenger ribonucleic acid; SNP, single nucleotide polymorphism.

Increasingly, genetic variation is being assessed at the level of the entire genome. Studies of genome-wide variation are part of the now well-known science of genomics.1 During the past decade, several important tools have emerged that allow investigators to collect and analyze genomic data.

The most widely used of these tools is the microarray (Fig. 10–1).2,3 To make a DNA microarray, single-stranded DNA sequences consisting of about 20 bases (oligonucleotides, from “a few” nucleotides) are robotically placed on a small glass slide. A single slide (1 cm2) can contain millions of different oligonucleotides. These oligonucleotides correspond to different alleles (DNA sequences at a specific chromosome location) in populations. Typically these alleles are single-nucleotide polymorphisms (SNPs). Some of the oligonucleotides may contain known disease-causing mutations. Fluorescently labeled single-stranded DNA from a subject is hybridized with the oligonucleotides on the slide to determine, for a specific region in the genome, which DNA sequence undergoes complementary base pairing with that of the subject. The pattern of hybridization signals is analyzed by a computer, providing a detailed profile of genetic variation specific to an individual’s DNA. With current technology, enough probes can be placed on a single microarray to analyze variation in one million SNPs in an individual.

Figure 10–1.

Schematic of a microarray, in which oligonucleotides are placed or synthesized on a glass slide and then hybridized with labeled single-stranded DNA from a subject. Complementary base pairing will occur between the subject DNA fragment and the oligonucleotide on the slide only if the sequences are complementary to one another. A fluorescent label on the subject’s DNA marks the location on the microarray at which the subject’s DNA undergoes hybridization, thus indicating the DNA sequence of the subject at a specific location in the genome.

(From Jorde LB, Carey JC, Bamshad MJ: Medical Genetics, 4th ed. Mosby/Elsevier, Philadelphia, 2010. With permission.)

SNP microarrays are now used routinely to perform genome-wide association studies, in which the frequencies of each SNP are compared in disease cases and unaffected controls.4 SNPs that show ...

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