Chapter 062. Principles of Human Genetics (Part 12) The Genetic Map Given the size and complexity of the human genome, initial efforts aimed at developing genetic maps to provide orientation and to delimit where a gene of interest may be located. A genetic map describes the order of genes and defines the position of a gene relative to other loci on the same chromosome. It is constructed by assessing how frequently two markers are inherited together (i.e., linked) by association studies. Distances of the genetic map are expressed in recombination units, or centiMorgans (cM). One cM corresponds to a recombination frequency of 1% between two polymorphic markers; 1 cM corresponds to ~1 Mb of DNA (Fig. 62-3). Any polymorphic sequence variation can be useful for mapping purposes. Examples of polymorphic markers include variable number of tandem repeats (VNTRs), RFLPs, microsatellite repeats, and SNPs; the latter two methods are now used predominantly because of the high density of markers and because they are amenable to automated procedures. The Physical Map Cytogenetics and chromosomal banding techniques provide a relatively low-resolution microscopic view of genetic loci. Physical maps indicate the position of a locus or gene in absolute values. Sequence-tagged sites (STSs) are used as a standard unit for physical mapping and serve as sequence-specific landmarks for arranging overlapping cloned fragments in the same order as they occur in the genome. These overlapping clones allow the characterization of contiguous DNA sequences, commonly referred to as contigs. This approach led to high-resolution physical maps by cloning the whole genome into overlapping fragments and has been essential for the identification of disease-causing genes by positional cloning. Recent insights into the structure of the normal human genome show that certain blocks of DNA sequences, often containing numerous genes, can be duplicated one or several times. This copy number variation (CNV), which tends to vary in a specific manner among different populations, is associated with hot spots of chromosomal rearrangements and is thought to play an important role in normal human variation and in genetic disease. The identification of the ~10 million SNPs estimated to occur in the human genome has generated a catalogue of common genetic variants that occur in human beings from distinct ethnic backgrounds (Fig. 62-7). SNPs that are in close proximity are inherited together, i.e., they are linked, and are referred to as haplotypes, hence the name HapMap (Fig. 62-8). The HapMap describes the nature and location of these SNP haplotypes and how they are distributed among individuals within and among populations. The HapMap information is greatly facilitating genome-wide association studies designed to elucidate the complex interactions among multiple genes and lifestyle factors in multifactorial disorders (see below). Moreover, haplotype analyses may become useful to assess variations in responses to medications (pharmacogenomics) and environmental factors, as well as the prediction of disease predisposition. Figure 62-7 Chromosome 7 is shown with the density of single nucleotide polymorphisms (SNPs) and genes above. A 200-kb region in 7q31.2 containing the CFTR gene is shown below. The CFTR gene contains 27 exons. More than 1420 mutations in this gene have been found in patients with cystic fibrosis. A 20- kb region encompassing exons 4–9 is shown in further amplified in order to illustrate the SNPs in this region. Figure 62-8 The origin of haplotypes is due to repeated recombination events occurring in multiple generations. Over time, this leads to distinct haplotypes. These haplotype blocks can often be characterized by genotyping selected Tag single nucleotide polymorphisms, an approach that now facilitates performing genome-wide association studies. . Chapter 062. Principles of Human Genetics (Part 12) The Genetic Map Given the size and complexity of the human genome, initial efforts aimed at. the identification of disease-causing genes by positional cloning. Recent insights into the structure of the normal human genome show that certain blocks of DNA sequences, often containing numerous. corresponds to ~1 Mb of DNA (Fig. 62-3). Any polymorphic sequence variation can be useful for mapping purposes. Examples of polymorphic markers include variable number of tandem repeats (VNTRs),