Chapter 062. Principles of Human Genetics (Part 12)

The Genetic MapGiven 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...
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Chapter 062. Principles of Human Genetics (Part 12) Chapter 062. Principles of Human Genetics (Part 12) The Genetic Map Given the size and complexity of the human genome, initial efforts aimedat developing genetic maps to provide orientation and to delimit where a gene ofinterest may be located. A genetic map describes the order of genes and definesthe position of a gene relative to other loci on the same chromosome. It isconstructed by assessing how frequently two markers are inherited together (i.e.,linked) by association studies. Distances of the genetic map are expressed inrecombination units, or centiMorgans (cM). One cM corresponds to arecombination frequency of 1% between two polymorphic markers; 1 cMcorresponds to ~1 Mb of DNA (Fig. 62-3). Any polymorphic sequence variationcan be useful for mapping purposes. Examples of polymorphic markers includevariable number of tandem repeats (VNTRs), RFLPs, microsatellite repeats, andSNPs; the latter two methods are now used predominantly because of the highdensity of markers and because they are amenable to automated procedures. The Physical Map Cytogenetics and chromosomal banding techniques provide a relativelylow-resolution microscopic view of genetic loci. Physical maps indicate theposition of a locus or gene in absolute values. Sequence-tagged sites (STSs) areused as a standard unit for physical mapping and serve as sequence-specificlandmarks for arranging overlapping cloned fragments in the same order as theyoccur in the genome. These overlapping clones allow the characterization ofcontiguous DNA sequences, commonly referred to as contigs. This approach ledto high-resolution physical maps by cloning the whole genome into overlappingfragments and has been essential for the identification of disease-causing genes bypositional cloning. Recent insights into the structure of the normal human genome show thatcertain blocks of DNA sequences, often containing numerous genes, can beduplicated one or several times. This copy number variation (CNV), which tendsto vary in a specific manner among different populations, is associated with hotspots of chromosomal rearrangements and is thought to play an important role innormal human variation and in genetic disease. The identification of the ~10 million SNPs estimated to occur in the humangenome has generated a catalogue of common genetic variants that occur inhuman beings from distinct ethnic backgrounds (Fig. 62-7). SNPs that are in closeproximity are inherited together, i.e., they are linked, and are referred to ashaplotypes, hence the name HapMap (Fig. 62-8). The HapMap describes thenature and location of these SNP haplotypes and how they are distributed amongindividuals within and among populations. The HapMap information is greatlyfacilitating genome-wide association studies designed to elucidate the complexinteractions among multiple genes and lifestyle factors in multifactorial disorders(see below). Moreover, haplotype analyses may become useful to assess variationsin responses to medications (pharmacogenomics) and environmental factors, aswell as the prediction of disease predisposition. Figure 62-7 Chromosome 7 is shown with the density of single nucleotidepolymorphisms (SNPs) and genes above. A 200-kb region in 7q31.2 containingthe CFTR gene is shown below. The CFTR gene contains 27 exons. More than1420 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 toillustrate the SNPs in this region. Figure 62-8 The origin of haplotypes is due to repeated recombination eventsoccurring in multiple generations. Over time, this leads to distinct haplotypes.These haplotype blocks can often be characterized by genotyping selected Tagsingle nucleotide polymorphisms, an approach that now facilitates performinggenome-wide association studies.