Chapter 062. Principles of Human Genetics (Part 13)

The Human DNA SequenceThe complete DNA sequence of each chromosome provides the highest resolution physical map. The primary focus of the HGP was to obtain DNA sequence for the entire human genome as well as model organisms. Although the prospect of determining the complete sequence of the human genome seemed daunting several years ago, technical advances in DNA sequencing and bioinformatics led to the completion of a draft human sequence in June 2000, well in advance of the original goal year of 2003. High-quality reference sequences, completed in 2003, further closed gaps and reduced remaining ambiguities, and the HGP...
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Chapter 062. Principles of Human Genetics (Part 13) Chapter 062. Principles of Human Genetics (Part 13) The Human DNA Sequence The complete DNA sequence of each chromosome provides the highestresolution physical map. The primary focus of the HGP was to obtain DNAsequence for the entire human genome as well as model organisms. Although theprospect of determining the complete sequence of the human genome seemeddaunting several years ago, technical advances in DNA sequencing andbioinformatics led to the completion of a draft human sequence in June 2000, wellin advance of the original goal year of 2003. High-quality reference sequences,completed in 2003, further closed gaps and reduced remaining ambiguities, andthe HGP announced the completion of the DNA sequence for the last of the humanchromosomes in May 2006. In addition to the human genome, the whole genomesof >2000 organisms have been sequenced partially or completely [GenomesOnline Database (GOLD); Table 62-1]. They include, among others, eukaryotessuch as man and mouse; S. cerevisiae, C. elegans, and D. melanogaster; bacteria(e.g., E. coli); and archeae, viruses, organelles (mitochondriae, chloroplasts), andplants (e.g., Arabidopsis thaliana). This information, together with technologicaladvances and refinement of computational bioinformatics, has led to a fast-pacedtransition from the study of single genes to whole genomes. The current directionsarising from the HGP include, among others, (1) the comparison of entire genomes(comparative genomics), (2) the study of large-scale expression of RNAs(functional genomics) and proteins (proteomics) in order to detect differencesbetween various tissues in health and disease, (3) the characterization of thevariation among individuals by establishing catalogues of sequence variations andSNPs (HapMap project), and (4) the identification of genes that play critical rolesin the development of polygenic and multifactorial disorders. Ethical Issues Implicit in the HGP is the idea and hope that identifying disease-causinggenes can lead to improvements in diagnosis, treatment, and prevention. It isestimated that most individuals harbor several serious recessive genes. However,completion of the human genome sequence, determination of the association ofgenetic defects with disease, and studies of genetic variation raise many newissues with implications for the individual and mankind. The controversiesconcerning the cloning of mammals and the establishment of human ES cellsunderscore the relevance of these questions. Moreover, the information gleanedfrom genotypic results can have quite different impacts, depending on theavailability of strategies to modify the course of disease. For example, theidentification of mutations that cause multiple endocrine neoplasia (MEN) type 2or hemochromatosis allows specific interventions for affected family members. Onthe other hand, at present, the identification of an Alzheimer or Huntington diseasegene does not alter therapy and outcomes. In addition, the progress in this area isunpredictable, as underscored by the finding that angiotensin II receptor blockersmay slow disease progression in Marfan syndrome. Genetic test results can generate anxiety in affected individuals and familymembers, and there is the possibility of discrimination on the basis of the testresults. Most genetic disorders are likely to fall into an intermediate categorywhere the opportunity for prevention or treatment is significant but limited (Chap.64). For these reasons, the scientific components of the HGP have been paralleledby efforts to examine ethical and legal implications as new issues arise. About 5%of the HGP budget has been allocated to studies addressing the ethical, legal, andsocial implications associated with the increasing knowledge about the humangenome and the genetic basis of disease. Many issues raised by the genome project are familiar, in principle, tomedical practitioners. For example, an asymptomatic patient with increased low-density lipoprotein (LDL) cholesterol, high blood pressure, or a strong familyhistory of early myocardial infarction is known to be at increased risk of coronaryheart disease. In such cases, it is clear that the identification of risk factors and anappropriate intervention are beneficial. Likewise, patients with phenylketonuria,cystic fibrosis, or sickle cell anemia are often identified as having a genetic diseaseearly in life. These precedents can be helpful for adapting policies that relate togenetic information. We can anticipate similar efforts, whether based on genotypesor other markers of genetic predisposition, to be applied to many disorders. Oneconfounding aspect of the rapid expansion o ...