Chapter 062. Principles of Human Genetics (Part 13)

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The Human DNA Sequence The 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) The Human DNA Sequence The 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 announced the completion of the DNA sequence for the last of the human chromosomes in May 2006. In addition to the human genome, the whole genomes
of >2000 organisms have been sequenced partially or completely [Genomes Online Database (GOLD); Table 62-1]. They include, among others, eukaryotes such as man and mouse; S. cerevisiae, C. elegans, and D. melanogaster; bacteria (e.g., E. coli); and archeae, viruses, organelles (mitochondriae, chloroplasts), and plants (e.g., Arabidopsis thaliana). This information, together with technological advances and refinement of computational bioinformatics, has led to a fast-paced transition from the study of single genes to whole genomes. The current directions arising 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 differences between various tissues in health and disease, (3) the characterization of the variation among individuals by establishing catalogues of sequence variations and SNPs (HapMap project), and (4) the identification of genes that play critical roles in the development of polygenic and multifactorial disorders. Ethical Issues Implicit in the HGP is the idea and hope that identifying disease-causing genes can lead to improvements in diagnosis, treatment, and prevention. It is estimated that most individuals harbor several serious recessive genes. However, completion of the human genome sequence, determination of the association of genetic defects with disease, and studies of genetic variation raise many new issues with implications for the individual and mankind. The controversies
concerning the cloning of mammals and the establishment of human ES cells underscore the relevance of these questions. Moreover, the information gleaned from genotypic results can have quite different impacts, depending on the availability of strategies to modify the course of disease. For example, the identification of mutations that cause multiple endocrine neoplasia (MEN) type 2 or hemochromatosis allows specific interventions for affected family members. On the other hand, at present, the identification of an Alzheimer or Huntington disease gene does not alter therapy and outcomes. In addition, the progress in this area is unpredictable, as underscored by the finding that angiotensin II receptor blockers may slow disease progression in Marfan syndrome. Genetic test results can generate anxiety in affected individuals and family members, and there is the possibility of discrimination on the basis of the test results. Most genetic disorders are likely to fall into an intermediate category where the opportunity for prevention or treatment is significant but limited (Chap. 64). For these reasons, the scientific components of the HGP have been paralleled by 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, and social implications associated with the increasing knowledge about the human genome and the genetic basis of disease. Many issues raised by the genome project are familiar, in principle, to medical practitioners. For example, an asymptomatic patient with increased low-
density lipoprotein (LDL) cholesterol, high blood pressure, or a strong family history of early myocardial infarction is known to be at increased risk of coronary heart disease. In such cases, it is clear that the identification of risk factors and an appropriate intervention are beneficial. Likewise, patients with phenylketonuria, cystic fibrosis, or sickle cell anemia are often identified as having a genetic disease early in life. These precedents can be helpful for adapting policies that relate to genetic information. We can anticipate similar efforts, whether based on genotypes or other markers of genetic predisposition, to be applied to many disorders. One confounding aspect of the rapid expansion of information is that our ability to make clinical decisions often lags behind initial insights into genetic mechanisms of disease. For example, when genes that predispose to breast cancer, such as BRCA1, are described, they generate tremendous public interest in the potential to predict disease, but many years of clinical research are still required to rigorously establish genotype and phenotype correlations. Whether related to informed consent, participation in research, or the management of a genetic disorder that affects an individual or their families, there is a great need for more information about fundamental principles of genetics. The pervasive nature of the role of genetics in medicine makes it imperative for physicians and other health care professionals to become more informed about genetics and to provide advice and counseling in conjunction with trained genetic counselors (Chap. 64). The application of screening and prevention strategies will
therefore require intensive patient and physician education, changes in health care financing, and legislation to protect patient's rights.