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

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.