The Human Genome Project

The Human Genome Project Brief History of the Human Genome Project Physical Chromosome Maps Genetic (or Linkage) Maps DNA Markers Sequencing and Annotating Genomic DNA What Have We learned from the HGP? Identification of Disease Genes Use of Genomics for Individualized Medicine Ethical, Legal, and Social Implications

Figure 9.1: Deletion Mapping. The human gene for acid phosphatase exists in two alleles, A and B. Karyotyping of a child of homozygous parents (A/A and B/B) revealed a chromosome translocation, which mapped the gene s locus to tip of the short arm of chromosome 2. After Sutton (1988)

Figure 9.2: Physical mapping by in situ hybridization

Figure 9.3: Physical mapping of chromosomes by contigs.

Figure 9.4: Linkage of the genes for nail-patella syndrome (NPS) and the A/ B/O blood types. In this human pedigree, the roman numerals represent three successive generations. The blood type designations reflect the underlying allele combinations. Members of this family who have NPS usually show the BO blood type, except for individuals marked with an asterisk.

Figure 9.5: Crossing over between homologous chromatids can generate new combinations of genetic alleles. Part (a) shows a pair of human chromosomes 9 as they would occur in individual I/2 of Figure 9.4. N = nail-patella mutant allele n = nail-patella wild-type allele I O, I B = blood antigen alleles After Cummings (2006)

Figure S9.c: Genetic Map of human chromosome 1 After Cummings (2006)

Figure 9.6: Single Nucleotide Polymorphism (SNP) After Thieman & Palladino (2004)

Figure 9.7: Variable Number Tandem Repeats, a.k.a. Microsatellites After Thieman & Palladino (2004)

Use of VNTRs in DNA Fingerprinting From Thieman & Palladino (2004)

Update 9.1: ENCyclopedia Of DNA Elements (ENCODE) Project Using hypersensitivity to DNaseI as a criterion, an international consortium of 442 scientists from 32 institutions has linked about 80% of the previously so-called junk DNA to some biochemical function. Such non-translated but functional DNA sequences include promoters, enhancers, sequences encoding regulatory RNAs, and protein-binding regions involved in DNA methylation as well as chromatin organization. Some of these sequences have probably played major roles in the evolution of complex traits. Six articles by consortium members in the 6 September 2012 issue of Nature.

Model organisms The translated regions of a few thousand genes, many of them involved in development, aging, and neural functions, have been highly conserved in evolution. Thus, the protein encoded by a human core gene is likely to be very similar in C. elegans, Drosophila, and Danio rerio. These organisms, because they are easy to maintain and breed in the laboratory, can serve as model organisms for medically relevant research.

Figure 9.8: Finding a human disease gene

Figure S9.d: Known genetic disorders of the human From Peltonen and Kusick (2001))

After Krogh (2005)

Figure 9.9: DNA microarray. After Krogh (2005)

Update 9.2 For $ 99 and a saliva sample, personal genome testing companies offer personal genome sequence data directly to consumers. The Federal Drug Administration has posted on their web site a warning letter to 23andMe charging that the company has not provided adequate evidence about the accuracy of their results. The concern is that false positives may mislead concerned customers, such as women with a family history of breast cancer, to take harmful but unnecessary preventative measures. Legal issue: Does 23andMe provide not only information but also medical advice, which should be regulated? New York Times, 26 November 2013

Update 9.3 Concerns about civil liberties are raised by laws that allow police to take blood or saliva samples from anyone who is arrested. DNA information from such samples is stored in a national data base and used to identify criminals. Such use may include searches for imperfect matches, which could turn up relatives of persons who left DNA at a crime scene. Such relatives would then have to deal with unjust suspicion. Officers of the federal government and more than half of the U.S. states may take samples immediately, i.e. before a prosecutor files charges. If charges are not filed or dropped later, it is often left to the arrestee to ensure that his/her data are expunged from the data base and that his/her samples are removed from storage (Murphy, 2013).

Figure S9.a: DNA cloning. Preparation and screening of a mouse DNA library in bacteriophage. From Kalthoff (2001)

Figure S9.b: DNA sequencing The DNA segment to be sequenced is replicated in vitro in a way that generates labeled segments terminated randomly by incorporation of a modified nucleotide. This photograph shows the results of four sequencing reactions, terminating with an A, C, G, or T, and repeated four times (brackets at bottom). The labeled segments are separated by gel electrophoresis and made visible by autoradiography. From Kalthoff (2001)

The Human Genome Project Brief History of the Human Genome Project Physical (or Molecular) Maps Genetic (or Linkage) Maps DNA Markers Sequencing and Annotating Genomic DNA Identification of Disease Genes Use of Genomics for Individualized Medicine Ethical, Legal, and Social Implications