FEATURE GENETICS
amino acid change at the b-globin chain. Yet, the first seeds of molecular
analysis were provided in the early days of recombinant DNA technology. Indeed, identification of disease-causing mutations was performed by constructing genomic DNA libraries from the affected individual, in order to first clone the mutated allele and then determine its nucleotide sequence. At the time, cDNA cloning and sequencing were invaluable tools for providing the basic knowledge on the primary sequence of various genes. The latter provided a number of DNA probes, allowing the analysis via Southern blotting of genomic regions, leading to the concept and application of restriction fragment length polymorphism (RFLP) analysis to track a mutant allele from heterozygous parents with high-risk pregnancy. In 1976, Kan and colleagues carried out, for the first time, prenatal diagnosis of a-thalassemia, using hybridization on DNA isolated from fetal fibroblasts. Later, Kan and Dozy (1978), implemented RFLP analysis to pinpoint sickle cell alleles of African descent. However, the first heritable human gene mutations to be characterized at the DNA level included gross deletions of the human a- and b-globin gene clusters giving rise to a- and b-thalassemia. Soon after, Chang and Kan (1979) implemented the newly discovered DNA sequencing techniques to characterize for the first time a point mutation leading to a genetic disease; a c.52A>T b-thalassemia mutation at codon 17 (p.K17X) of the human b-globin gene.
THE HUMAN GENOME PROJECT In the years 1984-1986, the US Department of Energy and others organized scientific meetings in which discussions included the idea of sequencing the entire human genome. A committee appointed by the US National Research Council endorsed the concept in 1988. As a result, the Human Genome Initiative came into existence as an international research program for the creation of detailed genetic and physical maps for each of the 24 different human chromosomes and the elucidation of the complete DNA sequence of the human genome. The Human Genome Project (HGP) arose from two key insights that emerged in the early 1980s: (1) the ability
MedLab Issue 3 2011 23
“A long-term project to catalogue genetic disorders in Arab populations was launched in 2004 at the Centre for Arab Genomic Studies”
to take global views of genomes could greatly accelerate biomedical research and (2) the making of such global views would require a communal effort in infrastructure building. As such, the Human Genome Project (HGP) adapted six scientific objectives: Construction of a high-resolution genetic map of the human genome Production of a variety of physical maps of the human genome Determination of the complete sequence of human DNA Parallel analysis of the genomes of a selected number of well-characterized, nonhuman model organisms Creation of instrumentation technologies to automate genetic mapping, physical mapping and DNA sequencing for the large-scale analysis of complete genomes Development of computational tools such as algorithms, software and databases for the collection, interpretation and dissemination of the vast quantities of
complex mapping and sequencing data that are generated by human genome research In 2000, a working draft of the genome
was released and, in April 2003, a complete map with high-quality reference sequence was completed, marking the end of the Human Genome Project; two years ahead of the original schedule. Coincidentally, it was also the 50th anniversary of Watson and Crick’s publication of the DNA structure. The completion of the Human Genome Project was a remarkable achievement and provided 3,164.7 million bases of reference nucleotides covering about 90% of the human genome, in which most of the 20,000 human genes are situated. In May 2006, another milestone was passed on the way to completion of the project, when the sequence of the last chromosome 1 was published in the journal Nature.
HUMAN GENOME VARIATION The completion of the human genome project has provided a large volume of data that represents the basis for the characterization of all human genes. The fact that each copy of the human genome is unique and differs in sequence from any other copy in the population by roughly 1 in 1,250 nucleotides developed the field of genetics to embrace the study of inter-individual genomic variation. This emerging discipline focuses on the 0.1% of our
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