Molecular Biological Basis of Personalized Medicine

Molecular Biological Basis of Personalized Medicine. Although several factors are involved in the development of personalized medicine, developments in molecular biology have played an important role. Some basic terms are defined briefly in this section. 

The Human Genome 

The total genetic material of an organism, that is, an organism’s complete DNA sequence is called a genome. The human genome is very complex and contains about 3-billion nucleotides. In 2001, the total number of genes in the human genome was estimated to be 25,000, which was much less than earlier larger estimates by the International Human Genome Sequencing Consortium in 2001.

By 2005, the three members of the International Nucleotide Sequence Database Collaboration (INSDC) − the European Molecular Biology Laboratory (EMBL) Bank, GenBank, and the DNA Data Bank of Japan (DDBJ) − reached a milestone as these databases for DNA and RNA sequences reached 100 gigabases of information. The 100,000,000,000 bases of genetic code, collected since 1982, comprise over 55 million sequence entries from more than 200,000 different organisms. This information was placed in the public domain where it has been freely accessible to the scientific community.

The nucleotide sequence data bases enable researchers to share completed genomes, the genetic makeup of entire ecosystems, and sequences associated with patents. Earlier manual data entry into the repository has been replaced by new automated technology, robotics, and bioinformatics. Combined with decreased cost, these have fostered faster data collection. The gene count of 25,000 came under scrutiny after the publication of the mouse genome in 2002 revealed that many human genes lacked mouse counterparts and vice versa. The possibility that some genes were misidentified was considered. To distinguish such misidentified genes from true ones, a research team at Broad Institute (Cambridge, MA) developed a method that takes advantage of another hallmark of protein-coding genes, i.e., conservation by evolution. 

The genes were considered to be valid if and only if similar sequences could be found in other mammals such as mouse and dog. Application of this technique invalidated a total of approximately 5,000 DNA sequences that had been incorrectly added to the lists of protein-coding genes, reducing the current gene estimate to approximately 20,500 (Clamp et al. 2007). This study suggests that nonconserved open reading frames should be added to the human gene catalog only if there is clear evidence of an encoded protein. It also provides a principled method for evaluating future proposed additions to the human gene catalog.


Each human chromosome is a long linear double-stranded DNA molecule (except the mitochondrial chromosome) ranging in size from 50 to 250 million base pairs (bp). An average chromosome contains 2,000–5,000 genes within 130 million bp and is equal to about 130 cM of genetic material. A typical microband on a chromosome contains 3–5 million bp and 60–120 genes. There are approximately 400 million nucleotides in a human chromosome, but only about 10% of them actually code for genes; the rest may play different roles such as regulating gene expression.

The complex of DNA and proteins of a chromosome is called chromatin and consists of histones and non-histone proteins. The basic structural unit of chromatin is a nucleosome – a complex of DNA with a core of histones. The amount of DNA associated with each nucleosome is about 200 bp. Nucleosomes are further compacted to solenoids which are packed into loops and each of these contains about 100,000 bps of DNA. The loops are the fundamental units of DNA replication and/or gene transcription. 

A karyotype describes an individual’s chromosome constitution. Each of the 46 human chromosomes can now be counted and characterized by banding techniques. Chromosomes X and Y are the sex chromosomes. Each man carries an X chromosome and a Y chromosome. Every woman carries two X chromosomes. As there are actually few genes on the Y chromosome, men and women each have one active X chromosome that codes most of the information. 

Scientists have determined 99.3% of the euchromatic sequence of the X chromosome (Ross et al. 2005). They found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumor types. A disproportionately high number of Mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence. Examples are defects in the gene responsible for Duchenne muscular dystrophy and fragile X mental retardation. As men have only one copy of the X chromosome, it is easier to find mutated genes on that one piece of DNA.


A gene is a sequence of chromosomal DNA that is required for the production of a functional product: a polypeptide or a functional RNA molecule. Genes range in size from small (1.5 kb for globin gene) to large (approximately 2,000 kb for Duchenne muscular dystrophy gene). A gene includes not only the actual coding sequences but also adjacent nucleotide sequences required for the proper expression of genes − that is, for the production of a normal mRNA molecule.

Mature mRNA is about onetenth the size of the gene from which it is transcribed. The same DNA strand of a gene is always translated into mRNA so that only one kind of mRNA is made for each gene. Transcription is gene in action. Genes are often described as blueprints of life ands transmit inherited traits from one generation to another.


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