School of Pharmacy, University of Nizwa The Human Genome Jamaluddin Shaikh, Ph.D. Associate Professor School of Pharmacy, University of Nizwa Lecture 3 September 16, 2013

Human Genome The human genome contains approximately 3 billion chemical nucleotide bases (A, C, T, and G). Genes appear to be concentrated in random areas along the genome, with vast expanses of noncoding DNA in between. The average gene consists of approximately 3000 bases, but sizes vary greatly, with the largest known human gene being dystrophin at 2.4 million bases.

Human Genome The total number of genes encoding proteins is estimated at 20,000-25,000. About 1-2% of the human genome codes for proteins. Some of the noncoding regions are considered regulatory, and other noncoding regions are considered "junk DNA" with no function. Changes in gene sequence can occur in 0.1% of the human genome and can be a source of genetic variation. Almost all (99.9%) gene sequences are exactly the same in all people.

Human Genome It is difficult to find the genetic changes that results in real changes in drug response (it is like finding “a needle in a haystack”). The more difficult is to describe the clinical phenotype that results from the genetic change. 

Human Genome Polymorphisms in the Genome: There are several types of mutations that result in polymorphisms. 1. Missense mutation: A substitution of one nucleotide for another changes the codon so that a different amino acid is involved into the protein.

Human Genome 2. Silent mutation: A substitution of one nucleotide for another changes the codon, but does not change the amino acid (because more than one codon can specify a single amino acid). This type of mutation is not detrimental to the protein since the amino acid sequence stays the same.

Human Genome 3. Nonsense mutation: A substitution of one nucleotide for another changes an amino acid codon into a stop codon, creating a truncated protein.

Human Genome 4. Frameshift mutation: A deletion or insertion of one or more nucleotides shifts the codons, so that incorrect amino acids are specified from the point of deletion or insertion onward in the protein.

Human Genome Polymorphisms in Promoter and Introns: Differences in the promoter or introns can affect the level of expression, or activity of the gene. Mutations in the introns can affect the splicing of the gene, creating an incorrect mRNA molecule.

Human Genome Polymorphisms in specific genes, promoters, or introns can lead to differences in response to drugs or disease susceptibility.

Human Genome Example: One genotype resulting in cystic fibrosis is a deletion of 3 nucleotides in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that causes a deletion of phenylalanine in the CFTR protein. This is the individual's genotype.

Human Genome The physical manifestation of the nucleotide deletion in CFTR is chronic respiratory infection, mucus build-up, and fat maldigestion. This is the individual's phenotype.

Haplotypes and HapMap Genetic polymorphisms that are located near each other on the chromosome are considered linked, and tend to be inherited together. This set of inherited polymorphisms is termed a haplotype. The International HapMap Project (www.hapmap.org) was designed to create a haplotype map containing common polymorphisms, and use these haplotypes for future genetic studies on drug response and disease susceptipility. A haplotype is a combination of alleles at adjacent location (loci) on the chromosome that are transmitted together. The International HapMap Project is a partnership of scientists and funding agencies from Canada, China, Japan, Nigeria, the United Kingdom and the United States to develop a public resource that will help researchers find genes associated with human disease and response to pharmaceuticals