Since the discovery and publication of the molecular structure of nucleic acids by Watson and Crick in 1954, the genetic basis for many conditions has been determined; however, misconceptions remain regarding the role of genetics and genomics in clinical medicine.3 Despite the commonly held notion that genetics had little influence on clinical medicine in the past, genetics has, in fact, played an important role in understanding disease, but only for a small number of conditions and patients. As a result of these, we have entered a period of tremendous growth in our knowledge of genomics that will eventually influence care for all patients.1 In order for clinicians to understand and participate in these advances, we must become “literate” in the language of genomic medicine. Box 53-1 includes some important definitions of genetic concepts for clinicians, some of which will be more completely developed below.
Box 53-1: Definitions
Allele: One of two or more versions of a genetic sequence at a particular location in the genome.
Base pair (bp): Two nitrogenous bases paired together in double-stranded DNA by weak bonds; specific pairing of these bases (adenine with thymine and guanine with cytosine) facilitates accurate DNA replication; when quantified (eg, 8 bp), bp refers to the physical length of a sequence of nucleotides.
Complex condition: A condition caused by the interaction of multiple genes and environmental factors. Examples of complex conditions, which are also called multifactorial diseases, are sepsis, cancer and heart disease.
DNA: Deoxyribonucleic acid, the molecules inside cells that carry genetic information and pass it from one generation to the next.
Exon: The portion of a gene that encodes amino acids.
Gene: The fundamental physical and functional unit of heredity. A gene is an ordered sequence of nucleotides located in a particular position on a particular chromosome that encodes a specific functional product (ie, a protein or an RNA molecule).
Gene chip: A solid substrate, usually silicon, onto which a microscopic matrix of nucleotides is attached. Gene chips, which can take a wide variety of forms, are frequently used to measure variations in the amount or sequence of nucleic acids in a sample.
Genome: The entire set of genetic instructions found in a cell. In humans, the genome consists of 23 pairs of chromosomes, found in the nucleus, as well as a small chromosome found in the cells’ mitochondria.
Genomewide association study (GWAS): An approach used in genetics research to look for associations between many (typically hundreds of thousands) specific genetic variations (most commonly, single-nucleotide polymorphisms) and particular diseases.
Genotype: A person’s complete collection of genes. The term can also refer to the two alleles inherited for a particular gene.
Haplotype: A set of DNA variations, or polymorphisms, that tends to be inherited together. A haplotype can refer to a combination of alleles or to a set of single-nucleotide polymorphisms found on the same chromosome.
HapMap: The nickname of the International HapMap (short for “haplotype map”) Project, an international venture that seeks to map variations in human DNA sequences to facilitate the discovery of genetic variants associated with health. The HapMap describes common patterns of genetic variation among people.
Human Genome Project: An international project completed in 2003 that mapped and sequenced the entire human genome.
Microarray: A technology used to study many genes at once. Thousands of gene sequences are placed in known locations on a glass slide. A sample containing DNA or RNA is deposited on the slide, now referred to as a gene chip. The binding of complementary base pairs from the sample and the gene sequences on the chip can be measured with the use of fluorescence to detect the presence and determine the amount of specific sequences in the sample.
Mutation: A change in a DNA sequence. Germ-line mutations occur in the eggs and sperm and can be passed on to offspring, whereas somatic mutations occur in body cells and are not passed on.
Pharmacogenomics: The branch of pharmacology which deals with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug’s efficacy or toxicity. By doing so, pharmacogenomics aims to develop rational means to optimize drug therapy, with respect to the patients’ genotype, to ensure maximum efficacy with minimal adverse effects.
Phenotype: The observable traits of an individual person, such as height, eye color, and blood type. Some traits are largely determined by genotype, whereas others are largely determined by environmental factors.
Point mutation: An alteration in DNA sequence caused by a single-nucleotide base change, insertion, or deletion.
Ribonucleic acid (RNA): The molecule synthesized from the DNA template; contains the sugar ribose instead of deoxyribose, which is present in DNA; three types of RNA exist, messenger RNA (mRNA), transfer RNA (tRNA), and ribosomal RNA (rRNA).
Single-nucleotide polymorphism (SNP): A single-nucleotide variation in a genetic sequence; a common form of variation in the human genome.
Systems biology: Research that takes a holistic rather than reductionist approach to understanding organism functions.
Transcription: The synthesis of an RNA copy from a sequence of DNA (a gene); a first step in gene expression.
Translation: During protein synthesis, the process through which the sequence of bases in a molecule of messenger RNA is read in order to create a sequence of amino acids.
Much is known about the human genome, including the fact that the minority of the 3 gigabases of DNA sequence codes for proteins. It is estimated that only 2% of our DNA sequence includes the codes for approximately 20,000 protein-coding genes. The function of the remaining 98% of DNA is perhaps the most fascinating aspect of genomics. Figure 53-1 illustrates the structure of a typical gene. The 5′ control region, often termed the “promoter,” includes DNA sequences that recognize and bind to proteins called transcription factors, whose function is to modify gene expression by controlling transcription. The “start codon” is a series of nucleotides that are recognized by the transcriptional machinery, which initiates the generation of messenger RNA (mRNA) from DNA. Not all of this mRNA sequence encodes for protein. Exons are the regions of DNA that are transcribed into RNA to make amino acids. In most genes, multiple exons are separated by introns, which are removed from mRNA prior to translation into protein. The end of transcription is signaled by a series of nucleotides at the end of the coding sequence, referred to as a “stop codon.” The DNA sequence after this stop codon, termed the 3′ control region, can influence the rate of gene transcription and may affect the stability of the mRNA sequence and its subsequent translation into protein, also.