Genome sequencing involves reading the complete set of genetic instructions present in an organism’s DNA. This analysis deciphers the precise order of the chemical building blocks, known as nucleotides—Adenine (A), Thymine (T), Cytosine (C), and Guanine (G)—that compose the entire genome. Determining this sequence provides insight into the molecular foundation of human health and disease. The information derived from sequencing has transformed medicine, ranging from predicting future health conditions to customizing current treatments.
Understanding the Genetic Blueprint
The genome is the instruction manual for the human body, composed of approximately 3 billion base pairs of DNA. Whole genome sequencing (WGS) is the laboratory procedure that generates the raw data—a massive text file containing the A, T, C, and G sequence of all chromosomes. WGS provides a comprehensive view far beyond examining only the protein-coding regions, or exome.
The specialized field of bioinformatics converts this raw data into meaningful information. Bioinformaticians use computational tools to align the sequenced letters against a standard human reference genome. This alignment identifies variations, such as single-nucleotide polymorphisms (SNPs) and structural changes, that distinguish the individual. These differences are then interpreted to determine if they are benign, pathogenic, or linked to a specific trait, transforming data into clinically actionable knowledge.
Identifying Inherited Disease Risk
Genome sequencing maps inherited (germline) variations, assessing an individual’s predisposition to various health conditions. This analysis reveals single-gene mutations responsible for monogenic disorders, which are caused by a change in one specific gene. Examples include identifying the F508del mutation associated with Cystic Fibrosis or mutations in genes like HTT that cause Huntington’s disease. Knowing this information allows for proactive monitoring or early intervention strategies.
Sequence data is also used to calculate a Polygenic Risk Score (PRS), which assesses the cumulative genetic likelihood for common, complex diseases. Conditions like coronary artery disease, Type 2 diabetes, and inflammatory bowel disease are influenced by thousands of common variants, each contributing a small amount of risk. The PRS aggregates the influence of these numerous variants into a single score. This score identifies individuals who possess a genetic risk comparable to those with a rare, high-risk mutation.
Sequencing can also determine carrier status for recessive disorders, which is relevant for family planning. A healthy individual may carry one copy of a mutation that causes a serious condition if two copies are inherited by a child. This analysis identifies healthy individuals who carry a mutation in high-penetrance susceptibility genes, such as BRCA1 and BRCA2. These genes confer an elevated lifetime risk for certain cancers in the carrier. These results indicate a predisposition or likelihood, not a certainty, as environmental factors and lifestyle choices also play a significant role.
Tailoring Medical Treatment
Sequencing data guides pharmacogenomics, which focuses on how an individual’s genetic makeup affects their response to medications. Genetic variations influence the efficacy and safety of drugs by altering how the body absorbs, distributes, metabolizes, and excretes them. This application helps physicians select the most effective drug and determine the appropriate dosage for a patient from the outset of treatment.
Drug metabolism is largely handled by the Cytochrome P450 (CYP450) enzyme system in the liver. Sequence variations in the genes that code for these enzymes, such as CYP2D6, CYP2C9, and CYP2C19, lead to different metabolic profiles. A patient might be classified as a poor metabolizer, where the drug accumulates to toxic levels, or an ultrarapid metabolizer, where the drug is cleared too quickly to be effective.
For instance, variations in CYP2D6 affect the metabolism of common antidepressants and pain medications, potentially leading to adverse reactions or treatment failure. Similarly, CYP2C9 variations influence the required dosage for the blood thinner warfarin, where miscalculation increases the risk of bleeding. By analyzing these specific genetic variants, physicians can personalize prescriptions, adjusting dosage or selecting an alternative medication to optimize therapeutic outcomes.
Analyzing Acquired Mutations in Cancer
Genome sequencing changes cancer treatment by analyzing acquired (somatic) mutations present only within tumor cells. This process, called tumor profiling, identifies genetic changes that drove the tumor’s growth and progression. The analysis identifies specific genetic alterations that serve as biomarkers to guide targeted therapeutic choices.
Identifying “driver” mutations, such as those in the EGFR, ALK, or ROS1 genes in lung cancer, directs the use of targeted therapies. These precision medicine drugs are designed to block the activity of the specific mutated protein. This approach treats cancer based on its specific molecular alterations rather than solely on its location in the body.
Sequencing also provides insight into tumor heterogeneity—the presence of different populations of cancer cells with varying mutations within the same tumor. This information helps explain why cancer may become resistant to treatment over time. Furthermore, repeat sequencing during treatment monitors for the emergence of new resistance mutations or tracks therapy effectiveness, allowing oncologists to make timely adjustments.