Genetics

The study of the human genome and the relevance of genetic variation to human health and disease is a field of rapid growth and progress, but also increasing complexity. The 20th-century genetic advancements began in 1961 when Marshall Nirenberg first deciphered the genetic code, identifying the first triplet codon (a sequence of three nucleotides that together form a unit of genetic code) in RNA and its relation to the amino acid uracil. The complete codon sequence for all 20 amino acids followed quickly, culminating in a Nobel Prize for Nirenberg in 1968.

The first genetic disorder to be mapped was Huntington’s disease in 1983, followed by cystic fibrosis in 1989. The Human Genome Project, one of the boldest scientific endeavors, began in 1990 and was completed in 2003. In the interim, researchers also completed sequencing the genomes of the fruit fly, Drosophila melanogaster, and the house mouse, Mus musculus. Sequencing of the human genome was a critical first step in the ability to apply genetic data to understanding diseases and health and development. However, the application of genetic data has required that both the driving underlying hypotheses, as well as the current methodologies, adapt to pivotal results and, at times, lack of consistency across studies.

Progress in human genetics has been intricately dependent on progress in engineering and computational science in addition to the necessary interface with both basic and clinical biological sciences. This entry presents a broad overview of the extensive growth of the field of genetics, focusing on the increasing interactive complexity between the genome and the environment that shapes how an organism functions and how an organism adapts to changes in the surrounding world.

Within almost all cells in every organism the genetic information of DNA is embedded in the sequence of four specific nucleic acids: adenine (A), cytosine (C), guanine (G), and thymine (T). The long strands of DNA (over 6 meters in each human cell) are tightly wound around protein structures creating pairs of chromosomes. In humans, one of each of the 23 pairs of chromosomes is derived from an individual’s parent. The pairing of the maternal and paternal chromosomes results in each individual having pairs of nucleotides, the building blocks of DNA that contain a nitrogen base, a five-carbon sugar, and phosphate groups, at each specific site across the genome.

One nucleotide is called an allele. The two alleles, one derived from the mother and one from the father, when combined, define a person’s genotype. At each position in the genome an individual can have two identical nucleotides termed a homozygote (e.g., CC), or have two different [Page 949]nucleotides, each called a heterozygote (CG). Initially, genetic studies of human disease focused on the identification of genetic mutations (disease-associated changes in the DNA sequence found in less than 1% of the population).

It was soon apparent that a select number of conditions were caused by mutations in single genes, but the majority were polygenic in etiology, meaning that they were the result of the interaction of different genes and, in some cases, different areas of the genome. These disorders, including psychiatric conditions, such as autism or schizophrenia, clearly have a genetic component and cluster within families. However, they do not exhibit “typical” Mendelian patterns of inheritance, meaning that fewer than expected individuals within a family have the disorder. For these complex traits, the influence of a single genotype is small, making it challenging to detect links between disease and genotype without large numbers of subjects.

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