VOLUME 27, NO. 3, WINTER 1995-96 GLOSSARY OF GENETIC TERMINOLOGY

GLOSSARY OF GENETIC TERMINOLOGY

Donald C Chambers, MD

Chromosomes Proteins, gene products

All cells in the human body (except red blood cells) contain a The gene is the functional unit of DNA. Each gene codes for the nucleus within which are long tightly coiled strands of DNA production of one specific protein and it is the interaction of all (deoxyribonucleic acid). During cell division the DNA strands these gene products (proteins) that leads to the form and func- become more clearly organized and are seen to be packaged tion of man. into 23 pairs of chromosomes, including 22 pairs of autosomes and a pair of sex chromosomes. One chromosome from each Genotype, phenotype pair comes from the individual’s biological mother and the other from the father. Chromosomes have a long (q) and a short (p) Genome, is a generic term referring to all the components of the arm on either side of a centromere. DNA in a life form. Genotype is the genetic makeup of an indi- vidual and includes all the pathological mutations and polymor- Genes phisms that are found in the person’s genome. The final product of one’s genes, i.e. the physical characteristics of a given human Like a string of pearls, genes occupy discrete locations along being, is called phenotype. specific strands of DNA. The locus (location) of a given gene is fixed on a specific chromosome and in a defined relationship Base pairs, sequences, mutations with adjacent genes. Because chromosomes are paired, genes are also paired. DNA is composed of two strands, held together by chemical bonds linking complementary nucleotides or base pairs. The Prior to analysis, chromosomes are usually stained with dyes sequence of these base pairs within a gene defines the genetic that reveal a banding pattern. One method of localizing a gene is code for that gene and determines what protein will be pro- by indicating the chromosome number and the position of the duced. Gene mutations are caused by alteration of this sequence. gene in relation to these bands. Thus, for example, the locus for the breast cancer gene, BRCA1, which is found at band 21 on Germline, somatic chromosome 17, is at 17q21. Mutations that exist in a father’s sperm or mother’s egg are Heterozygous, homozygous germline and, when transmitted to offspring, cause inherited disease. Gene mutations can also develop after conception and Genetic variation is what makes people different from one an- do not involve sperm or egg. These mutations are usually lim- other. Alternative forms ofa gene at a particular locus are called ited to a few cells or a tissue in a single body organ or part and alleles. When alleles within a gene pair differ, that situation is are somatic. Non hereditary genetic disease is caused by so- termed heterozygous. Paired alleles that are alike are homozy- matic mutations. gous. Each chromosome contains thousands of genes. There are approximately 100,000 genes in the human genome but only Categories of genetic disease four to 5000 cause disease when they are mutated. Most of the mutations in genes are not pathological but are called polymor- Genetic diseases can be caused by: phisms. inheriting a single mutant gene (single-gene disease); the interaction of two or more inherited mutant genes com- bined with a variety of environmental factors (multifacto- rial disease); Vice President and Chief Medical Director, Lincoln National Reinsurance Cos., Fort Wayne, Indiana

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3. chromosomal abnormalities (chromosomal disorder) that a mixed genetic and environmental etiology. This mode of trans- are inherited or develop in the egg or sperm prior to con- mission is termed multifactorial. An examination of the family ception; or pedigree fails to show simple Mendelian transmission but there 4. changes in genes acquired after birth (somatic mutations is often an increased frequency of a particular disease within the which are non-inherited, i.e. acquired, genetic disorders). family. Multifactorial disorders probably result when somatic mutations develop in a series of interacting genes. Single-gene disease Chromosomal disorders There are three types of single-gene disorders, commonly said to be the result of Mendelian transmission: Cytogenetics is the study of human chromosomes and their ab- normalities. There are various types of chromosomal abnormali- autosomal recessive, where the individual has a homozy- ties. The most common type of clinically significant chromo- gous mutation of both genes of a gene pair located on one some abnormality is aneuploidy, meaning there are more less of the 22 autosomes. This mutation was transmitted from than the normal complement of 46 chromosomes. A wide vari- both the mother and the father. If only one gene has muta- ety of chromosomal structural abnormalities occur as well. Many tion (the other gene being normal), the person is described human leukemias and lymphomas result from translocations in as a carrier. Carriers can transmit this defective gene to their which a piece of one chromosome separates and attaches to offspring, but they will not develop disease. Cystic fibrosis another chromosome. is an example of an autosomal recessive disease. The chromosome constitution of an individual is called a karyo- 2o autosomal dominant, where just one of a pair of genes is type. Karyotyping of fetal chromosomes allows for prenatal di- mutated but that one gene dominates the "good" (or wild agnosis of conditions like Down’s syndrome, where there is an type) gene and autosomal dominant disease develops. An extra chromosome 21 (trisomy 21). Fetal chromosomal abnor- example is Huntington’s disease where signs of disease are malities can be inherited, or they can develop early in fetal de- not expected to develop until adult life. Statistically half of velopment. They often lead to spontaneous abortion. the offspring of an affected parent will develop autosomal dominant diseases. Non-inherited (acquired) genetic disease

° X-linked, where a mutated gene located on the X chromo- Persons who are genetically normal at birth may develop dis- some causes disease in males only because no paired gene ease when DNA changes occur in one or more of their cells after exists on the Y (male) chromosome. Hemophilia and mus- conception (somatic mutations). As those cells divide, the colony cular dystrophy are X-linked diseases. of mutated cells expands and disease forms. Common cancers dominate this category of genetic disease. Malignant melanoma Those who possess single-gene mutations do not always de- is an example. The genome of a skin cell is damaged by ultravio- velop disease. When mutant genes do not result in disease, the let light. This mutation then leads to cancer. Tests of other tis- mutation is said to have reduced penetrance. BRCA1 is autoso- sues free of the melanoma will not reveal the mutation which mal dominant mutation with an 87 percent penetrance by age caused the cancer. 85. For a given individual however, penetrance is an all-or-none thing. Either you get the disease or you do not. Given that the underlying cause of all disease involves changes in DNA, all disease can be considered as genetic. Consequently Variations in the severity or age of onset of a genetic disease are all disease falls into one of the four categories of genetic disease termed variable expressivity. The trait is expressed, but the signs just mentioned. In the adult insurance-buying population, how- and symptoms may vary from mild to severe. Cystic fibrosis can ever, most disease has a multifactorial inheritance pattern and be mild or severe and thus has variable expressivity which is will not be readily diagnosed by genetic tests of leucocytes or probably related to different mutations in the gene. other usual test materials. Chromosomal diseases are uncom- monly encountered in adult life; and single-gene disease, al- Multifactorial disease though often discussed, may be even less commc~n.

Most adult disorders as coronary artery disease, NIDDM, hyper- tension, and obesity, where causes are many and complex have

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