Fundamentals
A gene is the basic physical and functional unit of heredity. Humans have between 20,000 and 25,000 genes. Genes vary in size from a few hundred DNA bases to more than 2 million bases per gene.
Genes are made of DNA. Many genes code for proteins. Some genes are non-coding genes, meaning they do not code for proteins.
Most DNA does not code for proteins. Instead, it serves other roles, such as:
- Regulatory elements (e.g., promoters, enhancers, repressors)
- Structural elements (e.g., telomeres, satellite DNA, introns)
Each individual has two copies of most genes: one inherited from the father and one from the mother. Alleles are different forms of the same gene that have small differences in their DNA base sequence.
DNA is packaged into thread-like structures called chromosomes. Each chromosome consists of DNA tightly coiled many times around proteins called histones. Each cell contains 23 pairs (46 total) chromosomes. Of these 23 pairs:
- 22 pairs are autosomes
- 1 pair is sex chromosomes: XX in females and XY in males
Common definitions used in genetics:
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Alleles: Variants of a given DNA sequence at a particular locus in the genome, or variants of the same gene. For example, there are different alleles for eye color (black, brown, blue, etc.).
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Allelic heterogeneity: Different mutations in the same gene that cause different phenotypic manifestations or disease severity. For example, androgen insensitivity can present in more or less severe forms depending on the type of mutation and how much functional loss occurs as a result.
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Non allelic or locus heterogeneity: The same phenotype is caused by mutations in genes at different chromosomal loci. For example, nephrogenic diabetes insipidus may be caused by mutations in either the aquaporin 2 gene or the AVPR2 gene.
Genetic heterogeneity is a result of allelic and locus heterogeneity.
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Homozygote: When both alleles at a particular gene locus are the same. A person may be homozygous for the normal allele or for a mutation.
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Heterozygote: When the two alleles at a particular gene locus are different. A heterozygous genotype may include one normal allele and one mutation, or two different mutations. The latter is called a compound heterozygote.
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Hemizygous: Having only one copy of a gene or DNA sequence in diploid cells. Males are hemizygous for most genes on the sex chromosomes because they have only one X and one Y chromosome. A person with a deletion in a region of an autosome would also be hemizygous for that region, with one remaining copy on the normal homologous chromosome.
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Dominant: Any trait that is expressed in a heterozygote.
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Dominant negative: A mutant gene whose product inhibits the function of the wild-type gene product in heterozygotes.
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Haploinsufficiency: When one copy of a gene is inactivated or deleted and the remaining functional copy is not adequate to produce the needed gene product to preserve normal function. Clinically, this manifests as a dominant trait.
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Haplotype: A set of closely linked genetic markers present on one chromosome that tend to be inherited together.
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Genotype: The set of alleles that make up an individual’s genetic make-up, either overall or at a given locus.
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Phenotype: The observable characteristics in an individual resulting from gene expression; the clinical presentation of an individual with a particular genotype.
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Proband: The individual through whom a family with a genetic disorder is ascertained. In males this is called a propositus, and in females it is called a proposita.
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Incomplete penetrance: When an individual carries a pathogenic genotype but does not phenotypically manifest the disease. For example, among individuals with inherited BRCA gene mutations, some develop cancers while others do not.
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Variable expressivity: The range of signs and symptoms that can occur in different people with the same genetic condition. People carrying the defective gene will express the disease, but in milder to more severe forms. For example, in Marfan syndrome, some individuals are tall with long fingers but have no cardiovascular involvement, while others may develop aortic dissection.
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Mosaicism: The occurrence of 2 or more cell lines with different genetic or chromosomal make-up within a single individual or tissue.