As mentioned earlier, the expression of a gene in an organism is called a phenotype . If one copy of the gene is required for the phenotypic trait to be expressed (heterozygous state), the gene is termed dominant. If two copies of a gene are required for phenotypic expression (homozygous state), the gene is called recessive.

The chromosomes that determine the sex of the individual are the X and the Y chromosome. Genetically, an individual with an X and a Y (an XY individual) will be male, and an individual with two X chromosomes (an XX individual) will be female. Mutations expressed in an allele on the X chromosome are usually more severe in males than females, because males have only one copy of the X chromosome, while females have two copies. In other words, when females have a mutation involving one allele on one X chromosome, the paired allele on the other X chromosome may produce enough of its product if not mutated, whereas an XY individual does not have an additional copy of the X chromosome in reserve. Rare variations of the genetic constitution exist with some individuals having an XXY or XXXY genome. These individuals are phenotypically male due to the presence of the Y chromosome , with extra copies of the X chromosome.

The translation of genetic code into functional products is quite complex and beyond the scope of this introductory chapter. In summary, start and stop codons regulate the transcription of a gene, and various forms of RNA are involved in this process (tRNA for translational RNA, mRNA for messenger RNA, etc.), in addition to other types of interactive genes. A gene will not entirely get translated into a protein; exons are those stretches of a gene that are ultimately expressed in a protein , and introns are those intervening genetic sequences that are removed before protein translation. Roughly 25–38% of the total DNA is spanned by genes; however only 1.1–1.4% of DNA consists of exons. The function of the rest of human DNA is yet unknown and is an area of active research.

Two important sets of genes that deserve a brief mention are suppressor and anti-suppressor genes [6]. A suppressor gene’s function is to suppress the phenotypic expression of another gene. An anti-suppressor’s function is to suppress the suppressor gene. The interaction and balance are extremely complex, yet exquisitely elegant. It should be noted that many genes are solely expressed, or activated, in certain tissue types. Thus a mutated gene will only cause disease in a particular tissue in which it is producing the product or diseased protein. One of the most studied cancers to date is retinoblastoma. The expression of retinoblastomas is due to the inactivation of a tumor suppressor gene affecting the retina [6–8]. Normal function of the suppressor gene is to inhibit the retinoblastoma gene from functioning. Loss of this suppressive factor allows the retinoblastoma gene to become active and produce a tumor.

Genetic changes that cause an abnormal phenotype in an individual are termed “pathogenic variants ” and are also called mutations; these affect the gene in which they are found. Other changes will have no effect at all and are termed “benign variants ” or polymorphisms . It can be very difficult to predict how some variants are going to affect the patient’s phenotype, and these are termed “variants of uncertain significance.” Additional functional studies on the particular variant may determine if it is pathogenic or benign. Generally, variants that are found in exons are more likely to be pathogenic if they result in a codon that translates into a different amino acid or a stop codon that truncates the protein product.

Another way to categorize variants of genetic changes is by structure. Point mutations change just one nucleotide, but can cause either a missense or nonsense variant. A missense variant changes just one codon in the sequence and may be tolerated by the gene or not. A nonsense mutation is very often pathogenic as it causes a premature stop codon to be inserted and prevents translation of the rest of the protein. Frameshift mutations are also often pathogenic, as they result from the addition or subtraction of nucleotides in such a way that the reading frame of the rest of the gene is disrupted, resulting in incorrect amino acids in the protein product. A splice site mutation results in insertion, deletion, or changes in the number of nucleotides in the specific site at which splicing of RNA takes place and can change the way the exons assemble. Inheritance patterns should be taken into account when interpreting each variant. Mutations that are not found in the parents are termed spontaneous or de novo and are more likely to cause sporadic disease. A database of variant alleles, collected from both affected and healthy individuals, allows an estimate of the allele frequency in the population. This measure allows for some prediction about the pathogenicity of a variant, as common variants are unlikely to cause rare diseases.