Genes and Chromosomes
The word gene comes from the Greek genes (“giving birth to”) and is used as a term for individual units of hereditary information. Genes are the basic units of inheritance and include the sequence of nucleotides that codes for a single trait or a single polypeptide chain and its associated regulatory regions. Human genes vary substantially in size, from approximately 500 base pairs (bp) to more than 2 million bp. However, more than 98% of human genes range in size from less than 10 kilobase pairs (kb; 1 kb = 1000 bp) to 500 kb. Many are considerably larger than 50 kb. Whereas a single human cell contains enough DNA for 6 million genes, approximately 20,000–25,000 genes are found among the 23 pairs of known chromosomes. Although the remaining 95% of genetic material is likely to be involved in the regulation of gene expression, its precise function is largely unknown.
The relative sequence of the genes, which are arranged linearly along the chromosome, is called the genetic map. The physical position or region on a chromosome occupied by a single gene is known as a locus. The physical contiguity of various gene loci becomes the vehicle for close association of genes with one another (linkage) and their clustering in groups that characteristically move together or separately (segregation) from one generation to the next.
Each normal human somatic cell has 46 chromosomes composed of 23 pairs. Each member of a homologous pair carries matched, though not necessarily identical, genes in the same sequence. One member of each chromosome pair is inherited from the father, and the other from the mother. Each normal sperm or ovum contains 23 chromosomes, 1 representative from each pair; thus, each parent transmits half of his or her genetic information to each child. Of the 46 chromosomes, 44 are called autosomes because they provide information on somatic characteristics; the remaining 2 chromosomes are X and Y (see the section X-Linked Inheritance earlier in this chapter).
It is important to know whether genes are located on the X chromosome, mitochondrial DNA, or the autosomes; however, there is rarely any clinical value in knowing in which autosome (1–22) a gene is located. In the past, when only a few eye disease genes were known or just the location of a gene was known, clinicians often remembered the chromosomal locations. Now, with certain diseases, such as RP, there are so many genes even ophthalmic geneticists do not remember them all. Information on genes, including their chromosomal locations, can be readily found in electronic databases, such as OMIM (https://www.ncbi.nlm.nih.gov/omim).
The alternative forms of a particular gene at the same locus on each of an identical pair of chromosomes are called alleles (Greek for reciprocals). If both members of a pair of alleles for a given autosomal locus are identical (ie, the DNA sequence is the same), the individual is homozygous (a homozygote). If the allelic genes are distinct from each other (ie, the DNA sequence differs), the individual is heterozygous (a heterozygote). Different gene defects can cause dramatically different phenotypes and still be allelic. For example, sickle cell disease (SS hemoglobinopathy) caused by homozygosity of 1 mutant gene is substantially different from the phenotypic expression of SC hemoglobinopathy, yet the Hb S gene and the Hb C gene are allelic.
The term polyallelism refers to the many possible variants or mutations of a single gene. Mutant proteins that correspond to mutant alleles frequently possess slightly different biochemical properties. Among the mucopolysaccharidoses, for example, the enzyme α-L-iduronidase is defective in both Hurler and Scheie syndromes. Because these disorders stem from mutations of the same gene, they are abnormalities of the same enzyme and are, thus, allelic. However, the clinical severity of these 2 disorders (age at onset; age at detection; and severity of affliction of skeleton, liver, spleen, and cornea) is entirely different, presumably because the function of the mutant enzyme is less altered by the Scheie syndrome mutation. Because the enzyme is a protein composed of hundreds of amino acids, a mutation resulting in a base substitution within a certain codon might cause a change in one or more amino acids in a portion of the enzyme remote from its active site, thus reducing its effect on the enzyme’s function. However, the substitution of 1 amino acid at a crucial location in the enzyme’s active site might abolish most or all of its enzymatic activity. Several examples of allelic disorders appear among the mucopolysaccharidoses.
The phenotype of the usual heterozygote is determined by 1 mutant allele and 1 “normal” allele. However, the genotype of a compound heterozygote comprises 2 different mutant alleles, each at the same locus. The genetic Hurler-Scheie compound heterozygote is biochemically proven and clinically manifests features intermediate between those in the homozygotes of the 2 alleles. Whenever detailed biochemical analysis is performed, the products of the 2 alleles manifest slightly different properties (eg, rates of enzyme activity or electrophoretic migration).
In contrast, and as noted earlier, some genetic disorders originally thought to be single and unique may, on close scrutiny, reveal two or more fundamentally distinct entities. Occasionally, this genetic heterogeneity is observed with diseases that are inherited in the same manner, such as tyrosinase-negative and tyrosinase-positive oculocutaneous albinism. Because these 2 conditions are phenotypically similar and each is inherited as an autosomal recessive trait, it was formerly assumed that they were allelic. When a tyrosinase-negative person with albinism bears children with a tyrosinase-positive person with albinism, the offspring appear clinically normal. This observation excludes the possibility that these 2 conditions are allelic: each form of albinism occurs only when an offspring is homozygous for one of the genes causing the condition. Defects in separate gene loci (the tyrosinase gene and the P gene) are now known to cause oculocutaneous albinism. The offspring of individuals with phenotypically similar but genotypically different disorders are called double heterozygotes because they are heterozygous for each of the 2 loci.
Ashworth JL, Biswas S, Wraith E, Lloyd IC. Mucopolysaccharidoses and the eye. Surv Ophthalmol. 2006;51(1):1–17.
Fenzl CR, Teramoto K, Moshirfar M. Ocular manifestations and management recommendations of lysosomal storage disorders I: mucopolysaccharidoses. Clin Ophthalmol. 2015;9:1633–1644.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.