Even if no information is known about the nature or function of a gene for a disease, linkage studies may be able to localize the gene to a given chromosome or a specific marker. In 1937, Bell and Haldane recognized the first linkage between 2 diseases on a human chromosome: congenital color vision deficiency and hemophilia on the X chromosome. Subsequent investigations have led to the chromosomal mapping of a large number of different human ocular diseases.
Every chromosome has numerous defined genes. The Human Genome Project identified and mapped approximately 20,000–25,000 genes. In addition, the database Online Mendelian Inheritance in Man, OMIM (https://omim.org), lists information on all known mendelian disorders. Human gene mapping has 2 major applications. The first is identification of the gene for a specific genetic disease by its linkage to a known marker. For example, suppose gene A causes a hereditary disease and gene B is a known enzyme or polymorphic marker closely linked to A. Even though no biochemical test exists for A, a tight linkage to B would allow a reasonable probability of identifying the disease for prenatal diagnosis and sometimes for carrier detection. The second impact of mapping is as an aid to understanding the cause of the phenotypic malformations in specific chromosomal diseases. For example, the phenotype of Down syndrome may result from triplication of only the distal long arm of chromosome 21 through a chromosome rearrangement rather than trisomy of the entire chromosome.
It is possible to detect linkage by observing the frequency with which a polymorphic marker is inherited with a disease trait. The physical distance represented by 1 cM corresponds to approximately 1 million bp (1000 kb) and to a 1% chance that recombination will result from a single meiosis (a 0.01 recombination fraction). When a genetic marker is sufficiently close to a disease gene, both are rarely separated by meiotic recombination. The frequency of this separation by chromosomal exchange at meiosis is termed the recombination frequency. To be linked, markers should be no more than about 20 cM apart. For perspective, the average chromosome contains about 150 cM, and there are approximately 3300 cM in the entire human genome, which corresponds to 3 × 109 bp.
When determining linkage between a gene and a marker, geneticists compare different models by calculating likelihood ratios. When the likelihood ratio is 1000:1 that the odds of one model are greater than those of another, the first is accepted over the second. The base 10 logarithm of the likelihood ratio (LOD score; logarithm of odds score) is usually reported. An LOD score of 1–2 is of potential interest in terms of linkage; 2–3 is suggestive; and greater than 3 is generally considered proof of linkage. Although an LOD score of 3 gives a probability ratio of 1000:1 in favor of linkage versus independent assortment, this score does not indicate a type I error as low as 0.001 but, in fact, indicates an error that is close to 0.05, the standard significance level used in statistics. (BCSC Section 1, Update on General Medicine, explains these concepts in depth.)
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.