Genomics and the Eye

THE EYE HAS HAD A PIVOTAL ROLE IN THE EVOLUTION OF HUMAN GENOMICS. At least 90% of the genes in the human genome are expressed in one or more of the eye's many tissues and cell types at some point during a person's life. Consistent with this impressive genomic footprint is the observation that about a third of entries in the Online Mendelian Inheritance in Man database for which a clinical synopsis is provided include a term that refers to the structure or function of the eye.(1) Moreover, the phenotypic effects of even small genetic variations are made readily apparent by the many layers of amplification in the human visual system. For example, a single-nucleotide change in PAX6 can cause an anatomic abnormality of the macula less than a millimeter in diameter that results in noticeably reduced visual acuity and nystagmus.(2) The heritable inability to correctly perceive the color green, known as Daltonism (after the English chemist John Dalton, who himself was affected), was the first human trait mapped to the X chromosome.(3) (See Fig. 1 for a timeline of historic discoveries.) The Coppock cataract was the first human trait mapped to an autosome,(4) and Leber's hereditary optic neuropathy was the first human disease shown to be caused by a mutation in mitochondrial DNA.(5) More recently, age-related macular degeneration (AMD) and glaucoma(6,7) - two common causes of human blindness - have been shown to be largely genetic, as has Fuchs' endothelial dystrophy,(8) the most common cause of corneal transplantation in developed countries. Here, we review discoveries in mendelian and complex ophthalmic disorders and their implications for genetic testing and therapeutic intervention.