Conversion and compensatory evolution of the γ-crystallin genes and identification of a cataractogenic mutation that reverses the sequence of the human CRYGD gene to an ancestral state

Abstract

We identified a mutation in the CRYGD gene (P23S) of the γ-crystallin gene cluster that is associated with a polymorphic congenital cataract that occurs with frequency of ∼0.3% in a human population. To gain insight into the molecular mechanism of the pathogenesis of γ-crystallin isoforms, we undertook an evolutionary analysis of the available mammalian and newly obtained primate sequences of the γ-crystallin genes. The cataract-associated serine at site 23 corresponds to the ancestral state, since it was found in CRYGD of a lower primate and all the surveyed nonprimate mammals. Crystallin proteins include two structurally similar domains, and substitutions in mammalian CRYGD protein at site 23 of the first domain were always associated with substitutions in the structurally reciprocal sites 109 and 136 of the second domain. These data suggest that the cataractogenic effect of serine at site 23 in the N-terminal domain of CRYGD may be compensated indirectly by amino acid changes in a distal domain. We also found that gene conversion was a factor in the evolution of the γ-crystallin gene cluster throughout different mammalian clades. The high rate of gene conversion observed between the functional CRYGD gene and two primate γ-crystallin pseudogenes (CRYGEP1 and CRYGFP1) coupled with a surprising finding of apparent negative selection in primate pseudogenes suggest a deleterious impact of recently derived pseudogenes involved in gene conversion in the γ-crystallin gene cluster. © 2007 by The American Society of Human Genetics. All rights reserved.