Human γ-crystallin genes. A gene family on its way to extinction

During hominoid evolution the γ-crystallins of the lens have decreased in quantity as well as complexity, a change correlated with an increased water content of the lens. To trace the molecular basis for the decrease in γ-crystallin gene expression, we have characterized the structure and expression of the human γ-crystallin gene family. We show that the human γ-crystallin gene family consists of six complete genes (γA, γB, γC, γD, ψγE and ψγF) and one second exon fragment, the γG gene. Model experiments showed that, although the γG sequence is bordered by consensus splice sites, it is most likely transcriptionally inactive in the lens. In the human embryonic lens the γC and γD genes accounted for 81 % of the γ-crystallin transcripts, the γA gene contributed 14% and the γB gene only 5%. The composition of the γ-crystallin mRNA pool changed only after birth, with the γD transcript as the only detectable transcript at ten years of age. The relative activities of the γA, γC and γD promoters in a transient expression system were in agreement with the ratio of their in vivo RNA levels, suggesting that the difference in accumulation of these transcripts is due to differences in the rate of transcription. The γB promoter was much more active than expected and had lost its tissue-specificity. Model experiments showed that the low yield of the γB transcript is due to post-transcriptional processes, most likely RNA instability mediated by third exon sequences. Together with previous data, our results show that the decrease in expression of the γ-crystallin genes in the human lens is the consequence of gene loss (γG), inactivation of coding sequences (ψγE and ψγF), decrease in rate of transcription (γA), increase in rate of RNA turn-over (γB) and a delay in the onset of transcription during development.