EVOLUTION OF SHORTER AND MORE HYDROPHILIC TRANSTHYRETIN N-TERMINI BY STEPWISE CONVERSION OF EXON-2 INTO INTRON-1 SEQUENCES (SHIFTING THE 3'-SPLICE-SITE OF INTRON-1)
Ar. Aldred et al., EVOLUTION OF SHORTER AND MORE HYDROPHILIC TRANSTHYRETIN N-TERMINI BY STEPWISE CONVERSION OF EXON-2 INTO INTRON-1 SEQUENCES (SHIFTING THE 3'-SPLICE-SITE OF INTRON-1), European journal of biochemistry, 246(2), 1997, pp. 401-409
Transthyretin cDNA was cloned from Eastern Grey Kangaroo liver and its
nucleotide sequence determined. Analysis of the derived amino acid se
quence of kangaroo transthyretin, together with data obtained previous
ly for transthyretins from other vertebrate species [Duan, W., Richard
son, S. J., Babon, J. J., Heyes, R. J., Southwell, B. R., Harms, P. J.
, Wettenhall, R. E. H., Dziegielewska, K. M., Selwood, L., Bradley, A.
J., Brack, C. M. & Schreiber, G. (1995) Eur. J. Biochem. 227, 396-406
], showed that the N-terminus is the region which changes most distinc
tly during evolution. It has been shown for human, mouse and rat trans
thyretins, that this region is encoded by DNA at the border of exon 1
and exon 2. Therefore, this section of transthyretin genomic DNA was a
mplified by PCR and directly sequenced for the Buffalo Rat, Tammar Wal
laby, Eastern Grey Kangaroo, Stripe-faced Dunnart, Short-tailed Grey O
possum and White Leghorn Chicken. The splice sites at both ends of int
ron 1 were identified by comparison with the cDNA sequences. The obtai
ned data suggest that the N-termini of transthyretin evolved by succes
sive shifts of the 3' splice site of intron 1 in the 3' direction, res
ulting in successive shortening of the 5' end of exon 2. At the protei
n level, this resulted in a shorter and more hydrophilic N-terminal re
gion of transthyretin. Successive shifts in splice sites may be an evo
lutionary mechanism of general importance, since they can lead to step
wise changes in the properties of proteins. This could be a molecular
mechanism for positive Darwinian selection.