SELECTIVE NEUTRALITY

CASE STUDY IN MOLECULAR EVOLUTION NO. 6
Written by Harold B. White 9/93 and revised most recently 2002
C-647 BIOCHEMICAL EVOLUTION, FALL 2002

Page 2: Sense and Nonsense

Most evolutionary geneticists could not accept that multiple alleles could have the same fitness (11), i.e. be selectively neutral. Nevertheless several bold scientists challenged the dogma (12-15) and provoked an intense debate about the relative importance of neutral mutations in molecular evolution. In their classic paper, King and Jukes (12) made the following statement to describe what at the time seemed to be a convincing example of selectively neutral mutations:

". . . there are 61 amino-acid-specifying codons. Since each of the three base pairs can mutate in any of three ways, each codon can mutate in any of nine ways by single substitutions. Of the 549 possible single-base substitutions, 134 (one fourth) are substitutions to synonymous codons. These are heritable changes in the genetic material, hence true mutations. As far as is known, synonymous mutations are truly neutral with respect to natural selection." In the absence of known gene sequences, it made sense to assume that selection operated on protein function. After all, they reasoned, if a mutation would not alter the amino acid sequence of a protein, it should not alter the function and therefore should be invisible to selection. In the following decades recombinant DNA technology enabled the isolation and sequencing of many genes. The hypothesis that synonymous mutations were neutral could be tested. The gene coding for glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a glycolytic enzyme in the yeast, Saccharomyces cerevisiae, was among the early genes sequenced (16). The codons specifying each of the 331 amino acids in GAPDH are tabulated below.

Assignment: Examine the codon usage table for yeast GAPDH that follows.
 
Codon Utilization Table for the Yeast (Saccharomyces cerevisiae) Gene for Glyceraldehyde-3-Phosphate Dehydrogenase
Codon Position 2
U
C
A
G
AA
 Cdn # AA Cdn #
AA
 Cdn #
AA
 Cdn #
C

o

d

o

n
 
 

P

o

s

i

t

i

o

n
 
 

1
 

U
PHE
 UUU 0
 

SER

 

 UCU 13
TYR		 UAU 0
CYS		 UGU 2
U
C

o

d

o

n
 
 

P

o

s

i

t

i

o

n
 
 

3
UUC 10 UCC 12 UAC 11 UGC 0
C

 
 
 

LEU

 UUA 0 UCA 0
STOP		 UAA (1) STOP UGA 0
A
UUG 21 UCG 0 UAG 0 TRP UGG 3
G

 

C

 CUU 0
 

PRO

 CCU 0
HIS		 CAU 0
 

ARG

 CGU 0
U
CUC 0 CCC 0 CAC 8 CGC 0
C
CUA 0 CCA 12
GLN		 CAA 5 CGA 0
A
CUG 0 CCG 0 CAG 0 CGG 0
G

 

A
ILE
 AUU 9
 

THR

 ACU 12
ASN		 AAU 0
SER		 AGU 0
U
AUC 11 ACC 12 AAC 12 AGC 0
C
AUA 0 ACA 0
LYS		 AAA 1
ARG		 AGA 11
A
MET
 AUG 7 ACG 0 AAG 25 AGG 0
G

 

G
 

VAL

 GUU 22
 

ALA

 GCU 25 ASP GAU 9
 

GLY

 GGU 25
U
GUC 15 GCC 7 GAC 16 GGC 0
C
GUA 0 GCA 0 GLU GAA 12 GGA 1
A
GUG 0 GCG 0 GAG 2 GGG 0
G

What conclusions can you make? How might one explain the observations?

References:
11. Gould, S. J. (1975) A threat to Darwinism, Nat. History 84 (10), 489.
12. King, J. L. and Jukes, T. H. (1969) Non-Darwinian evolution, Science 164, 788-797.
13. Kimura, M. (1968) Evolutionary rate at the molecular level, Nature 217, 624-626.
14. Kimura, M. and Ohta, T. (1971) Protein polymorphism as a phase of molecular evolution, Nature229, 467-469.
15. Kimura, M. (1983) The Neutral Theory of Molecular Evolution, Cambridge University Press.
16. Holland, J. P. and Holland M. J. (1980) Structural comparison of two nontandemly repeated yeast glyceraldehyde-3-phosphate dehydrogenase genes, J. Biol. Chem. 255, 2596-2605.

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Created  7 November 2000. Last updated 10 November 2002 by Hal White
Copyright 2002, Harold B. White, Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716