Protein evolution from peptides, gene duplications and deletions in polypeptides and cytochrome 

Cantor, C. R.

Jukes, T. H.

English

NASA Technical Reports Server

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REPETITIONS I N  THE POLYPEPTiDE 
SEQUENCE OF CYTOCHROMES 
Charles R. Cantor and Thomas H. Jukes 
Department of Chcmistry and Space Sciences Laboratory 
Berkeley, Cal i fornie* 
Univcrsi t y  of C n I  i for-nin, 
Rece i ved 
It seems likely that many proteins have evoived from comparatively short 
primordial peptides by processes of duplication, deletions, and amino ecid sub- 
stitutions due to point mutations (Eck and Dayhoff, 1966; Jukes, 1366a). 
In most cases, the evidence for this may have vanlshed due to the masking 
effect of evolutionary changes in the amino acid sequences. In  a few ceses, 
however, remnants of the early peptides are still discernible in the forms 
of partially repetitive sequences. Proteins from "primitive" organisms may 
be the best source in which to search for such manifestations. 
The phenomena of gene duplications and deletions are perceptible as trans- I 
lations of the genetlc message in the polypeptide sequences of certain pro- 
teins. Presumably this indicates an evolutionary origin and significance 
for the occurrence of these phenomena in these instances. Examples are to be I 
found in the 01 and B chains of hemoglobin A, the genes for which occupy 
separate chromosomal loci. Their separation is thought to result from dup- 
lication and translocation (Ingrw, 1963). The two chains also show the I 
occurrence of deletions, indicated by the presence of gaps in the homology 
of the polypeptides, for instance - 
I 
- * 
Supported by e National Science Foundation Cooperative Graduate Fellwship 
and by grant NsC 479 by the National Aeronautics and Space Administration to 
the .UnIversi ty of Cal ifornie. 
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Rcs idue 'No. I2 
25 
(r a l a  a l a  t r p  gly l ys  va1 g l y  a l a  h i s  a l a  g l y  g l u  t y r  g l y  
13 24 
Q a l a  I c u  t r p  g l y  l ys  vi11 - - asn v a l  asp g l u  v a l  g l y  
B,\SC 
C tiangcs 0 2 0 0 0 0  1 1 1 0 2 0  
The prcscnce o f  a gap corresponding to  t l ~ c  d e l e t i o n  o f  6 consecuttve base p a i r s  
i n  tho, gena i s  i n f e r r e d  from the comparison o f  thesc scquenccs. The comparison 
a l s o  shows t h a t  7 p o i n t  mutations have takcn place i n  the gene to produce changes 
a t  5 hwnologous p a i r s  o f  l o c i  corresponding to i n d i v i d u a l  amino a c i d  residues 
ind ica ted  by base changes. Such amino-acid changes, when to lerated,  ma'y become 
so numerous as to obscure the o r i g i n a l  homology, thus eras ing  the record o f  
the p r i m o r d i a l  dup l i ca t ion .  An example o f  t h i s  i s  g iven below for  human cyto-  
chrome 6 The comparison o f  any two polypept ide chains i s  aided by enumerating 
the minimum number o f  base changes i n  the coding t r i p l e t s  (Btimacombe, e t  al, 
1965) corresponding to each p a i r  of amino a c i d  residues a t  two homologous 
s i tes .  In  the comparison above, these are 1 i s t e d  underneath the sequences. 
I n  t h i s  way two amino ac ids t h a t  are r e l a t e d  by a single-base change i n  the 
code are noted as being more c l o s e l y  r e l a t e d  than t w o  which are separated by 
a two-base or three-base change. Three-base changes a t  a locus are, o f  course, 
d i f f i c u l t  to  de tec t  because o f  the extensive synonymity i n  the t h i r d  p o s i t i o n s  
of the coding t r i p l e t s  (Brimacornbe, et& 1965). 
P a r t i a l  genet ic  dupl i c a t i o n  i s  ev ident  i n  the haptoglobins (Smithies, 
1964) and i n  C l o s t r i d i u m  pastcurianum f e r r e d o x i n  (Jukes, 1966b). 
F i t c h  (1965) has propssed a method f o r  examining polypept ide c h a l ~ s  for  
reg ions o f  p a r t i a l  i n t e r n a l  gene dupl icat ion,  depending upon determining the 
minimum number o f  nuc leot ides which must be a l t e r e d  t o  permi t  the conversion 
of one sequence i n t o  the other. 
puter .  We have devised a s i m i l a r  tes t ,  d e t a i l s  of which w i l l  be publ ished l a t e r .  
Having detected a homology by means o f  t h i s  test ,  i t  i s  often poss ib le  t o  make 
The t e s t  i s  c a r r i e d  out by means o f  a com- 
i t  v i s u a l l y  obvious by means of  the procedure used above with the hemoglobin 
. 
pep t i dcs. 
An examination o f  the primary structure of the cytochromes 2 indicates 
a region o f  partial duplication in thc cytochrome 5 o f  Neurospora crassa 
(Hellcr and Smith, 1965). Using throughout the numbering system employed for 
the vertebrate cytochromes 4, residucs 5 to I9 are homologous with resldues 
20 to 34 as fo l lows:  
Residua No. 
5 19 
lys gly ala asn I P U  phe lys thr arg cys ala glu cys his gly 
20 34 
glu gly gly asn leu thr gln lys ile gly pro ala leu his gly 
Base 
Changes 1 0 1 0 0 2 1 1 1 1 1 1 2 0 0  
This internal homology i s  not perceptible in the cytochromes 5 o f  other 
species, including those o f  certain vertebrates (Margo1 iash and Smith, 1965), 
two yeasts (bakers yeast and Candida k r u s c i )  (Narita, et al, 1963; Narita and 
Titani, 1965) and the moth Samia Cynthia (Chan and Margoliash, 1966). As an 
example, the corresponding sequences for human cytochrome 5 show no evidence 
o f  homology beyond what might be interpreted as being coincidental, as follows: 
R*b idue No. 
5 19 
20 34 
l y s  gly lys lys ile phe ile met lys cys ser gln cys his thr 
Val glu lys gly gly lys his lys t h r  gly pro asn l e u  his gly 
R a c e  
-"e- 
Changes 2 1 0 2 2 3 2 1 1 1 1 2 2 0 2  
T I L  only two identical pairs are the lysines at positions 7 and 22 and the 
;.istidines at 18 and 33. In other cytochromes 5 this last vestige o f  a c m o n  
oriyifi o f  the tvs sequences in this region has disappeared; residues 22 and 33 
are occupied by asparagine and tryptophan in tuna fish cytochrome 5 (Kreil, 1963) 
as follows: 
Residue No. 
5 19 
20 34 
iys gly lys lys tht phe Val gln lys cys ala gln cys his thr 
val giu  asn gly gly Iys his  lys Val gly pro asn leu trp gly 
Base 
Changes 2 1 1 2 2 3 2 1 2 1 1 2 2 3 2  
. 8 
Evp lu t i on  can thus I n  sonic cases erode thc t races o f  an i nc fdcn t  I n  i t s  e a r l y  
h i s t o r y .  I n  o t h c r  instances, such as i n  thc o f t e n - c i t e d  Pxample of  the i n v a r i a n t  
scqticnce o f  1 1  amino a c i d  r a s i d u c s  i n  l o c i  70 to 80 o f  the cytochromes 5 an 
c s s c n t i a l  p o r t i o n  o f  the same molccrilr has rpmaincd unchangttl t lur inq the evolu- 
t i o n  o f  a d i v e r s i t y  o f  l i v i n q  spccic'i from a comnon o r i n i n  (k \arqol ia?h and Smith, 
1965). i t  would scen tha t  evo lu t ionary  changes i n  the reg ion  o f  residues 5 to 
34 have proccedcd more s low ly  i n  NcuroFpora cra5sa cytochroma 5 than i n  the 
o the r  cytochromes 4 whose pr imary s t ruc tu re  has been described. However, another 
example o f  homology i n  the same reg ion  i s  ev idcn t  when a t y p i c a l  ver tebra te  
cytochrome 5 i s  compared w i t h  the dihemo pept ide  from the v a r i a n t  heme p r o t e i n  
RHP, o f  the photoanaerobe Chromatiurn (Dus, Bartsch and Kamen, 1962) as fo l lows, 
assuming a s i n g l e  amino a c i d  gap between residues 19 and 20 i n  the ve r teb ra te  
cytochrome 5: 
i Tuna IO 19 
cytochrome 5: phe v a l  g l n  l y s  cys a l a  g l n  cys h i s  thr - 
20 24 
va l  g l u  asn g l y  g l y  . 
1 10 
i i Chromatiurn phe a l a  g l y  l y s  cys ser g l n  cys h i s  t h r  leu 
v a l  a l a  asp g l u  g l y  - - - - ser  a l a  l y s  cys h i s  t h r  phe 16 20 
27 - - asp g l u  g l y  ser  
Base changes, 
i z. i i :  0 1 1 1 0 0 1 2 0 0 1 0 0 0 0 -  
Base changes, 
i n t e r n a l  i n  ii: - - O O O 1 - - - 1 1 1 0 0 0 1 
The pr imary s t r u c t u r e  o f  the remainder o f  the Chrematim heme-carrying p r o t e i n  
i s  n o t  a v a i l a b l e  and would be o f  great i n t e r e s t  as poss ib l y  revea l ing  a second 
inc iden t  o f  i n t e r n a l  d u p l i c a t i o n  i n  the regions preceding and f o l l o w i n g  the 
known peptide. 
RE FE RE NC E S L .  
Brimacomhc, R., J. Trirpin, H. Nircnbcrq, P. Ledcr,  M. Barnf ie ld ,  end T. Jeounl. 
l9b5. Proc. Nat l .  Acad. S c i . ,  U . S . ,  51+:95’#. 
, Ctmn, S.K. and E. Margoliasti. 1966. J. Oiol. Chem. 241:335. 
Dus, K. ,  R .  C. nartsch, and M. D. Knmcn. 1362. J. Biol.  Chem. 237:3083. 
Ingram, V.M. 1963. l h e  tlcrnoglobins i n  Ccnet lcs  end Evolut ion,  Columbie 
U n i v e r s i t y  Press, N.Y. 
Jukes, T.H. l36Ga. Molecules and Evolut ion.  Columbia U n i v e r t i  t y  Press, N.Y. 
( i n  the press). 
Jukes, T.H. 1966b. Science ( i n  the press) .  
K r e i l ,  G. 1963. 2. Physiol. Chem. 334:15’4. 
Margoliash, E. and E .  L. Smith. 1965. In  V. Bryson and H. J. Vogel (Ed,.), 
Evo lv ing  Genes aiid Proteins,  p. 221. Academic Press, N.Y. 
Nar i ta ,  K., K. T i tan i ,  Y. Yaoi, and H. Murakami. 1963. Biochem. Biophyr. Acta 
77 : 688. 
Nar i ta ,  K. and K. T i t a n i .  1965. Proc. Japan Acad. 4\:83\. 
Smithies, 0. 1964. Cold Spr lng  H a r b o r  Symp. Quant. 8101. 29:30g. 


Repetitions in the polypeptide sequence of cytochromes

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