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									  Compensatory evolution in
mammalian mitochondrial tRNAs

Andrew D. Kern and Fyodor A. Kondrashov



 Center for Population Biology, Section of Evolution and Ecology
                 University of California at Davis
Fitness
                     Genotype


          Genotype
Polymeropoulos MH, et al., Science, 1997
Compensated Pathogenic Deviation (CPD)
      Molecular event (substitution or other) that is
present in a wild-type in one species and is pathogenic in
another species.

Compensatory Deviation
       Molecular event (substitution or other) that negates
the deleterious effect of a Pathogenic Mutation
MITOMAP
A human mitochondrial genome database
A compendium of polymorphisms and mutations of
the human mitochondrial DNA


   Are tRNAs more likely to contain CPDs compared with proteins?


   Can we predict the compensatory-compensated interactions?


   Will this ever lead to anything useful?


   Who cares?
Some assumptions


1) Pathogenic mutations are deleterious


2) They are fixed in the orthologous species


3) CPDs cannot be fixed without a compensation
Why we think these assumptions are not bad assumptions


1) Pathogenic mutations are deleterious: Polymorphisms
   are more frequently found in orthologs


2) They are fixed in the orthologous species: We checked
   all primate species with 2 available mitochondrial
   genomes


3) The pathogenic mutation cannot be fixed without a
   compensatory event: The diseases are really bad
Disease                        Symptoms
Chronic Progressive External   exercise intolerance, mild bilateral ptosis, limb weakness,
Ophthalmoplegia                and respiratory chain complex III deficiency,

Leber Hereditary Optic         mid-life, acute or subacute, painless, central vision loss
Neuropathy                     leading to central scotoma, mean age onset 27-34

Mitochondrial                  episodic vomiting, seizures, and recurrent cerebral insults
Encephalomyopathy              resembling strokes and causing hemiparesis, hemianopsia, or
                               cortical blindness. 80% of cases affected patients aged 5 to
                               15 years
Mitochondrial Myopathy         proximal and subsequently distal muscle fatigability and
                               weakness at ages 5 to 10 years

mitochondrial                  pigmentary retinopathy, dementia, hypoparathyroidism, and
encephalomyopathy              diabetes mellitus. Early childhood onset.

Leigh syndrome                 early-onset progressive neurodegenerative disorder with a
                               characteristic neuropathology consisting of focal, bilateral
                               lesions in one or more areas of the central nervous system,
                               including the brain stem, thalamus, basal ganglia,
                               cerebellum, and spinal cord
Methods.

           Genbank                         22 tRNA multiple
                                          alignments with 106
                                           mammals and with
                      Phylogeny               marked CPDs
  Complete           information
 mammalian
mitochondrial
  genomes

                                                    Pathogenic
                                                    mutations
      Synteny
 preserved in most
 mammals (except               Multiple           Secondary
    marsupials)               alignment         structure info
     A multiple alignment of primate orthologs for Glycine (G) tRNA.




human                   actcttttagtataaat--agtaccgttaacttccaattaactagttttgac-aacattcaaaaaagagta
chimpanzee actcttttagtataaGt--agtaccgttaacttccaattaactagttttgac-aacattcaaaaaagagta
pygmy chimpanzee        actcttttagtataaGc--agtaccgttaacttccaattaactagttttgac-aacattcaaaaaagagta
gorilla                 actcttttagtataatt--agtaccgttaacttccaattaaccagttttggt-agtacccaaaaaagagta
orangutan               actcttttagtataaGc--agtaccgttaacttccaattaaccagttttgac-aacactcaaaaaagagta
Sumatran orangutan      actcttttagtataaac--agtaccgttaacttccaattaactagttttgac-aacGcccaaaaaagagta
hamadryas baboon        actcttttagtataatt--agtacaAttgacttccaatcaatcagctttgac-aatattcaaaaaagagta
Barbary ape actcttttagtataacc--agtacaAttgacttccaatcaatcagttttgac-aacattcaaaaaagagta
common gibbon           actcttttagtataaac--agtactgttaacttccaattaaccagcttcgat-aacGctcgaaaaagagta
capuchin    attctcttagtataaac--agtacaAttgacttccaattaataggccttgat-aa-acccaagagagaata
ring-tailed lemur       attcttttagtatcgacccaatacaAttgacttccaattaattaacttcggtgaa-aaccggaaaagaata
slow loris gctcttttagtacaact--agtacaAttgacttccaatcaataggatttggtaaataaccaaaagagagca
western tarsier         gttcctttagtatcaatt-agtacaAttgacttccaatcaattagccctagtacaattctaggaaggaaca
                              .        *     .   *                              *
    A multiple alignment of selected mammalian orthologs for Luicine UUR (L1).


human                      gttaagatggcagagcccggtaatcgcataaaacttaaaactttacagt-cagaggttcaattcctcttcttaaca
western tarsier            gttaagatggcagagcccggCaattgcataaaacttaaaactttattat-cagaggttcaactcctcttcttaaca
northern tree shrew        gttaaggtggcagagcccggtcattgcctaaaacttaagattttaAgta-cagaagttcaaatcctctccttaaca
European hare gttaaggtggcagagcccggCaattgcataaaacttaaaactttataat-cagaggttcaactcctctccttaaca
Egyptian jerboa            gctaagatggcagagcccggtaattgcaCaagacttaaaccCttgAatc-cagaggttcaactcctcttcttaGca
Eurasian red squirrel      attaagatggcagagcccggcaattgcataagatttaaaacCttactat-cagaggttcaactcctcttcttaaTa
Madagascar hedgehog        attaagatggcagagcc-ggtaattgcaCaagacttaaaccCttgctgt-cagaggttcaatCcctcttcttaaTa
little red flying fox      gttaggatggcagagcccggCaattgcataaaacttaagcttttataat-cagaggttcaactcctcttcctaaca
Japanese house bat         gttaaagtggcagagaccggtaattgcataaaacttaagattttagagc-cagaggttcaactcctctctttaaTa
polar bear                 gttagggtggcagagcccggtGattgcataaaacttaaacctttatact-cagaggttcaaatcctctccctaaca
Atlantic walrus            gttagggtg-cagagcccggtaattgcataaaacttaaacttttacccc-cagaggttcaactcctctccctaaTa
greater Indian rhino       gttaggatggcagagcccggtaactgcataaaacttaaacctttataac-cagaggttcaactcctcttcctaaca
narwhal                    gttgggatggcagagtacggCaattgcataaaacttaaacctttatacc-cagaggttcaaatcctcttcccaaca
Indus River dolphin        gttgaggtggcagagtccggCaattgTataaaacttaaacttttacact-cagaggttcaaatcctctccccaaca
pig                        attagggtggcagagaccggtaattgcgtaaaacttaaacctttattac-cagaggttcaactcctctccctaaTa
nine-banded armadillo      gttaagatggcagagacaggtaattgcataagacttaaacctttattac-cagaggttcaaatcctcttcttaaca
aardvark                   gttaaggtggcagagcccggtaattgcataaaacttaagcttttacaac-cagaggttcaattcctctccttaaca
Asiatic elephant           gttaagatagcaaaaattggtcactgcataaaacttaagcttttactca-cGgaggttcaactcctcttcttaaca
African elephant           gttaagatagcaaaaactggtcactgcataaaacttaagcttttactca-cGgaggttcaactcctcttcttaaca
wallaroo                   attaaggtggcagagcc-ggCaattgcataaaacttaaacctttataat-cagaggttcaaatcctctccttaaTa
common wombat attaaggtggcagagca-ggtaattgcataaaacttaagcctttacaac-cagaggttcaaaCcctctccttaaTa
platypus                   attaaggtgacagagaccggtaattgTgtaaaacttaagcttttatagt-cagaggttcaaatcctctccttaaTa
Australian echidna         attaaggtgacagagaccggCaattgTgtaaaacttaagcttttataat-cagaggttcaaatcctctccttaaTa
                                        .     .**. . * * . .        * . *     *       . *           **
Can we say anything about a molecular or structural basis of compensations?

                                              Homo sapiens tRNAAsn


                                                             3’
                                                      5’ G
                                                       U A
                                                       A U Acceptor
                                                      G C stem
                                                       A U
                                                       U G
                                                       U G
                                                      G U           U GA
                                                      A    UACCC
                                        UUG          A                  A
                                                           GUGGG
                                       G      A CCG         U       U UU
                                       A                    U TYC-
                                        U U AG G G U        U
                                                    G      G stem/loop
                                         D-stem/     C GU
                                         loop        U A
                                                     U A Anticodon
                                                     A U stem/loop
                                                     G C
                                                    C    A
                                                    U    A
                                                     GU U
        Pan troglodytes
     (chimpanzee) tRNAAsn

                   3’
              5’   G
                U  A
                A  U
      Acceptor G   C
      stem      A  U
                U  A G
                U  A G
               G   U        U GA
               A    UACCC
 UUG          A                  A
                    GUGGG
G     A CCG          U      U UU
A                    U TYC-
 U U AG G G U        U
             G      G  stem/loop
 D-stem/
           C  U AU
 loop         U A G
              U A
              A U Anticodon
              G C stem/loop
             C    A
             U    A
              GU U

  Figure 2a
      Cynocephalus variegatus
    (Malayan flying lemur) tRNALys
                     3’
                     A
               5’ C G Acceptor
                  A U stem
             C U A G
             U C A
                  G C
                  U AUU C
     D-stem/ A G C             CA
     loop        A     C CUUC      A
               A U GG A A G        U   C
     AG U CG                   UA C
C
     AC A G C          U
                        A AA G
                    U A        A
     U U      A        G TYC-
                U A A stem/loop
                U A
     Anticodon A U
     stem/loop A U
                C G
              C      A
              U      A
               UUU


       Figure 2b
      Ceratotherium simum
    (white rhinoceros) tRNATrp
                    3’
              5’   G
       Acceptor A U
       stem
                G C
             A G C U
                 A U
                 A U
                 U A TYC-
                 U A stem/loop
   A                           C
                U   UUCA U A
   C AU        A                  A
 A       UGG        A AGU A A
 C                   C U       C
   C AG A C C         G     U    C
                               G
UA
    D-stem/   A       A
               A U  A
    loop                C
               G C
            A G C
            G A C Anticodon
               C G stem/loop
              C    A
              U    A
               UC A
 Figure 2c
       Ursus maritimus
    (polar bear) tRNASer(UCN)
                      3’
                 A
               5’ G
                 U
               A U
          A G C U
               A U Acceptor
          A G U
               A U stem          U

 A        U
               G C          U CA
     G              CUUCC
              A                  G
 U GAU A C         G A GGG
G                G
                    A       U UC
G U U A UG       U
                U C
                      G
                         TYC-
            A      C
         G U
                         stem/loop
  C C             U
 D-stem/ G A U C
 loop     G U A G
             U A Anticodon
             G C stem/loop
             G C
           C      A
           U      A
             UGA

   Figure 2d
      Spalax ehrenbergi
 (Ehrenberg's mole-rat) tRNAIle
                   3’
                 A
            5’ A U
               G C
     Acceptor A U
     stem      A U
               A U       TYC-
           U C G A       stem/loop
               A U           CG A
       U      U    UC UCC        A
   A G C C UG      A G A G G CA
                             U
 U                 U
 A CAGA              A G A C UU
   A
            G        A
     A
 D-stem/     U A AU
 loop        U G A
             A U Anticodon
             C G stem/loop
             U A
           U     G
           U     A
            GAU

Figure 2e
    Tamandua tetradactyla
 (southern tamandua) tRNAIle
                  3’
              5’   A
                 A U
                 G C
       Acceptor A U
                 A U
       stem      A U       TYC-
                 U A    C stem/loop
                 A U         C GA A
   U     U      U UCU CC
                                 C
     A G C C UG     AG AGG
  C                  U       U CA A
  A AGG A             A GA
    A                        CU
                                 U
D-stem/       A       C
         A            A U
loop
            G U A
                  AA     U
               U
               A U
               C G Anticodon
               U A stem/loop
             U     G
             U      A
              GAU
        Hyperoodon ampullatus
(northern bottlenose whale) tRNALeu(UUR)
                       3’
                 5’
                       A
                     G C Acceptor
                     U A
                     U A stem
                 A   G C U
                 A   G U            U
      D-stem/        G C
  C              A   G C U
      loop
                    U             U AA
C       G                U C UC C
   CU A            G                  A
  U        GA CG         AG A GG
  G                       C       U UC
   G       C UGU       U C TYC-
     CA   A             G C stem/loop
           U C C A         A
    U               U AC
                    A U
         Anticodon A U
         stem/loop A U C
                    A U
                  C     C A
                 U      A
                   UA  A

  Figure 2f
       Tachyglossus aculeatus
   (Australian echidna) tRNALeu(UUR)
                      3’
                 5’ A
                   A U
              G U A C
                  U A Acceptor
                   A U stem
                   A U            U
     D-stem/ A
                  G C
 C                G C U        U AA
     loop    G U U CU C C
   A GA                             A
 C              G     A G A GG
C       GACA
                      C        U UC
G       U UGU           U TYC-
 G                       A stem/loop
   C AA         G
         C C            A G
 U                    U
              A U A
                 A U C
                 A U
       Anticodon A U
       stem/loop A U C
               C     C A
               U     G A
                UAA
   Oryctolagus cuniculus
      (rabbit) tRNACys
                  3’
            5’   U
              A U
              G C
              C G
          U   C G
              C G         A
          C   U G      C
        A     G C          C A
              A    CG UC U     A
  U G        G
A    G G UG       GC AGC       C
C                   A      U U
      ACA U
 UA                 A
            A    AG
        U    U A
      U
             U A G
             G C
             A U
             A U
            U    A
            U    A
             GC A
                                               Canis familiaris
                                              (dog) tRNALeu(UUR)
                                                         3’
                                                   5’   A
                                                     G C
                                                     U A Acceptor
                                                     U A stem
                                                     A U
                                                 A   G C U
                                                  A G C

                                       C GG   A G G C U           U UA
                                     C                   UCUCC
                                                   U                  A
                                    C       G A CG       A G A GG C
                                    G                     C       UU
                                            C U GC          U TYC-
                                     G     A       G
                                       UA                  A stem/loop
                                             UC
                                      D-stem/    A U AC U     G
                                      loop
                                                   A U      A
                                                   A U Anticodon
                                                   A U stem/loop
                                                   A C
                                                  C   C A
                                                  U    A
Wittenhagen, L.M. & Kelley, S.O.,                  UAA
Nat. Struct. Biol. (2002) and
Trends Biochem. Sci. (2003),
                                       Molecular characteristics of the pathogenic mutations

                                 GC ->     GC pair     AU ->       AU pair     Mutation in loop or    Total
                                  GU      destroyed     GU        destroyed      between stems:
                                              8                       7                 18             52
                                                                                   In stem, not
                                   5                     12                     disruptive to WC
                                                                                      pair: 2
 Mechanisms     Restoring
       of      Watson-Crick
compensation   Interactions      3 (2)      6(2)        9(3)        7(2)                0            25(9)
in mammalian
               New Watson-
   (primate)
                   Crick
    species
                interaction       1         2(2)        3(2)        2(1)                0             8(4)

                 AU -> GC
                                  0           1           3           0                 0              4
               Change in loop
                 length or
                 sequence         1           0           1           0                 1              3
                   Multiple
                 interactions
               strengthened or
               newly evolved      2         3(1)          4           2                 0            11 (1)
               Compensation
                 unclear
                                 3(1)         0        4 (2)          0             19(14)           26(17)
1) Pathogenic mutation in humans may reverse humans to an ancestral state

2) CPDs and Compensatory substitutions occur, seemingly, simultaneously

3) Convergent evolution of CPD-Compensatory interaction is common
                                           0.09
Fraction of CPDs among all substitutions

                                           0.08
                                                                                          Hylobates lar
                                                           Pan troglodytes
                                           0.07
                                                           Pan paniscus

                                           0.06
                                                                                 Pongo pygmaeus           Cebus albifrons     Nycticebus coucang


                                           0.05
                                                                                                  Papio hamadryas
                                                                                                                                Tarsius bancanus
                                           0.04

                                                                             Pongo pygmaeus abelii                              Lemur catta
                                                       Gorilla gorilla                                      Macaca sylvanus
                                           0.03



                                           0.02



                                           0.01



                                             0
                                                  0   50                  100               150               200             250              300

                                                                   Number of substitutions in all tRNAs
So what?


1) This can be used to study the limits of tRNA
   stability in evolution
2) DM incompatibilities are intergenic, not expected
   to be revealed in F1 generation
3) Molecular basis of compensatory evolution is
   much more varied than has been appreciated
4) Fitness ridges of tRNAs are very epistatic such
   that 50% of all substitutions are compensatory
5) Fixation of CPD and/or Compensatory mutations
   occurs under positive selection
Fitness
                     Genotype


          Genotype
         Primate tRNASer(UCN)
|gaaaaag|t|catg|gaggc|catg|gg|gttgg|cttgaaa|ccagc|tttg|ggggg|ttcgatt|ccttc|ctttttt|g
|gaaaaag|t|catg|gaggt|catg|gg|gttgg|cttgaaa|ccagc|ttta|ggggg|ttcgatt|ccttc|ctttttt|g
|gaaaaag|t|catg|ggggt|catg|gg|gttgg|cttgaaa|ccagc|ttta|ggggg|ttcgatt|ccttc|ctttttt|g
|gaaaaag|t|catg|aaggt|catg|gg|gttgg|cttgaaa|ccagc|tttg|ggggg|ttcgatt|ccttc|ctttttt|g
|gaaaaag|t|catg|ggggt|Tatg|gg|gttgg|cttgaaa|ccagc|ttta|ggagg|ttcgatt|ccttc|ctttttt|g
|gaaaaag|t|catg|gaggt|Tgtg|gg|gttgg|cttgaaa|ccagc|ttta|ggagg|ttcgatt|ccttc|ctttttt|g
|gaaaaag|t|tata|ggggc|Tata|ag|gctgg|cttgaaa|ccagt|ttta|ggggg|ttcgact|ccctc|ctttttc|g
|gaaaaag|t|tata|agggt|Tata|ag|actgg|cttgaaa|ccagt|tcta|ggggg|ttcgact|ctctc|ctttttc|g
|gaaaaag|t|cata|gaggt|Tatg|gg|gctgg|cttgaaa|ccagt|ttta|ggggg|ttcgatt|ccttc|ctttttt|g
|gaaaaag|t|cata|gggtc|Tatg|gg|attgg|cttgaaa|ccaAt|tttt|ggggg|ttcaaat|ccttc|ctttttc|g
|aaGaaag|t|tgta|gtggt|Tacg|cg|gttgg|cttgaaa|ccaAt|ttta|gaggg|ttcgatt|ccttc|ctttctt|g
|aaGaaag|t|catg|g-ggt|Tatg|gg|gttgg|cttgaaa|ccaAt|ttta|ggggg|ttcgatt|cctcc|ctttctt|g
|aaGaaag|a|cata|gtggt|Tatg|ag|gttgg|cttgaaa|ccaAt|ctta|ggggg|ttcaatt|ccttc|ctttctt|g



       Primate tRNAAla
|aagggct|ta|gctt|aa-tta|aagt|g|gctga|tttgcgt|tcagt|tgat|gcaga|gtggggt|tttgc|agtcctt|a
|aagggct|ta|gctt|aa-tta|aagt|g|gctga|tttgcgt|tcagt|tgat|gcaga|gtggggt|tttgc|agtcctt|a
|aagggct|ta|gctt|aa-tta|aagt|g|gctga|tttgcgt|tcagt|tgat|gcaga|gtggggt|tttgc|agtcctt|a
|aagggct|ta|gctt|aa-tta|aagt|g|gctga|tttgcgt|tcagt|tgat|gcaga|gtagggt|tttgc|agtcctt|a
|Gagggct|ta|gctt|aa-tta|aagt|g|gctga|tttgcgc|tcagt|tgat|gcaaa|gtggggt|tttgc|agtcctt|a
|Gagggct|ta|gctt|aa-tta|aagt|g|gctgg|tttgcgt|tcagt|tgat|gcaga|gcggggc|tttgc|agtcctt|a
|aagggct|ta|gttt|aa-tta|aagC|g|attga|tttgcgt|tcagt|tgat|gcgga|gtaggtg|tctgc|agtcctt|a
|aagggct|ta|gctt|aa-tta|aagt|a|gttga|tttgcgt|tcaat|tgat|gcaga|gcaggtg|tttgc|agtcctt|a
|aagggct|ta|gctt|aa-tta|aagt|g|actga|tttgcgt|tcggt|tgat|gcaaa|gt-gggc|tttgc|agtcctt|g
|Gagggct|ta|gctt|aa-tta|aagt|a|gttga|tttgcgt|tcaat|tgat|gcaag|gtatag-|tttgc|agtcctt|a
|Gaggatt|ta|gctt|aa-tta|aagt|g|attga|tttgcgt|tcagt|tgat|gtaag|atataat|cttgc|agtcctt|a
|Gaggact|ta|gctt|aa-tta|aagt|a|attga|tttgcgt|tcagt|tgat|gtagg|a-gaagt|cttgc|agtcctt|a
|Gaggact|ta|gctt|aagtta|aagt|a|gctaa|tttgcag|ttagt|tgat|gtaga|gtgagtc|tttgc|agtcctt|a
                                                                Stems only
            0.7




            0.6
                                                polymorphisms
                                                pathogenic
            0.5
Frequency




            0.4




            0.3




            0.2




            0.1




             0

                  in primates not compensated   in primates compensated      not in mammals or only in
                                                  and/or in mammals not       mammals compensated
                                                       compensated
Polymeropoulos MH, et al., Science, 1997
             Site 53 of alpha-synuclein


                                        72       A Macaca mulatta
                                             A
                               66                A Macaca fascicularis
                                    A
                      89                         A Erythrocebus patas
                           A
                                                 A Homo sapiens
             30                              A
                  T                     26       A Pongo pygmaeus abelii
                                                 T Saguinus labiatus
    91                              T            T Ateles geoffroyi
         T                     77
                                             T
                                        91       T Lagothrix lagotricha

T                                                T Rattus norvegicus
                                             T
                                        94       T Mus musculus
                                                 T Gallus gallus
                                                 T Xenopus laevis
A universal trend of amino acid gain and loss in protein
                       evolution



   I. King Jordan1, Fyodor A. Kondrashov2, Ivan A. Adzhubei3, Yuri I.
  Wolf1, Eugene V. Koonin1, Alexey S. Kondrashov1, Shamil Sunyaev3




         1National  Center for Biotechnology Information, NIH,
   2Section of Evolution and Ecology, University of California at Davis

  3Division of Genetics, Department of Medicine, Brigham & Women's

                   Hospital, Harvard Medical School
                          Beta hemoglobin

Mouse MVHLTDAEKSAVSCLWAKVNPDEVGGEALGRLLVVYPWTQRYFDSFGDLSSASAIMGNPK 60
Rat   MVHLTDAEKAAVNGLWGKVNPDDVGGEALGRLLVVYPWTQRYFDSFGDLSSASAIMGNPK
Human MVHLTPEEKSAVTALWGKVNVDEVGGEALGRLLVVYPWTQRFFESFGDLSTPDAVMGNPK

Mouse VKAHGKKVITAFNEGLKNLDNLKGTFASLSELHCDKLHVDPENFRLLGNAIVIVLGHHLG 120
Rat   VKAHGKKVINAFNDGLKHLDNLKGTFAHLSELHCDKLHVDPENFRLLGNMIVIVLGHHLG
Human VKAHGKKVLGAFSDGLAHLDNLKGTFATLSELHCDKLHVDPENFRLLGNVLVCVLAHHFG

Mouse KDFTPAAQAAFQKVVAGVATALAHKYH 147
Rat   KEFSPCAQAAFQKVVAGVASALAHKYH
Human KEFTPPVQAAYQKVVAGVANALAHKYH



                             Sister-1       Ala Val Met Phe
 Parsimony polarization      Sister-2       Ala Gly Ile Phe
                             Outgroup       Ala Val Leu Ser
                                                 *
    Does amino acid composition evolve?


            T          C           A            G
      TTT   F    TCT   S     TAT   Y      TGT   C
      TTC   F    TCC   S     TAC   Y      TGC   C
T     TTA   L    TCA   S     TAA   STOP   TGA   STOP
      TTG   L    TCG   S     TAG   STOP   TGG   W
      CTT   L    CCT   P     CAT   H      CGT   R
      CTC   L    CCC   P     CAC   H      CGC   R
C     CTA   L    CCA   P     CAA   Q      CGA   R
      CTG   L    CCG   P     CAG   Q      CGG   R
      ATT   I    ACT   T     AAT   N      AGT   S
      ATC   I    ACC   T     AAC   N      AGC   S
A     ATA   I    ACA   T     AAA   K      AGA   R
      ATG   M    ACG   T     AAG   K      AGG   R
      GTT   V    GCT   A     GAT   D      GGT   G
      GTC   V    GCC   A     GAC   D      GGC   G
G     GTA   V    GCA   A     GAA   E      GGA   G
      GTG   V    GCG   A     GAG   E      GGG   G
Substitutions to and from an amino acid in Muridae
Cys            Met             His             Ser             Phe

2547 / 1729    5920 / 4205     5702 / 4752     19904 / 18108   4461 / 3895
+0.19*         +0.17*          +0.09*          +0.05*          +0.07*
+0.18*         +0.06*          -0.00           -0.01           +0.09*
Asn            Thr             Ile             Val             Arg
8238 / 8956    15045 / 12720   10458 / 11678   16810 / 14108   13228 / 9275
-0.04*         +0.08*          -0.06*          +0.09*          +0.18*
-0.03*         -0.00           -0.03*          +0.03*          +0.12*
Gln            Trp             Leu             Tyr             Asp
6910 / 8265    732 / 589       10479 / 11447   2538 / 2750     8799 / 8107
-0.09*         +0.11*          -0.04*          -0.04*          +0.04*
-0.09*         +0.20*          +0.05*          +0.05*          +0.02*
Lys            Gly             Glu             Ala             Pro
6829 / 10089   8238 / 8677     8056 / 11269    1559 / 1733     7350 / 9883
-0.19*         -0.03*          -0.17*          -0.05*          -0.15*
-0.11*         +0.05*          -0.19*          -0.03*          -0.07*
15 sets of whole genome, triple multiple alignments


 Hominidae
 Muridae
 Saccharomyces
 Pyrococcus
 Escherichia
 Salmonella
 Buchnera
 Vibrio
 Pseudomonas
 Bordetella
 Helicobacter
 Chlamydia
 Bacillus
 Streptococcus
 Staphylococcus
Taxon              GC         Pu/Py
                 contents   imbalance
Hominidae        -0.098      +0.051
                                        Changes in amino acid
Muridae          -0.003      +0.007
                                        composition is not due to the of
Saccharomyces    +0.135      +0.011     evolution of nucleotide
Pyrococcus       +0.160      -0.138     composition
Escherichia      -0.188      -0.005
Salmonella       -0.162      -0.052
Buchnera         +0.504      -0.097
Vibrio           +0.057      -0.031
Pseudomonas      -0.508      +0.046
Bordetella       -0.453      +0.016
Helicobacter     +0.356      -0.073
Chlamydia        +0.272      +0.021
Bacillus         +0.160      -0.006
Streptococcus    +0.312      -0.015
Staphylococcus   +0.385      -0.049
What is going on??


1) Immediate forces

    a) Global warming
    b) Armageddon
    c) Slowing down of Earth rotation
    d) Increased proximity to the Sun
    e) More sulfur in the atmosphere (more Cys and Met)


2) Common history



Parallel evolution may be the result of common historical
constraints. In this case, before the divergence of all life (LUCA).
                                        Amino acid   Abundance in
                                                     Murchison meteorite

                                        Gly          +++
                                        Pro          ++
                                        Glu          ++
                                        Ala          ++
                                        Val          ++
                                        Asp          +
                                        Leu          +
                                        Ile          +
                                        Tyr          -
                                        Gln          -
                                        Arg          -
                                        Lys          -
                                        Trp          -
                                        Thr          -
                                        Asn          -

      Murchison meteorite               Phe          -
Victoria Australia September 28, 1969   Ser          -
          Possibly a comet              His          -
                                        Met          -
                                        Cys          -
                     Amino acid   Abundance in spark
                                  experiments
                     Ala          +++
                     Gly          +++
                     Glu          +
                     Pro          +
                     Leu          +
                     Asp          +
                     Ser          +
                     Thr          +
                     Ile          +
                     Val          +
                     Arg          -
                     Gln          -
                     Trp          -
                     Lys          -
                     Asn          -
                     Phe          -
                     Tyr          -
 Stanley L. Miller   His          -
Experiment in 1952   Met          -
                     Cys          -
                                Amino acid   Consensus order of
                                             recruitment
                                Gly                   1
                                Ala                   2
                                Asp                   3
                                Val                   4
                                Pro                   5
                                Ser                   6
                                Glu                   7
                                Leu                   8
                                Thr                   9
                                Arg                  10
                                Gln                  11
                                Ile                  12
                                Asn                  13
     Edward N. Trifonov
                                His                  14
Compiled a “consensus” of all   Lys                  15
   available inferences         Cys                  16
                                Phe                  17
                                Tyr                  18
                                Met                  19
Amino acid@   Rank   Consensus order of   Abundance in spark   Abundance in
                     recruitment          experiments          Murchison meteorite
Pro           1      5                    +                    ++
Ala           2      2                    +++                  ++
Glu           3      7                    +                    ++
Gly           4      1                    +++                  +++
Lys           5      15                   -                    -
Asp           6      3                    +                    +
Tyr           7      18                   -                    -
Leu           8      8                    +                    +
Trp           9      20                   -                    -
Gln           10     11                   -                    -
Arg           11     10                   -                    -
Val           12     4                    +                    ++
Ile           13     12                   +                    +
Thr           14     9                    +                    -
Asn           15     13                   -                    -
Phe           16     17                   -                    -
Ser           17     6                    +                    -
His           18     14                   -                    -
Met           19     19                   -                    -
Cys           20     16                   -                    -
                 Rank of amino acid by loss rate agianst order of
                                  apeparance

                 25
                                             R = 0.52
                 20
Consensus rank
  (Trifonov)




                 15

                 10

                  5

                  0
                      0      5        10          15      20        25
                                     ranks by loss rate
                               Rank of AA by loss vs order of appearance (-Y,W)

                      20
                      18
                                          R = 0.68
Order of appearance




                      16
                      14
                      12
                      10
                       8
                       6
                       4
                       2
                       0
                           0          5              10            15      20     25
                                                     Rank by loss rate
  Gainer      Rate of gain   Current   Asymptotic      No. of
                              freq.       freq.     substitutions
Amino Acids                                         since origin
    Cys       +0.0067 ±      0.012       0.032         1.363
               0.00171
    Met       +0.0088 ±      0.025       0.038         1.595
               0.00126
    His       +0.0073 ±       0.02       0.032         1.592
               0.00107
    Ser       +0.0167 ±      0.062       0.080         1.597
               0.00356
    Phe       +0.0042 ±      0.042       0.053         4.067
               0.00091
    Asn       +0.0073 ±      0.040       0.048         1.985
               0.00268
    Thr       +0.0091 ±      0.051       0.061         1.957
               0.00282
    Ile       +0.0089 ±      0.068       0.077         2.120
               0.00500
    Val       +0.0098 ±      0.069       0.078         1.927
               0.00182
    Arg       +0.0038 ±      0.051       0.056         3.195
               0.00433
    Gln       +0.0020 ±      0.038       0.041         3.821
               0.00184
  Looser         Rate of loss     Current   Asymptotic   Initial
                                   freq.       freq.      freq.
Amino Acids


    Trp       +0.0002 ± 0.00041   0.011       0.012


    Leu       -0.0017 ± 0.00346   0.103       0.100      0.109


    Tyr       -0.0005 ± 0.00118   0.032       0.031      0.034


    Asp       -0.0039 ± 0.00229   0.052       0.047      0.074


    Lys       -0.0065 ± 0.00333   0.059       0.051      0.092


    Gly       -0.0063 ± 0.00253   0.072       0.059      0.093


    Glu       -0.0137 ± 0.00244   0.065       0.048      0.136


    Ala       -0.0239 ± 0.00862   0.081       0.058      0.242


    Pro       -0.0139 ± 0.00262   0.043       0.022      0.101
Why so slow??




                Proteins, like chairs, depend on
                three dimensional structure for
                proper function.
As more materials (amino acids) become available,
a chair (protein) can be improved. This must be a slow
process because the chair (protein) needs to remain
functional at every step.

         wood




                                   cloth

                 metal
                         Amino    Numbers of polymorphisms      Numbers of substitutions
                          Acid
                   Cys           1046 / 484, +0.367          137 / 72, +0.311
                   Met           1219 / 811, +0.201          324 / 204, +0.227
                   His           1616 / 835, +0.319          297 / 206, +0.181
Human
                   Ser           2589 / 2321, +0.055         633 / 586, +0.039
polymorphisms
                   Phe           1046 / 572, +0.293          231 / 115, +0.335
display the same
                   Asn           1199 / 940, +0.121          340 / 277, +0.102
pattern!!!
                   Thr           2109 / 1839, +0.068         504 / 524, -0.019
                   Ile           1660 / 1245, +0.143         525 / 450, +0.077
                   Val           2459 / 2038, +0.094         725 / 674, +0.036
                   Arg           2321 / 3665, -0.225         570 / 670, -0.081
                   Gln           1510 / 1151, +0.135         359 / 291, +0.105
                   Trp           557 / 221, +0.432           61 / 25, +0.419
                   Leu           2178 / 1690, +0.126         394 / 397, -0.004
                   Tyr           609 / 440, +0.161           96 / 114, -0.086
                   Asp           927 / 1300, -0.167          197 / 308, -0.220
                   Lys           1370 / 1032, +0.141         336 / 292, +0.070
                   Gly           1374 / 1954, -0.174         294 / 342, -0.075
                   Glu           926 / 1729, -0.302          232 / 386, -0.249
                   Ala           1505 / 2740, -0.291         517 / 606, -0.079
                   Pro           1118 / 2331, -0.352         204 / 437, -0.363
Least common ancestor (LUCA) lived ~ 4 billion years ago


Therefore:
Order of amino acid assimilation, billions of years ago
continues to influence patterns of molecular evolution in all
sampled taxa.


Late amino acids continue to populate modern proteins.


Modern human polymorphisms depend, in part, on the order
of evolutionary events ~ 4 billion years ago.
        Are the authors insane?



 When you have eliminated all which is impossible, then
whatever remains, however improbable, must be the truth.
                                        ~ Sherlock Holmes
                           Acknowledgements



Compensatory evolution       Andrew D. Kern          UC Davis

Amino acid gain and loss     I. King Jordan          NCBI
                             Ivan A. Adzhubei        Harvard Medical School
                             Yuri I. Wolf            NCBI
                             Eugene V. Koonin NCBI
                             Alexey S. Kondrashov    NCBI
                             Shamil Sunyaev          Harvard Medical School


Special thanks               Lisa Horth              Old Dominion
                                                     University

Financial Support            Val Faybushevich        Northeastern University

								
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