On 2015 Jan 11, Donald Forsdyke commented:

CONTINUING SUPPORT FOR GRANTHAM'S GENOME HYPOTHESIS

Richard Grantham (1980), after examination of a mere 160 short sequences, proposed his ‘genome hypothesis.’ For nucleic acids he envisaged ‘manifold constraints and adaptations, of both structural and functional natures.’ These ‘could exist, independently of protein coding.’ Thus, there was ‘protein-independent molecular evolution of a non-neutral character.’ The distinctive ‘coding strategy of an organism’ was ‘at the heart of the problem of molecular evolution,’ and was likely to prove of fundamental importance for ‘speciation and systematics in general’ (Grantham et al. 1986).

These observations won extensive support when thousands of much longer sequences became available, even though many were incomplete (Forsdyke and Mortimer 2000; Mortimer and Forsdyke 2003; Lee et al. 2004). The data, consistent with the early base compositional studies of Chargaff, Sueoka and Szybalski, are now further affirmed by this comprehensive new work involving thousands of entirely complete sequences (Goncearenco and Berezovsky 2014).

However, while there is little disagreement on data and the need for evolutionary trade-offs (‘mutual adjustment of the nucleotide and amino acid compositions’), readers should note that there remains disagreement over interpretations (see my comments on a previous paper and my textbook; Zeldovich et al. 2007, Forsdyke 2011). Readers should also note that the present text (p. 3) has proline (P) listed in both the high GC% saturation group and the low GC% saturation group. In error, phenylalanine (F) was replaced by P in the latter. The GC% low and medium groups have amino acids listed in order of increasing codon GC% saturation, but the GC% high group has amino acids listed (p. 3) in decreasing order of codon GC% saturation (see Fig. S3). And it is puzzling that Figures 1a and 1b appear the same, with just axis labels interchanged, yet some points seem incorrectly interchanged. The rectilinear interpretations of obvious curvilinear relationships (Figs. 8, S9) are also problematic, as noted by Reviewer 2.

The notion that aspartate and glutamate (with purine-rich codons GAY and GAR) ‘cannot be used for the efficient tuning of the nucleotide composition,’ does not hold for the tuning of AG%. Furthermore, it should be noted that as GC% increases, the decline of A and T does not affect both bases equally. While G% and T% tend to remain constant, C increases at the expense of A. Likewise, when GC% decreases, A increases at the expense of C (Mortimer and Forsdyke 2003). This A-for-C transversional trading, most evident at extreme GC% values (Fig. S10), should decrease the probabilities of G-quadruplexes and thymine dimers. Finally, noting for example the high AG% in thermophiles, it may be premature to conclude that tradeoffs are a ‘purely compositional phenomenon, linking the realms of nucleic and amino acids in prokaryotes regardless of their life styles, environments, and phylogeny.’ Grantham’s admonition regarding speciation and systematics should not go unheeded.

Forsdyke DR: Evolutionary Bioinformatics. 2nd edition. New York: Springer, 2011.

Forsdyke DR, Mortimer JR: Chargaff’s legacy. Gene 2000, 261:127-137.Forsdyke DR, 2000

Goncearenco A, Berezovsky IN: The fundamental trade-off in genomes and proteomes of prokaryotes established by the genetic code, codon entropy, and physics of nucleic acids and proteins. Biology Direct 2014, 9:29.Goncearenco A, 2014

Grantham R: Workings of the genetic code. Trends Biochem Sci 1980, 5:327-331.

Grantham R, Perrin P, Mouchiroud D: Patterns in codon usage of different kinds of species. Oxford Surv Evol Biol 1986, 3:48-81.

Lee S-J, Mortimer JR, Forsdyke DR: Genomic conflict settled in favour of the species rather than of the gene at extreme GC% values. Applied Bioinformatics 2004, 3:219-228.Lee SJ, 2004

Mortimer JR, Forsdyke DR: Comparison of responses by bacteriophage and bacteria to pressures on the base composition of open reading frames. Applied Bioinformatics 2003, 2:47-62.Mortimer JR, 2003

Zeldovich KB, Berezovsky IN, Shakhnovich EI: Protein and DNA sequence determinants of thermophilic adaptation. PLoS Comput Biol 2007, 3(1):e5.Zeldovich KB, 2007

On 2015 Jan 11, Donald Forsdyke commented:

CONTINUING SUPPORT FOR GRANTHAM'S GENOME HYPOTHESIS

Richard Grantham (1980), after examination of a mere 160 short sequences, proposed his ‘genome hypothesis.’ For nucleic acids he envisaged ‘manifold constraints and adaptations, of both structural and functional natures.’ These ‘could exist, independently of protein coding.’ Thus, there was ‘protein-independent molecular evolution of a non-neutral character.’ The distinctive ‘coding strategy of an organism’ was ‘at the heart of the problem of molecular evolution,’ and was likely to prove of fundamental importance for ‘speciation and systematics in general’ (Grantham et al. 1986).

These observations won extensive support when thousands of much longer sequences became available, even though many were incomplete (Forsdyke and Mortimer 2000; Mortimer and Forsdyke 2003; Lee et al. 2004). The data, consistent with the early base compositional studies of Chargaff, Sueoka and Szybalski, are now further affirmed by this comprehensive new work involving thousands of entirely complete sequences (Goncearenco and Berezovsky 2014).

However, while there is little disagreement on data and the need for evolutionary trade-offs (‘mutual adjustment of the nucleotide and amino acid compositions’), readers should note that there remains disagreement over interpretations (see my comments on a previous paper and my textbook; Zeldovich et al. 2007, Forsdyke 2011). Readers should also note that the present text (p. 3) has proline (P) listed in both the high GC% saturation group and the low GC% saturation group. In error, phenylalanine (F) was replaced by P in the latter. The GC% low and medium groups have amino acids listed in order of increasing codon GC% saturation, but the GC% high group has amino acids listed (p. 3) in decreasing order of codon GC% saturation (see Fig. S3). And it is puzzling that Figures 1a and 1b appear the same, with just axis labels interchanged, yet some points seem incorrectly interchanged. The rectilinear interpretations of obvious curvilinear relationships (Figs. 8, S9) are also problematic, as noted by Reviewer 2.

The notion that aspartate and glutamate (with purine-rich codons GAY and GAR) ‘cannot be used for the efficient tuning of the nucleotide composition,’ does not hold for the tuning of AG%. Furthermore, it should be noted that as GC% increases, the decline of A and T does not affect both bases equally. While G% and T% tend to remain constant, C increases at the expense of A. Likewise, when GC% decreases, A increases at the expense of C (Mortimer and Forsdyke 2003). This A-for-C transversional trading, most evident at extreme GC% values (Fig. S10), should decrease the probabilities of G-quadruplexes and thymine dimers. Finally, noting for example the high AG% in thermophiles, it may be premature to conclude that tradeoffs are a ‘purely compositional phenomenon, linking the realms of nucleic and amino acids in prokaryotes regardless of their life styles, environments, and phylogeny.’ Grantham’s admonition regarding speciation and systematics should not go unheeded.

Forsdyke DR: Evolutionary Bioinformatics. 2nd edition. New York: Springer, 2011.

Forsdyke DR, Mortimer JR: Chargaff’s legacy. Gene 2000, 261:127-137.Forsdyke DR, 2000

Goncearenco A, Berezovsky IN: The fundamental trade-off in genomes and proteomes of prokaryotes established by the genetic code, codon entropy, and physics of nucleic acids and proteins. Biology Direct 2014, 9:29.Goncearenco A, 2014

Grantham R: Workings of the genetic code. Trends Biochem Sci 1980, 5:327-331.

Grantham R, Perrin P, Mouchiroud D: Patterns in codon usage of different kinds of species. Oxford Surv Evol Biol 1986, 3:48-81.

Lee S-J, Mortimer JR, Forsdyke DR: Genomic conflict settled in favour of the species rather than of the gene at extreme GC% values. Applied Bioinformatics 2004, 3:219-228.Lee SJ, 2004

Mortimer JR, Forsdyke DR: Comparison of responses by bacteriophage and bacteria to pressures on the base composition of open reading frames. Applied Bioinformatics 2003, 2:47-62.Mortimer JR, 2003

Zeldovich KB, Berezovsky IN, Shakhnovich EI: Protein and DNA sequence determinants of thermophilic adaptation. PLoS Comput Biol 2007, 3(1):e5.Zeldovich KB, 2007