Deleterious Mutations and Neutral Substitutions

Abstract

CLARKE¹ says that his observations “invalidate” several “less critical” studies, in which category he places one by us². Clarke's calculations are based essentially on two contributions by others; these are the “objective classification of the chemical properties of the amino-acids” by Sneath³ and two tables in Dayhoff's Atlas⁴. We believe that classification procedures for amino-acids should be used with caution. Indeed, Clarke quotes a remark by Zuckerkandl and Pauling⁵ that “apparently chemists and protein molecules do not share the same opinions regarding the definition of the most prominent properties of a residue”. There is much point to this remark. In the few large families of homologous proteins that have been studied (haemoglobins, cytochromes and immunoglobulins), many sites are occupied by six or more different amino-acids². This implies, as is well known, that a great deal of interchangeability is possible at such sites. The flexibility of interchange may reflect a lack of close proximity to other residues in the tertiary structure of the protein.