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Background  The ratio of the rates of non-synonymous and synonymous substitution ( d   N  / d   S  ) is commonly used to estimate selection in coding sequences. It is often suggested that, all else being equal,  d   N  / d   S   should be lower in populations with large effective size ( N  e ) due to increased efficacy of purifying selection. As  N  e  is difficult to measure directly, life history traits such as body mass, which is typically negatively associated with population size, have commonly been used as proxies in empirical tests of this hypothesis. However, evidence of whether the expected positive correlation between body mass and  d   N  / d   S   is consistently observed is conflicting.    Results  Employing whole genome sequence data from 48 avian species, we assess the relationship between rates of molecular evolution and life history in birds. We find a negative correlation between  d   N  / d   S   and body mass, contrary to nearly neutral expectation. This raises the question whether the correlation might be a method artefact. We therefore in turn consider non-stationary base composition, divergence time and saturation as possible explanations, but find no clear patterns. However, in striking contrast to  d   N  / d   S  , the ratio of radical to conservative amino acid substitutions ( K   r  / K   c  ) correlates positively with body mass.    Conclusions  Our results in principle accord with the notion that non-synonymous substitutions causing radical amino acid changes are more efficiently removed by selection in large populations, consistent with nearly neutral theory. These findings have implications for the use of  d   N  / d   S   and suggest that caution is warranted when drawing conclusions about lineage-specific modes of protein evolution using this metric.    Electronic supplementary material  The online version of this article (doi:10.1186/s13059-014-0542-8) contains supplementary material, which is available to authorized users.

K r /K c but not d N /d S correlates positively with body mass in birds, raising implications for inferring lineage-specific selection