摘要：Lagging-strand genes accumulate more deleterious mutations. Genes are thus preferably located on the leading strand, an observation known as strand-biased gene distribution (SGD). Despite of this mechanistic understanding, a satisfactory quantitative model is still lacking. Replication-transcription-collisions induce stalling of the replication machinery, expose DNA to various attacks, and are followed by error-prone repairs. We found that mutational biases in non-transcribed regions can explain ~71% of the variations in SGDs in 1,552 genomes, supporting the mutagenesis origin of SGD. Mutational biases introduce energetically cheaper nucleotides on the lagging strand, and result in more expensive protein products; consistently, the cost difference between the two strands explains ~50% of the variance in SGDs. Protein costs decrease with increasing gene expression. At similar expression levels, protein products of leading-strand genes are generally cheaper than lagging-strand genes; however, highly-expressed lagging genes are still cheaper than lowly-expressed leading genes. Selection for energy efficiency thus drives some genes to the leading strand, especially those highly expressed and essential, but certainly not all genes. Stronger mutational biases are often associated with low-GC genomes; as low-GC genes encode expensive proteins, low-GC genomes thus tend to have stronger SGDs to alleviate the stronger pressure on efficient energy usage.
