High genomic deleterious mutation rates in hominids

It has been suggested that humans may suffer a high genomic deleterious mut ation rate(1,2). Here we test this hypothesis by applying a variant of a mo lecular approach(3) to estimate the deleterious mutation rate in hominids f rom the level of selective constraint in DNA sequences. Under conservative assumptions, we estimate that an average of 4.2 amino-acid-altering mutatio ns per diploid per generation have occurred in the human lineage since huma ns separated from chimpanzees. Of these mutations, we estimate that at leas t 38% have been eliminated by natural selection, indicating that there have been more than 1.6 new deleterious mutations per diploid genome per genera tion. Thus, the deleterious mutation rate specific to protein-coding sequen ces alone is close to the upper limit tolerable by a species such as humans that has a low reproductive rate(4), indicating that the effects of delete rious mutations may have combined synergistically, Furthermore, the level o f selective constraint in hominid protein-coding sequences is atypically lo w, A large number of slightly deleterious mutations may therefore have beco me fixed in hominid lineages.