We can also look at mutation rate at another level of scale. Instead of considering the rate per nucleotide per replication, we can examine the rate of mutation across an entire genome in one generation. While it is clear from Fig. 14.1 that the rate of mutation per nucleotide per replication in most multicellular organisms is low, the rate of mutation per genome per generation depends on the size of the genome and the number of cell divisions per generation. Taking into account genome size and cell divisions per generation, the rate of new mutations across the whole genome per generation is shown in Fig. 14.2. Note that, while humans have the smallest rate of mutation per nucleotide per replication (Fig. 14.1), humans also have the largest rate of mutation per genome per generation (Fig. 14.2). This seeming paradox arises because humans have a large genome and undergo many cell divisions per generation.

In humans, the average number of newly arising nucleotide-substitution mutations per genome in one generation is about 30, or about 60 per diploid zygote. However, about 80% of the newly arising mutations in a zygote come from the father. This is because, in a human male at age 30, the diploid germ cells have gone through about 400 cycles of DNA replication and cell division before meiosis takes place, as compared with about 30 cycles in females. Moreover, while the number of newly arising mutations from the mother remains approximately constant with mother’s age, the number of newly arising mutations from the father increases with age. Sperm from men of age 40 contain about twice as many newly arising mutations as sperm from men of age 20.

Such a large number of new mutations as occurs in the human genome in one generation would be intolerable in organisms with a high density of protein-coding genes, such as bacteria or fungi. It is tolerable in humans and other mammals only because more than 90% of the nucleotides in the genome seem free to vary without deleterious consequences for the organism, and a mere 2.5% of the genome code for protein (Chapter 13). The vast majority of newly arising mutations therefore occur in noncoding DNA and are likely neutral or very nearly neutral in their effects. It is these mutations, accumulated through many generations and shuffled by recombination and independent assortment (Chapter 11), that account for the genetic diversity of most populations and the genetic uniqueness of each individual.