13.0: Introduction

In which we consider how mutations (changes in genomic DNA) appear and become alleles within a population and distinguish between the effects of chance and selection on allele frequencies.

We are far enough along to recognize that beginning with a particular genome any change, such as those due to errors in DNA replication as well as un-repaired or mis-repaired environmentally induced damage involving chemical reactions or the effects of radiation results in a mutation. If the cell/organism survives the mutational event and if the mutation lies within a gene, it can produce what is known as an allele, a specific version of a gene. If it lies outside of a gene, it becomes known as a sequence polymorphism or sequence variation. With the advent of economical genome sequencing and related technologies, it is possible to estimate the rates of mutation in a particular organism or in a particular cell type.^[456] Here we distinguish between mutations in the germ line (leading to eggs and sperm) that can be inherited by offspring and those that occur in somatic cells, the cells of the body. Mutations not inherited from one's parents are said to occur spontaneously. A spontaneous mutation may be passed on to offspring only if it occurs in a germ line cell.

As a first approximation, mutations occur randomly within genomes, although there are known mutational "hotspots". CpG dinucleotides are mutated ~10X more frequently than other dinucleotides. In addition to single nucleotide changes, mutations can involve small insertions and deletions of nucleotides known as indels. Indels are defined to be less than 20 base pairs (bps) in length to distinguish them from larger changes, known as structural variants; these can be thousands to millions of bases in lenght. It has been estimated that each generation sees the addition of ~3 indels and ~0.16 structural variants in a person's germ line. Another type of structural variant, known as a copy number variation (CNV), involves changes in the number of copies of a particular DNA region. It can lead to multiple copies of gene(s).^[457] There are also mutations influencing cell division that can lead to the loss or gain of a chromosome or the duplication of the entire genome.

Mutations occur more frequently in the soma of an organism than in the germ line because there are more cells (trillions) and so more cycles of DNA replication and cell division involved. Similarly, there are fewer cell divisions involved in the generation of oocytes than in the generation of sperm and the number of mutations in the male germ line increases with age. Germ line mutations can be passed from generation to generation, while somatic mutations are lost on the death of the organism. A current estimate is that the chance of a de novo germ line mutation in humans is ~1x10^-8 per base pair per generation (the human genome contains ~6 x 10⁹ base pairs of DNA ). We will discuss both germ line and somatic mutations and their effects soon.

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