Along the spectrum of diversity from rare to common variants, the different kinds of mutation occur in the context of such fundamental processes of cell division as DNA replication, DNA repair, DNA recombination, and chromosome segregation in mitosis or meiosis. The frequency of mutation per locus per cell division is a basic measure of how error prone these processes are, which is of fundamental importance for genome biology and evolution. However, of greatest importance to medical geneticists is the frequency of mutation per dis ease locus per generation, rather than the overall mutation rate across the genome per cell division. Measuring disease- causing mutation rates can be difficult, however, because many mutations cause early embryonic lethality before the result can be recognized in a fetus or new born. Further, some people with a disease- causing variant may manifest the condition only late in life or may never show signs of the disease. Despite these limitations, we have made great progress in determining the overall frequency— sometimes referred to as the genetic load— of all mutations affecting the human species.

These major types of mutation occur at appreciable frequencies in many different cells in the body. In the practice of genetics, we are principally concerned with inherited genome variation; however, all such variation had to originate as a new (de novo or spontaneous) change in a germ cell. From this unique start in the population, the ultimate frequency of each variant over time depends on chance and on the principles of inheritance and population genetics. Although the original mutation would have occurred only in the DNA of a cell in the germline, any progeny derived from that cell would then carry it as a constitutional variant in essentially all the cells of the body.

In contrast, somatic mutations, depending on when they arise, occur in different proportions of cells throughout the body, but they cannot be transmitted to the next generation of individuals (unless they involved a germline cell). Given the rate of mutation (see later in this section), one would predict that every cell in an individual has a slightly different version of the genome, depending on the number of cell divisions that have occurred since conception. Such genomic heterogeneity is particularly likely to be apparent in highly proliferative tissues, such as intestinal epithelia or hematopoietic cells. However, most such variants are not typically detected because, in clinical testing, one usually sequences DNA from many millions of cells, among which the base sequence present at conception will predominate, and rare somatic mutations will be largely invisible and unascertained. Such variants, however, can be of clinical importance in disorders associated with somatic mosaicism, caused by mutation in only a subset of cells in certain tissues.

While somatic mutations will typically remain undetected within any multicell DNA sample, cancer pro vides the major exception. The mutational basis for the origins of cancer and the clonal nature of tumor evolution drive certain somatic changes to be present in essentially all the cells of a tumor. Indeed, 1000 to 10,000 somatic variants (and sometimes many more) are readily found in the genomes of most adult tumors, with mutation frequencies and patterns specific to different cancer types.

Chromosome Alterations

 Events that produce a change in chromosome number because of chromosome missegregation are among the most common sources of variation seen in humans, with a rate of one event per 25 to 50 meiotic cell divisions. This estimate is clearly minimal because the developmental consequences of many such events are likely so severe that the resulting embryos are aborted spontaneously shortly after conception without being detected.

Structural Variation

Alterations affecting the structure or regional organization of chromosomes can arise in a number of different ways. Duplications, deletions, and inversions of a segment of a single chromosome are predominantly the result of homologous recombination between DNA segments with high sequence homology at more than one chromosomal site. Not all structural mutations are the result of homologous recombination, however. Others, such as chromosome translocations and some inversions, can occur at the sites of spontaneous double- stranded DNA breaks. Once breakage occurs at two places anywhere in the genome, the two broken ends can be joined together, even without any obvious sequence homology between the two ends (a process termed nonhomologous end- joining repair).

Mutation in Genes

Gene or DNA variants, including base pair substitutions, insertions, and deletions (Fig. 1), can originate by either of two basic mutational mechanisms: errors introduced during DNA replication or arising from a failure to properly repair DNA after damage. Many such mutation events are spontaneous, arising during the normal (but imperfect) processes of DNA replication and repair, whereas others are induced by physical or chemical agents called mutagens.

Fig1. Examples of mutations in a portion of a hypothetical gene with five codons shown (delimited by the dotted lines). The first base pair of the second codon in the reference sequence (shaded in blue) is mutated by a base substitution, deletion, or insertion. The base substitution of a G for the T at this position leads to a codon change (shaded in green) and, assuming that the upper strand is the sense or coding strand, a predicted nonsynonymous change from a serine to an alanine in the encoded protein; all other codons remain unchanged. Both the single base pair deletion and insertion lead to a frameshift mutation in which the translational reading frame is altered for all subsequent codons (shaded in green), until a termination codon is reached.

DNA Replication Errors

 Typically, the process of DNA replication is highly accurate. Most replication errors (i.e., bases other than the complementary bases inserted into the double helix) are rapidly removed from the DNA and corrected by a series of DNA repair enzymes. A process termed DNA proofreading first recognizes which strand in the newly synthesized double helix contains the incorrect base and then replaces it with the proper complementary base. DNA replication needs to be a remarkably accurate process; otherwise, the burden of mutation on the organism and the species would be intolerable. The enzyme, DNA polymerase, faithfully duplicates the two strands of the double helix based on strict base- pairing rules (A pairs with T, C with G) but errs about once in every 10 million bp. Additional proofreading then corrects more than 99.9% of these errors of DNA replication. Thus the overall mutation rate per base as a result of replication errors is a remarkably low 1 × 10⁻¹⁰ per cell division— fewer than one mutation per genome per cell division.

Repair of DNA Damage

In addition to replication errors, about 10,000 to 1,000,000 nucleotides are damaged per human cell per day by (1) spontaneous chemical processes such as depurination, demethylation, or deamination, (2) reaction with chemical mutagens (natural or otherwise) in the environment, or (3) exposure to ultraviolet or ionizing radiation. Some but not all of this damage is repaired. Even if such damage is recognized and excised, the repair machinery may introduce incorrect bases. Thus in contrast to replication- related DNA changes, which are usually corrected through proofreading mechanisms, nucleotide changes introduced by DNA damage and repair are often permanent.

A particularly common spontaneous mutation is the substitution of T for C (or A for G on the other strand). The explanation for this observation comes from considering the major form of epigenetic modification in the human genome: DNA methylation. Spontaneous deamination of 5- methylcytosine to thymine in the CpG doublet gives rise to C to T or G to A mutations (depending on which strand the 5- methylcytosine is deaminated). Such spontaneous mutations may not be recognized by the DNA repair machinery, thus becoming established in the genome after the next round of DNA replication. More than 30% of all single nucleotide substitutions are of this type, and they occur at a rate 25 times greater than those of other single nucleotide mutations. Thus the CpG doublet represents a true hot spot for mutation in the human genome.

Overall Rate of DNA Mutation

The rate of DNA mutation at specific loci has been estimated using a variety of approaches. The impact of replication and repair errors on the occurrence of new variants throughout the genome can now be determined directly by whole genome sequencing (WGS), using trios consisting of a child and both parents, looking for new sequences in the child that are not present in either parent. The overall rate of new mutations, averaged between maternal and paternal gametes, is ~1.2 × 10⁻⁸ per base pair per generation. This rate, however, varies from gene to gene and perhaps from population to population, or even individual to individual. This rate of change, combined with considerations of population growth and dynamics, predicts that there must be an enormous number of relatively new (and thus very rare) variants among the current worldwide population of 7.9 billion individuals.

As might be predicted, the vast majority of these will be single nucleotide variants in noncoding portions of the genome and will probably have little or no functional significance. Nonetheless, at the level of populations, the potential collective impact of these new mutation changes on genes of medical importance should not be overlooked. In the United States, for example, with over 4 million live births each year, ~6 million new changes will occur in coding sequences; thus even for a single protein- coding gene of average size, we can anticipate several hundred newborns each year with a new variant in the coding sequence of that gene.

Conceptually similar studies have determined the rate of mutation for CNVs, where the generation of a new length variant depends on recombination, rather than on errors in DNA synthesis. The measured rate of formation of new CNVs (≈1.2 × 10⁻² per locus per generation) is orders of magnitude higher than that of base substitutions.

Rate of Disease- Causing Variations

The most direct way of estimating the rate of disease- causing mutation, resulting in a pathogenic variant, for a given locus is to measure the incidence of new cases of a genetic condition that is clearly recognizable in all neonates who have a particular genetic alteration. Achondroplasia, a condition of reduced bone growth leading to short stature, is a condition that meets these requirements. In one series of 242,257 consecutive births, 7 children with achondroplasia were born to parents of average stature; because achondroplasia always manifests when a pathogenic variant is present, all were considered to represent new mutations. Thus the new mutation rate at this locus can be calculated to be 7 new mutations in a total of 2 × 242,257 copies of the relevant gene, or ~1.4 × 10⁻⁵ pathogenic variants per locus per generation. This high mutation rate is particularly striking because virtually all cases of achondroplasia are due to the identical variant: a G to A transition that changes a glycine codon to an arginine in the encoded protein.

The rate of pathogenic mutation has been estimated for a number of other disorders in which the occurrence of a new variant was identified by the appearance of a detectable disease (Table 1). The measured rates for these and other disorders vary over a 1000- fold range, from 10−4 to 10⁻⁷ mutations per locus per generation. The basis for these differences may be related to some or all of the following: the size of different genes, the fraction of all variants in that gene that will lead to the disease, the age and sex of the parent in whom the mutation occurred, the mutational mechanism, and the presence or absence of mutational hot spots in the gene. Indeed, the high rate of the particular site- specific mutation event in achondroplasia may be partially explained by it being at a hot spot for mutation by deamination, as discussed earlier.

Table1. Estimates of Mutation Rates for Selected Human Disease Genes

Notwithstanding this range of rates among different genes, the median gene mutation rate is ~1 × 10⁻⁶. Given that there are at least 5000 genes in the human genome in which variants are currently known to cause a discernible disease or other trait , ~1 in 200 persons is likely to receive a new pathogenic variant in a known disease- associated gene due to mutation in one or the other parent.

Sex Differences and Age Effects on Mutation Rates

Because the DNA undergoes far more replication cycles in sperm than in ova, there is greater opportunity for errors to occur in sperm, suggesting that new variants will be more often paternal than maternal in origin. Indeed, where this has been explored, new variants responsible for certain conditions (e.g., achondroplasia, as just discussed) are usually missense variants that arose nearly always in the paternal germline. Furthermore, the older a man is, the more rounds of replication have preceded the meiotic divisions, thus the frequency of new paternal variants might be expected to increase with the age of the father. Indeed, increased paternal age is correlated with increased incidence of SNVs for a number of disorders (including achondroplasia) and with the incidence of CNVs in autism spectrum disorders and intellectual disability. For other diseases, however, the parent- of- origin and age effects on mutational spectra are, for unknown reasons, not as striking.

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مواضيع ذات صلة

Noninvasive Prenatal Screening by Analysis of Cell- Free Fetal DNA

Screening for Down Syndrome and Other Aneuploidies

Screening for Neural Tube Defects

Genetic Alterations Associated with Acromegaly

The Profession of Genetic Counseling

Applying Genomics to Individualize Cancer Therapy

The Role of Epigenetics in Cancer

Screening for Genetic Susceptibility to Disease

Pharmacogenomics

Monogenic Diseases Show One of Three Patterns of Inheritance

Tumor Suppressor Genes in Autosomal Dominant Cancer Syndromes

Activated Oncogenes in Hereditary Cancer Syndromes