The origins, patterns and implications of human spontaneous mutation

The germline mutation rate in human males, especially older males, is generally much higher than in females, mainly because in males there are many more germ-cell divisions. However, there are some exceptions and many variations. Base substitutions, insertion–deletions, repeat expansions and chromosomal changes each follow different rules. Evidence from evolutionary sequence data indicates that the overall rate of deleterious mutation may be high enough to have a large effect on human well-being. But there are ways in which the impact of deleterious mutations can be mitigated.

Key Points

  • Germline base substitution mutations occur more frequently in males than in females, especially in older males.

  • The main explanation for the sex and age effect is that a much larger number of germline divisions occurs in the male than in the female, and continues throughout male adulthood.

  • Point mutations at some loci occur almost exclusively in males, whereas others have a smaller excess, roughly ten times more than in females. Which is more typical remains to be determined.

  • For mutations other than point mutations, sex biases in the mutation rate are very variable. However, small deletions are more frequent in females.

  • The total rate of new deleterious mutations for all genes is estimated to be about three per zygote. This value is uncertain, but it is likely that the number is greater than one.

  • It is suggested that quasi-truncation selection is the principal explanation for how the population can rid itself of a large number of mutations with a relatively low fitness cost.

  • Since this form of selection is effective only with sexual reproduction, perhaps the fact that humans reproduce sexually has made it possible to have such a long life cycle.

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Figure 1: Wilhelm Weinberg.
Figure 2: Cell divisions during oogenesis and spermatogenesis.
Figure 3: Relative frequency of de novo achondroplasia and Apert syndrome for different paternal ages.
Figure 4: Relative frequency of de novo neurofibromatosis for different paternal ages.
Figure 5: Relative frequency of all trisomies for different maternal ages.


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Apert syndrome

basal cell nevus

CHARGE syndrome

cri-du-chat syndrome

Crouzon syndrome

Down syndrome

Duchenne muscular dystrophy

factor VIII locus

factor IX locus



fragile X syndrome

haemophilia A

haemophilia B

Huntington disease

Lesch–Nyhan syndrome

Marfan syndrome



myotonic dystrophy

neurofibromatosis type I

OTC deficiency

Pfeiffer syndrome

Progeria syndrome



Waardenburg syndrome

Wilm tumour

Wolf–Hirschhorn syndrome



A chromosome other than the X or Y.


Having three copies of a chromosome.


Having an unbalanced chromosome number. An example is trisomy.


A trait determined by many genes, almost always interacting with environmental influences.


A nucleotide change that alters the coded amino acid.


A mutation that is selectively equivalent to the allele from which it arose.


Insertion or deletion in a chromosome.


A measure of the capacity to survive and reproduce.


A pre-reproductive death or failure to reproduce.


Approximate or inexact truncation selection — selection in which all individuals below a certain threshold survive and reproduce equally; the others are eliminated.


A statistical distribution in which the probability of an individual event is small, but the number of opportunities is large enough that several occur.

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Crow, J. The origins, patterns and implications of human spontaneous mutation . Nat Rev Genet 1, 40–47 (2000).

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