The genetics of inbreeding depression

Key Points

  • Inbreeding depression is the reduced survival and fertility of offspring of related individuals. Large effects are documented in wild animal and plant populations, as well as in humans. Intercrossing inbred strains improves yield (heterosis).

  • Inbreeding depression implies that genetic variation exists in species for alleles that affect fitness. It is important for the evolutionary maintenance of outcrossing mating systems.

  • Inbreeding depression and heterosis could be caused either by the presence of (largely recessive) deleterious mutations that are present at low frequencies in populations (so that inbreeding increases the frequency of individuals expressing their effects; the 'dominance hypothesis') or by alleles with heterozygote advantage that are maintained by balancing selection at intermediate frequencies (here, homozygotes would have lower fitness; the 'overdominance hypothesis').

  • These two hypotheses are genetically distinct but, if deleterious mutations are common, genome regions may frequently carry mutations in different genes in repulsion. Therefore, homozygotes for each chromosome type might express fitness-reducing recessive mutations, and heterozygotes (with wild-type function of both genes) would have higher fitness owing to complementation. The region would therefore show heterozygote advantage even though no overdominant gene is present. Distinguishing this 'pseudo-overdominance' from true overdominance is difficult.

  • Rather than excluding overdominance, much work has focused on assessing the extent to which genetic variation in populations can be accounted for purely by deleterious mutations.

  • The overall data suggest that inbreeding depression is predominantly caused by recessive deleterious mutations in populations, so we argue that the same applies to heterosis and that the appearance of overdominance is often due to pseudo-overdominance.

  • This suggestion is consistent with fine-mapping data from genetic analyses of heterosis and with molecular evolutionary data that suggests that purifying selection is pervasive in functional genes but that long-term balancing selection (of which overdominance is a sub-category) is infrequent.


Inbreeding depression — the reduced survival and fertility of offspring of related individuals — occurs in wild animal and plant populations as well as in humans, indicating that genetic variation in fitness traits exists in natural populations. Inbreeding depression is important in the evolution of outcrossing mating systems and, because intercrossing inbred strains improves yield (heterosis), which is important in crop breeding, the genetic basis of these effects has been debated since the early twentieth century. Classical genetic studies and modern molecular evolutionary approaches now suggest that inbreeding depression and heterosis are predominantly caused by the presence of recessive deleterious mutations in populations.

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Figure 1: Summary of the main genetic hypotheses for inbreeding depression.
Figure 2: Molecular hypotheses for heterosis or heterozygote functional superiority.


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This research was supported by US National Institutes of Health grant GM073990 to J.H.W. We thank B. Charlesworth for discussions.

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Correspondence to Deborah Charlesworth.

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Nature Reviews Genetics article series on Fundamental Concepts in Genetics


Fitness-related characters

Survival, growth rate and fertility.

Inbreeding coefficient

The probability that two alleles in an individual were both descended from a single allele in an ancestor (that is, that they are 'identical by descent').

Mutation–selection balance

The balance between mutations that introduce deleterious alleles into the population and the removal of such alleles by natural selection. The result is that such mutations are present at low frequencies but, despite selection, are never entirely absent.

Balancing selection

Selection — such as heterozygote advantage and frequency-dependent selection — that maintains genetic variants in a population.


Reducing the frequencies of deleterious mutations in inbred populations, thereby lowering the mutational load (the presence of deleterious mutations in populations).

Balancer stock

A strain of fly that contains a chromosome with genetic markers and with an inversion to prevent recombination with other arrangements. Such chromosomes are used to breed stocks with 'extracted' wild-type chromosomes for estimates of homozygous and heterozygous effects.


An individual with both male and female reproductive functions (including monoecious plants, which have separate male and female flowers).

Darwinian fitness

Survival from zygote to maturity (viability) and reproductive performance (fertility); often measured as the product of viability and fertility measures.


Rearrangement in which part of a chromosome is inverted in order with respect to a homologous chromosome in the same species or in a different species.

Meiotic drive regions

Regions containing genes that have non-Mendelian segregation in heterozygotes because one allelic version of the region is rendered non-functional during meiosis.


Restoration of function in heterozygotes for two genes with recessive loss-of-function mutations (unless both mutations are in the trans configuration in the same gene, so that neither allele is functional).


The system in Hymenoptera (bees, wasps and their relatives) in which fertilized eggs develop into females and unfertilized eggs develop into (haploid) males.

Large-effect mutations

In the context of this Review, mutations that cause major phenotypic abnormality, disease, lethality or sterility.

Outbreeding depression

Reduced fitness of F1 or F2 individuals after a cross between two species or strains.

Genetic variance

The variance of trait values that can be ascribed to genetic differences among individuals. The total genetic variance in a trait can be dissected into additive, dominance and other components; in populations, these components depend on the frequencies of the alleles at loci affecting the trait.

Additive variance

The component of genetic variance that is due to the additive effects of alleles. It is the primary contributor to resemblances between parents and offspring and to evolutionary responses to selection.

Dominance variance

The component of genetic variance that arises from deviations of heterozygotes from the mean of the two homozygotes (this will be large for loci with overdominant alleles).

Quantitative trait locus mapping

The use of genetic mapping to locate genome regions that contain a gene or genes that affect character values.

Mutation accumulation lines

Lines developed by multiple generations of breeding in such a way as to minimize the action of natural selection (for example, by using the same number of progeny from each breeding individual in each generation).


The situation in a diploid organism when an allele of interest at one locus (for example, a mutant allele) came from a gamete contributed by one parent, and an allele at another locus came from the other parent (for example, the genotype +−/−+, in which – denotes mutant alleles and+ denotes wild-type alleles).

Recombinant inbred lines

A population of fully homozygous individuals obtained through the repeated selfing of an F1 hybrid.


The dependency of the effects of alleles at one locus on the genotypes at other loci in the genome.


Crossing strains or species in such a way as to introduce some of the genome of one of the parents into that of the other, often by repeated backcrossing and selecting for certain genetic markers or phenotypic characters.

Selection coefficient

The strength of selection, measured as the difference in fitness from genotypes of interest (for instance, a homozygote for a lethal allele has a selection coefficient of 1 if the fitness of the wild-type homozygote is denoted by 1).

Synonymous changes

Mutations or substitutions in a coding sequence are synonymous if they do not change the amino acid sequence of the protein encoded (non-synonymous changes are ones that do change the amino acid sequence).

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Charlesworth, D., Willis, J. The genetics of inbreeding depression. Nat Rev Genet 10, 783–796 (2009).

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