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.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Darwin, C. R. The Effects of Cross and Self Fertilization in the Vegetable Kingdom (John Murray, London, 1876).
Darwin, C. R. The Various Contrivances by which Orchids are Fertilised by Insects. (John Murray, London, 1862).
Darwin, C. R. The Different Forms of Flowers on Plants of the Same Species (John Murray, London, 1877).
McCune, A. R. et al. A low genomic number of recessive lethals in natural populations of bluefin killifish and zebrafish. Science 296, 2398–2401 (2002).
Zhang, H.-Y. et al. A genome-wide transcription analysis reveals a close correlation of promoter INDEL polymorphism and heterotic gene expression in rice hybrids. Mol. Plant 1, 720–731 (2008). A fascinating, detailed study of gene expression differences in rice, together with information about DNA sequence differences in non-coding regions that are adjacent to genes. It also contains clear models that show the possible expression patterns that can arise.
Duvick, D. N. Biotechnology in the 1930s: the development of hybrid maize. Nature Rev. Genet. 2, 69–74 (2000).
Grossniklaus, U., Nogler, G. A. & Dijk, P. J. v. How to avoid sex: the genetic control of gametophytic apomixis. Plant Cell 13, 1491–1498 (2004).
Lewontin, R. C. The Genetic Basis of Evolutionary Change (Columbia Univ. Press, New York, 1974).
Crow, J. F. Mutation, mean fitness, and genetic load. Oxf. Surv. Evol. Biol. 9, 3–42 (1993).
Barrière, A. et al. Detecting heterozygosity in shotgun genome assemblies: lessons from obligately outcrossing nematodes. Genome Res. 19, 470–480 (2009).
Sved, J. A. An estimate of heterosis in Drosophila melanogaster. Genet. Res. 18, 97–105 (1971).
Latter, B., Mulley, J., Reid, D. & Pascoe, L. Reduced genetic load revealed by slow inbreeding in Drosophila melanogaster. Genetics 139, 287–297 (1998).
Willis, J. H. Genetic analysis of inbreeding depression caused by chlorophyll-deficient lethals in Mimulus guttatus. Heredity 69, 562–572 (1992).
Klekowski, E. J., Lowenfeld, R. L. & Hepler, P. K. Mangrove genetics II. Outcrossing and lower spontaneous mutation rates in Puerto Rican Rhizophora. Int. J. Plant Sci. 155, 373–381 (1994).
Ohnishi, O. Population genetics of cultivated buckwheat, Fagopyrum esculentum Moench. I. Frequency of chlorophyll-deficient mutants in Japanese populations. Jpn J. Genet. 57, 623–639 (1982).
Ohnishi, O. Population genetics of cultivated buckwheat, Fagopyrum esculentum Moench. III. Frequency of sterility mutants in Japanese populations. Jpn J. Genet. 60, 391–404 (1985).
Willis, J. H. The contribution of male sterility mutations to inbreeding depression in Mimulus guttatus. Heredity 83, 337–346 (1999). This genetic study extends the evidence for large-effect mutations that segregate in natural populations to species other than D. melanogaster.
Werren, J. in The Natural History of Inbreeding and Outbreeding (ed. Thornhill, N. W.) 42–59 (Univ. Chicago Press, 1993).
Henter, H. J. Inbreeding depression and haplodiploidy: experimental measures in a parasitoid and comparisons across diploid and haplodiploid insect taxa. Evolution 57, 1793–1803 (2003).
Fisher, R. A. Average excess and average effect of a gene substitution. Ann. Eugen. 11, 53–63 (1941). An important theoretical paper that first introduced and showed the genetic transmission advantage of inbreeding.
Nagylaki, T. A model for the evolution of self fertilization and vegetative reproduction. J. Theor. Biol. 58, 55–58 (1976).
Stebbins, G. L. Variation and Evolution in Plants (Columbia Univ. Press, New York, 1950).
Lloyd, D. G. Some reproductive factors affecting the selection of self-fertilization in plants. Am. Nat. 113, 67–79 (1979).
Porcher, E. & Lande, R. The evolution of self-fertilization and inbreeding depression under pollen discounting and pollen limitation. J. Evol. Biol. 18, 497–508 (2005). An important, integrated model of outcrossing rate evolution that includes several biologically relevant processes.
Charlesworth, D. & Charlesworth, B. Inbreeding depression with heterozygote advantage and its effect on selection for modifiers changing the outcrossing rate. Evolution 44, 870–888 (1990).
Johnston, M. O. et al. Correlations among fertility components can maintain mixed mating in plants. Am. Nat. 173, 1–11 (2009).
Byers, D. L. & Waller, D. M. Do plant populations purge their genetic load? Effects of population size and mating history on inbreeding depression. Annu. Rev. Ecol. Syst. 30, 479–513 (1999).
Carr, D. E. & Dudash, M. Recent approaches into the genetic basis of inbreeding depression in plants. Philos. Trans. R. Soc. Lond. B 358, 1071–1084 (2003).
Crnokrak, P. & Barrett, S. C. D. Perspective: purging the genetic load: a review of the experimental evidence. Evolution 56, 2347–2358 (2002).
Charlesworth, B., Charlesworth, D. & Morgan, M. T. Genetic loads and estimates of mutation rates in very inbred plant populations. Nature 347, 380–382 (1990).
Ohta, T. & Cockerham, C. C. Detrimental genes with partial selfing and effects on a neutral locus. Genet. Res. 23, 191–200 (1974).
Wang, J., Hill, W. G., Charlesworth, D. & Charlesworth, B. Dynamics of inbreeding depression due to deleterious mutations in small populations: I. Mutation parameters and inbreeding rate. Genet. Res. 74, 165–178 (1999).
Charlesworth, D., Morgan, M. T. & Charlesworth, B. Inbreeding depression, genetic load and the evolution of outcrossing rates in a multi-locus system with no linkage. Evolution 44, 1469–1489 (1990).
Willis, J. H. The role of genes of large effect on inbreeding depression in Mimulus guttatus. Evolution 53, 1678–1691 (1999). An ingenious experimental approach to understanding how much inbreeding depression can be accounted for by large-effect deleterious mutations.
Fox, C. W., Scheibly, K. L. & Reed, D. H. Experimental evolution of the genetic load and its implications for the genetic basis of inbreeding depression. Evolution 62, 2236–2249 (2008).
Moll, R. H., Cock, C. C., Stuber, C. W. & Williams, W. P. Selection responses, genetic–environmental interactions, and heterosis with recurrent selection for yield in maize. Crop Sci. 18, 641–645 (1978).
Charlesworth, D. & Charlesworth, B. Inbreeding depression and its evolutionary consequences. Ann. Rev. Ecol. Syst. 18, 237–268 (1987).
Falconer, D. S. & Mackay, T. F. C. Introduction to Quantitative Genetics (Longman, Harlow, 1996).
Haldane, J. B. S. Parental and fraternal correlations in fitness. Ann. Eugen. 14, 288–292 (1949).
Houle, D., Hoffmaster, D. K., Assimacopoulos, S. & Charlesworth, B. The genomic rate of mutation for fitness in Drosophila. Nature 359, 58–60 (1992).
Mukai, T., Cardellino, R. A., Watanabe, T. K. & Crow, J. F. The genetic variance for viability and its components in a local population of Drosophila melanogaster. Genetics 78, 1195–1208 (1974).
Charlesworth, B., Miyo, T. & Borthwick, H. Selection responses of means and inbreeding depression for female fecundity in Drosophila melanogaster suggest contributions from intermediate-frequency alleles to quantitative trait variation. Genet. Res. 89, 85–91 (2007).
Charlesworth, B. & Hughes, K. A. in Evolutionary Genetics: From Molecules to Morphology (eds Singh, R. S. & Krimbas, C. B.) 369–392 (Cambridge Univ. Press, 2000).
Charlesworth, B. & Hughes, K. A. Age-specific inbreeding depression and components of genetic variance in relation to the evolution of senescence. Proc. Natl Acad. Sci. USA 93, 6140–6145 (1996).
Charlesworth, B. & Charlesworth, D. The genetic basis of inbreeding depression. Genet. Res. 74, 329–340 (1999).
Kelly, J. K. & Willis, J. H. Deleterious mutations and genetic variation for flower size in Mimulus guttatus. Evolution 55, 937–942 (2001).
Kelly, J. K. Deleterious mutations and the genetic variance of male fitness components in Mimulus guttatus. Genetics 164, 1071–1085 (2003). An integrated analysis that uses quantitative genetic approaches to detect the effects of deleterious mutations on a fitness-related character.
Schultz, S. & Willis, J. H. Individual variation in inbreeding depression: the roles of inbreeding history and mutation. Genetics 141, 1209–1223 (1995). The authors extend models that are used to predict the overall average inbreeding depression to predict the distribution of effects.
Stuber, C. W., Lincoln, S. E., Wolff, D. W., Helentjaris, T. & Lander, E. S. Identification of genetic factors contributing to heterosis in a hybrid from two elite maize inbred lines using molecular markers. Genetics 132, 823–839 (1992).
Garcia, A., Wang, S., Melchinger, A. E. & Zeng, Z. B. Quantitative trait loci mapping and the genetic basis of heterosis in maize and rice. Genetics 180, 1707–1724 (2008).
Graham, G., Wolff, D. & Stuber, C. Characterization of a yield quantitative trait locus on chromosome five of maize by fine mapping. Crop Sci. 37, 1601–1610 (1997).
Latter, B. Mutant alleles of small effect are primarily responsible for the loss of fitness with slow inbreeding in Drosophila melanogaster. Genetics 148, 1143–1158 (1998).
Noor, M. A. F., Cunningham, A. & Larkin, J. Consequences of recombination rate variation on quantitative trait locus mapping studies: simulations based on the Drosophila melanogaster genome. Genetics 159, 581–588 (2001).
McMullen, M. D. et al. Genetic properties of the maize nested association mapping population. Science 325, 737–740 (2009).
Mitchell-Olds, T. Interval mapping of viability loci causing heterosis in Arabidopsis. Genetics 140, 1105–1109 (1995).
Radoev, M., Becker, H. & Ecke, W. Genetic analysis of heterosis for yield and yield components in rapeseed (Brassica napus L.) by quantitative trait locus mapping. Genetics 179, 1547–1558 (2008).
Wright, S. Evolution and the Genetics of Populations Vol. 3 (Univ. Chicago Press, 1977).
Redei, G. P. Single locus heterosis. Z. Indukt. Abstamm. Vererbungsl. 93, 164–170 (1962).
Schuler, J. F. Natural mutations in inbred lines of maize and their heterotic effect. I. Comparison of parent, mutant and their F1 hybrid in a highly inbred background. Genetics 39, 908–922 (1954).
Schuler, J. F. & Sprague, G. F. Natural mutations in inbred lines of maize and their heterotic effect. II. Comparison of mother line versus mutant when outcrossed to related inbreds. Genetics 41, 281–291 (1955). An important early test to distinguish between true overdominance and pseudo-overdominance.
Xiao, J., Li, J., Yuan, L. & Tanksley, S. Dominance is the major genetic-basis of heterosis in rice as revealed by QTL analysis using molecular markers. Genetics 140, 745–754 (1995).
Li, Z., Pinson, S. R. M., Park, W. D., Patterson, A. H. & Stansel, J. W. Epistasis for three grain yield components in rice (Oryza sativa L.). Genetics 145, 453–465 (1997).
Li, Z. et al. Overdominant epistatic loci are the primary genetic basis of inbreeding depression and heterosis in rice. I. Biomass and grain yield. Genetics 158, 1737–1753 (2001).
Luo, X. et al. Additive and over-dominant effects resulting from epistatic loci are the primary genetic basis of heterosis in rice. J. Integr. Plant Biol. 51, 393–408 (2009).
Kusterer, B. et al. Heterosis for biomass-related traits in Arabidopsis investigated by quantitative trait loci analysis of the triple testcross design with recombinant inbred lines. Genetics 177, 1839–1850 (2007).
Kusterer, B. et al. Analysis of a triple testcross design with recombinant inbred lines reveals a significant role of epistasis in heterosis for biomass-related traits in Arabidopsis. Genetics 175, 2009–2017 (2007).
Melchinger, A. E. et al. Genetic basis of heterosis for growth-related traits in Arabidopsis investigated by testcross progenies of near-isogenic lines reveals a significant role of epistasis. Genetics 177, 1827–1837 (2007).
Semel, Y. et al. Overdominant quantitative trait loci for yield and fitness in tomato. Proc. Natl Acad. Sci. USA 103, 12981–12986 (2006).
Nakazato, T., Bogonovich, M. & Moyle, L. C. Environmental factors predict adaptive phenotypic differentiation within and between two wild Andean tomatoes. Evolution 62, 774–792 (2008).
Eshed, Y. & Zamir, D. An introgression line population of Lycopersicon pennellii in the cultivated tomato enables the identification and fine mapping of yield-associated QTL. Genetics 141, 1147–1162 (1995).
Remington, D. & O'Malley, D. Whole-genome characterization of embryonic stage inbreeding depression in a selfed loblolly pine family. Genetics 155, 337–348 (2000).
Remington, D. & O'Malley, D. Evaluation of major genetic loci contributing to inbreeding depression for survival and early growth in a selfed family of Pinus taeda. Evolution 54, 1580–1589 (2000).
Huang, X. et al. High-throughput genotyping by whole-genome resequencing. Genome Res. 19, 1068–1076 (2009).
Springer, N. & Stupar, R. Allelic variation and heterosis in maize: how do two halves make more than a whole? Genome Res. 17, 264–275 (2007).
Song, X., Ni, Z., Yao, Y., Zhang, Y. & Sun, Q. Identification of differentially expressed proteins between hybrid and parents in wheat (Triticum aestivum L.) seedling leaves. Theor. Appl. Genet. 118, 213–225 (2009).
Swanson-Wagner, R. A. et al. All possible modes of gene action are observed in a global comparison of gene expression in a maize F1 hybrid and its inbred parents. Proc. Natl Acad. Sci. USA 103, 6805–6810 (2006).
Auger, D. et al. Nonadditive gene expression in diploid and triploid hybrids of maize. Genetics 169, 389–397 (2005).
Uzarowska, A. et al. Comparative expression profiling in meristems of inbred-hybrid triplets of maize based on morphological investigations of heterosis for plant height. Plant Mol. Biol. 63, 21–34 (2007).
Guo, M. et al. Genome-wide transcript analysis of maize hybrids: allelic additive gene expression and yield heterosis. Theor. Appl. Genet. 113, 831–845 (2006).
Stupar, R. M. et al. Gene expression analyses in maize inbreds and hybrids with varying levels of heterosis. BMC Plant Biol. 8, 33 (2008).
Lemos, B., Araripe, L. O., Fontanillas, P. & Hartl, D. L. Dominance and the evolutionary accumulation of cis- and trans-effects on gene expression. Proc. Natl Acad. Sci. USA 105, 14471–14476 (2008).
Zhao, X., Chai, Y. & Liu, B. Epigenetic inheritance and variation of DNA methylation level and pattern in maize intra-specific hybrids. Plant Sci. 172, 930–938 (2007).
Frazer, K. A., Murray, S. S., Schork, N. J. & Topol, E. J. Human genetic variation and its contribution to complex traits. Nature Rev. Genet. 10, 241–251 (2009).
Valdar, W., Flint, J. & Mott, R. Simulating the collaborative cross: power of quantitative trait loci detection and mapping resolution in large sets of recombinant inbred strains of mice. Genetics 172, 1783–1797 (2006).
Valdar, W. et al. Genome-wide genetic association of complex traits in heterogeneous stock mice. Nature Genet. 38, 879–887 (2006).
Macdonald, S. & Long, A. Joint estimates of quantitative trait locus effect and frequency using synthetic recombinant populations of Drosophila melanogaster. Genetics 176, 1261–1281 (2007).
Gruber, J. D., Genissel, A., Macdonald, S. & Long, A. How repeatable are associations between polymorphisms in achaete–scute and bristle number variation in Drosophila? Genetics 175, 1987–1997 (2007).
Charlesworth, D. Balancing selection and its effects on sequences in nearby genome regions. PLoS Genet. 2, e64 (2006).
Currat, M. et al. Molecular analysis of the β-globin gene cluster in the Niokholo Mandenka population reveals a recent origin of the βS Senegal mutation. Am. J. Hum. Genet. 70, 207–223 (2002).
Hamblin, M. T. & Rienzo, A. D. Detection of the signature of natural selection in humans: evidence from the Duffy blood group locus. Am. J. Hum. Genet. 66, 1669–1679 (2000).
Helgason, A., Pálsson, S., GuÐbjartsson, D. F., Kristjánsson, þ . & Stefánsson, K. An association between the kinship and fertility of human couples. Science 319, 813–816 (2008).
Bittles, A. H. & Neel, J. V. The costs of human inbreeding and their implications for variations at the DNA level. Nature Genet. 8, 117–121 (1994).
Stoltenberg, C., Magnus, P., Skrondal, A. & Lie, R. Consanguinity and recurrence risk of stillbirth and infant death. Am. J. Public Health 89, 517–523 (1999).
Stoltenberg, C., Magnus, P., Skrondal, A. & Lie, R. Consanguinity and recurrence risk of birth defects: a population-based study. Am. J. Med. Genet. 82, 423–428 (1999).
Rudan, I. et al. Inbreeding and risk of late onset complex disease. J. Med. Genet. 40, 925–932 (2003).
Weeks, S. C., Reed, S., Ott, D. & Scanabissi, F. Inbreeding effects on sperm production in clam shrimp (Eulimnadia texana). Evol. Ecol. Res. 11, 125–134 (2009).
Hoare, K. & Hughes, R. N. Inbreeding and hermaphroditism in the sessile, brooding bryozoan Celleporella hyalina. Mar. Biol. 139, 147–162 (2001).
Husband, B. C. & Schemske, D. W. Evolution of the magnitude and timing of inbreeding depression in plants. Evolution 50, 54–70 (1995).
Escobar, J., Nicot, A. & David, P. The different sources of variation in inbreeding depression, heterosis and outbreeding depression in a metapopulation of Physa acuta. Genetics 180, 1593–1608 (2008).
Dolgin, E., Charlesworth, B., Baird, S. & Cutter, A. Inbreeding and outbreeding depression in Caenorhabditis nematodes. Evolution 61, 1339–1352 (2007).
Weller, S. G., Sakai, A. K., Thai, D. A., Tom, J. & Rankin, A. E. Inbreeding depression and heterosis in populations of Schiedea viscosa, a highly selfing species. J. Evol. Biol. 18, 1434–1444 (2005).
Richards, C. Inbreeding depression and genetic rescue in a plant metapopulation Am. Nat. 155, 383–394 (2000).
Crow, J. F. & Simmons, M. J. in The Genetics and Biology of Drosophila (eds Ashburner, M., Carson, H. L. & Thompson, J. N.) 1–35 (Academic Press, London, 1983).
Hoffmann, A. A. & Rieseberg, L. H. Revisiting the impact of inversions in evolution: from population genetic markers to drivers of adaptive shifts and speciation. Ann. Rev. Ecol. Evol. Syst. 39, 21–42 (2008).
Dyer, K. A., Charlesworth, B. & Jaenike, J. Chromosome-wide linkage disequilibrium as a consequence of meiotic drive Proc. Natl Acad. Sci. USA 104, 1587–1592 (2007).
Glemin, S., Bataillon, T., Ronfort, J., Mignot, A. & Olivieri, I. Inbreeding depression in small populations of self-incompatible plants. Genetics 159, 1217–1229 (2001).
Pankey, M. & Wares, J. Overdominant maintenance of diversity in the sea star Pisaster ochraceus. J. Evol. Biol. 22, 80–87 (2009).
Scoville, A., Lee, Y. W., Willis, J. H. & Kelly, J. K. The contribution of chromosomal polymorphisms to the G-matrix of Mimulus guttatus. New Phytol. 183, 803–815 (2009).
Fishman, L. & Saunders, A. Centromere-associated female meiotic drive entails male fitness costs in monkeyflowers. Science 322, 1559–1562 (2008).
Williams, W. Heterosis and the genetics of complex characters. Nature 184, 527–530 (1959).
Schnell, F. & Cockerham, C. Multiplicative vs. arbitrary gene action in heterosis. Genetics 131, 461–469 (1992).
Bataillon, T. & Kirkpatrick, M. Inbreeding depression due to mildly deleterious mutations in finite populations: size does matter. Genet. Res. 75, 75–81 (2000).
Glémin, S., Ronfort, J. & Bataillon, T. Patterns of inbreeding depression and architecture of the load in subdivided populations. Genetics 165, 2193–2212 (2003). By analysing a model of deleterious mutations in a biologically realistic model of population structure, the authors reveal heterosis in inter-population crosses and within-population inbreeding depression.
Schierup, M. H., Vekemans, X. & Charlesworth, D. The effect of subdivision on variation at multi-allelic loci under balancing selection. Genet. Res. 76, 51–62 (2000).
Coyne, J. A. & Orr, H. A. Speciation (Sinauer, Sunderland, 2004).
Song, L., Guo, W. & Zhang, T. Interaction of novel Dobzhansky–Muller type genes for the induction of hybrid lethality between Gossypium hirsutum and G. barbadense cv. Coastland R4-4. Theor. Appl. Genet. 119, 33–41 (2009).
Bomblies, K., Lempe, J., Dangl, J. & Weigel, D. Autoimmune response as a mechanism for a Dobzhansky–Muller-type incompatibility syndrome in plants. PLoS Biol. 5, 1962–1972 (2007).
Seidel, H. S., Rockman, M. V. & Kruglyak, L. Widespread genetic incompatibility in C. elegans maintained by balancing selection. Science 319, 589–594 (2008).
Hurst, L. D. Genetics and the understanding of selection. Nature Rev. Genet. 10, 83–93 (2009).
Yang, J., Gu, Z. & Li, W. Rate of protein evolution versus fitness effect of gene deletion. Mol. Biol. Evol. 20, 772–774 (2003).
Kondrashov, A. S. & Crow, J. F. A molecular approach to estimating the human deleterious mutation-rate. Hum. Mutat. 2, 229–234 (1993).
Keightley, P. D. & Eyre-Walker, A. Deleterious mutations and the evolution of sex. Science 290, 331–333 (2000).
Haag-Liautard, C. et al. Direct estimation of per nucleotide and genomic deleterious mutation rates in Drosophila. Nature 445, 82–85 (2007). This paper provides direct evidence that the deleterious mutation rate is high in D. melanogaster.
Haddrill, P. R., Charlesworth, B., Halligan, D. L. & Andolfatto, P. Patterns of intron sequence evolution in Drosophila are dependent upon length and GC content. Genome Biol. 6, R67 (2005).
Katzman, S. et al. Human genome ultraconserved elements are ultraselected. Science 317, 915 (2007).
Parmley, J. L., Chamary, J. V. & Hurst, L. D. Evidence for purifying selection against synonymous mutations in mammalian exonic splicing enhancers. Mol. Biol. Evol. 23, 301–309 (2006).
Keightley, P. D., Kryukov, G. V., Sunyaev, S., Halligan, D. L. & Gaffney, D. J. Evolutionary constraints in conserved nongenic sequences of mammals. Genome Res. 15, 1373–1378 (2006).
Asthana, S. et al. Widely distributed noncoding purifying selection in the human genome. Proc. Natl Acad. Sci. USA 104, 12410–12415 (2007).
Wright, S. & Andolfatto, P. The impact of natural selection on the genome: emerging patterns in Drosophila and Arabidopsis. Annu. Rev. Ecol. Evol. Syst. 39, 193–213 (2008).
Eyre-Walker, A., Woolfit, M. & Phelps, T. The distribution of fitness effects of new deleterious amino acid mutations in humans. Genetics 173, 891–900 (2006). The authors make sophisticated use of population genetics theory to estimate the distribution (rather than the average value) of selection coefficients of deleterious mutations.
Boyko, A. R. et al. Assessing the evolutionary impact of amino acid mutations in the human genome. PLoS Genet. 4, e1000083 (2008).
Keightley, P. & Halligan, D. Analysis and implications of mutational variation. Genetica 136, 359–369 (2009).
Loewe, L., Charlesworth, B., Bartolomé, C. & Nöel, V. Estimating selection on nonsynonymous mutations. Genetics 172, 1079–1092 (2006).
Loewe, L. & Charlesworth, B. Inferring the distribution of mutational effects on fitness in Drosophila. Biol. Lett. 2, 426–430 (2006).
Keightley, P. & Eyre-Walker, A. Joint inference of the distribution of fitness effects of deleterious mutations and population demography based on nucleotide polymorphism frequencies. Genetics 177, 2251–2261 (2007).
Bubb, K. L. et al. Scan of human genome reveals no new loci under ancient balancing selection. Genetics 173, 2165–2177 (2006).
Asthana, S., Schmidt, S. & Sunyaev, S. A limited role for balancing selection. Trends Genet. 21, 30–32 (2005). References 136 and 137 give evidence that overdominance is not common.
Fumagalli, M. et al. Widespread balancing selection and pathogen-driven selection at blood group antigen genes. Genome Res. 19, 199–212 (2009).
Calafell, F. et al. Evolutionary dynamics of the human ABO gene. Hum. Genet. 124, 123–135 (2008).
Moss, D., Arce, S., Otoshi, C. & Moss, S. Inbreeding effects on hatchery and growout performance of Pacific white shrimp, Penaeus (Litopenaeus) vannamei. J. World Aquacult. Soc. 39, 467–476 (2008).
Richards, C. M., Church, S. & McCauley, D. E. The influence of population size and isolation on gene flow by pollen in Silene alba. Evolution 53, 63–73 (1999).
Mori, K., Saito, Y., Sakagami, T. & Sahara, K. Inbreeding depression of female fecundity by genetic factors retained in natural populations of a male-haploid social mite (Acari: Tetranychidae). Exp. Appl. Acarol. 39, 15–23 (2005).
Schneller, J. J. & Holderegger, R. Vigor and survival of inbred and outbred progeny of Athyrium filix-femina. Int. J. Plant Sci. 158, 79–82 (1997).
Klekowski, E. J. Genetic load in Osmunda regalis populations. Am. J. Bot. 60, 146–154 (1973). The studies reported in references 143 and 144 show evidence for recessive large-effect deleterious mutations in natural populations of ferns, a type of organism that should be more widely used in such studies.
Keller, L. F. Inbreeding and its fitness effects in an insular population of song sparrows (Melospiza melodia). Evolution 52, 240–250 (1998).
Ritland, K. Inferences about inbreeding depression based upon changes of the inbreeding coefficient. Evolution 44, 1230–1241 (1990).
Liautard, C. & Sundstrom, L. Estimation of individual level of inbreeding using relatedness measures in haplodiploids. Insectes Soc. 52, 323–326 (2005).
Camara, M., Evans, S. & Langdon, C. Parental relatedness and survival of Pacific oysters from a naturalized population. J. Shellfish Res. 27, 323–336 (2008).
Herlihy, C. R. & Eckert, C. G. Genetic cost of reproductive assurance in a self-fertilizing plant. Nature 416, 320–323 (2002).
Bierne, N., S. Launey, Y. Naciri-Graven & Bonhomme, F. Early effect of inbreeding as revealed by microsatellite analyses on Ostrea edulis larvae. Genetics 148, 1893–1906 (2000).
Launey, S. & Hedgecock, D. High genetic load in the pacific oyster Crassostrea gigas. Genetics 159, 255–265 (2001).
Fu, Y.-B. & Ritland, K. Evidence for the partial dominance of viability genes in Mimulus guttatus. Genetics 136, 323–331 (1993).
Fu, Y.-B. & Ritland, K. On estimating the linkage of marker genes to viability genes controlling inbreeding depression. Theor. Appl. Genet. 88, 925–932 (1994).
Haag, C. & Ebert, D. D. Genotypic selection in Daphnia populations consisting of inbred sibships. J. Evol. Biol. 20, 881–891 (2007).
This research was supported by US National Institutes of Health grant GM073990 to J.H.W. We thank B. Charlesworth for discussions.
- 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).
About this article
Cite this article
Charlesworth, D., Willis, J. The genetics of inbreeding depression. Nat Rev Genet 10, 783–796 (2009). https://doi.org/10.1038/nrg2664
Journal of Animal Science and Biotechnology (2022)
Mechanisms of dispersal and colonisation in a wind-borne cereal pest, the haplodiploid wheat curl mite
Scientific Reports (2022)
Conservation Genetics (2022)
Fluctuating asymmetry in the insular population of ayu, Plecoglossus altivelis ryukyuensis, estimating its genetic diversity at extinction
Ichthyological Research (2022)
Evolutionary Ecology (2022)