Within-Generation Mutation Variance for Litter Size in Inbred Mice

Casellas, J.; Medrano, Juan F.

doi:10.1534/genetics.108.088070

Cited by 22 publications

(46 citation statements)

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“…Despite its promising features, the animal model approach to estimating mutational variance has been applied on few occasions and only in highly manipulated populations (Keightley and Hill 1992;Casellas and Medrano 2008;Casellas et al 2010). Casellas and colleagues adapted the approach of Wray (1990) to estimate the mutational variance in reproductive traits in a pedigreed inbred laboratory population of mice (Casellas and Medrano 2008) and an experimental flock of sheep (Casellas et al 2010) within a Bayesian framework.…”

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confidence: 99%

Simultaneous Estimation of Additive and Mutational Genetic Variance in an Outbred Population of Drosophila serrata

2015

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How new mutations contribute to genetic variation is a key question in biology. Although the evolutionary fate of an allele is largely determined by its heterozygous effect, most estimates of mutational variance and mutational effects derive from highly inbred lines, where new mutations are present in homozygous form. In an attempt to overcome this limitation, middle-class neighborhood (MCN) experiments have been used to assess the fitness effect of new mutations in heterozygous form. However, because MCN populations harbor substantial standing genetic variance, estimates of mutational variance have not typically been available from such experiments. Here we employ a modification of the animal model to analyze data from 22 generations of Drosophila serrata bred in an MCN design. Mutational heritability, measured for eight cuticular hydrocarbons, 10 wing-shape traits, and wing size in this outbred genetic background, ranged from 0.0006 to 0.006 (with one exception), a similar range to that reported from studies employing inbred lines. Simultaneously partitioning the additive and mutational variance in the same outbred population allowed us to quantitatively test the ability of mutation-selection balance models to explain the observed levels of additive and mutational genetic variance. The Gaussian allelic approximation and house-of-cards models, which assume real stabilizing selection on single traits, both overestimated the genetic variance maintained at equilibrium, but the house-of-cards model was a closer fit to the data. This analytical approach has the potential to be broadly applied, expanding our understanding of the dynamics of genetic variance in natural populations.

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Simultaneous Estimation of Additive and Mutational Genetic Variance in an Outbred Population of Drosophila serrata

2015

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“…generation of reliable data) and statistical (i.e. appropriate analytical models and computational requirements) limitations have led to the small number of estimates of additive mutational variance (s m 2 ) in experimental species during recent decades, a few of them obtained from populations of inbred mice (Keightley and Hill, 1992;Caballero et al, 1995;Casellas and Medrano, 2008). The magnitude of this new source of additive genetic variability was reviewed by Lynch (1988) and Houle et al (1994), and they have reported a narrow range of values accounting for between 0.05% and 1% of the phenotypic variability.…”

Section: Polygenic Mutational Variancementioning

confidence: 99%

“…Of course, the contribution of one or a few new mutations in a single individual would be small or even null, but these new polymorphisms can accumulate generation by generation, maintaining a certain degree of genetic variability in our inbred strains until they are fixed or dropped off due to mating between relatives. This mainframe idea was not investigated until a recent study was carried out by Casellas and Medrano (2008) in C57BL/6J mice, which showed that , 4.5% of the total phenotypic variability for litter size was accounted for by new mutations that had accumulated during the last few generations. This result showed an astonishing amount of genetic variability, clearly impairing the genetic stability of our inbred strains.…”

Section: Polygenic Mutational Variancementioning

confidence: 99%

“…Following Festing (1981), members of an inbred strain should be isogenic at .98% of the chromosomal loci that originally segregated from the founder population. Nevertheless, this assumption has been weakened by recent research in which the genetic homogeneity and stability of inbred strains were partially refuted (Keightley, 1998;Hill, 2000;Casellas and Medrano, 2008). These results do not invalidate the usefulness of inbred strains in biomedical and behavioral frameworks, although they revealed an unexpected degree of genetic variability with potential consequences for the analysis of experimental data.…”

Section: Introductionmentioning

confidence: 99%

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Inbred mouse strains and genetic stability: a review

Casellas

2011

Animal

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Inbred mice were essential animal models for scientific research during the 20th century and will contribute decisive results in the current and next centuries. Far from becoming an obsolete research tool, the generation of new inbred strains is continuing and such strains are being used in many research fields. However, their genetic properties have been overlooked for decades, although recent research has revealed new insights into their genetic fragility and relative instability. Contrary to what we usually assume, inbred mice are far from being completely isogenic and both single-gene major mutations and polygenic mutational variability are continuously uploading into inbred populations as new sources of genetic polymorphisms. Note that several inbred strains from new major mutations are released every year, whereas small mutations can accumulate up to accounting for a significant percentage of the phenotypic variance (e.g. 4.5% in a recent study on C57BL/6J mice). Moreover, this genetic heterogeneity can be maintained for several generations by heterozygote selection and, if fixed instead of dropping off, genetic drift must be anticipated. The contribution of accidental genetic contamination in inbred strains must also be considered, although its incidence in current breeding stocks should be minimal, or even negligible. This review revisits several relevant topics for current inbred strains, discussing the latest cutting-edge results within the context of the genetic homogeneity and stability of laboratory mice. Inbred mice can no longer be considered as completely isogenic, but provide a remarkably homogeneous animal model with an inevitable moderate-to-low degree of genetic variability. Despite a certain degree of genetic heterogeneity becoming inescapable, inbred mice still provide very useful animal models with evident advantages when compared with outbred, that is, highly variable, populations.Keywords: heterozygote selection, inbred strain, isogenicity, mouse, mutation Implications Inbred mice are basic tools for multiple research fields. Despite their relevance, their genetic architecture was overlooked for decades and recent research evidenced their genetic fragility, and even instability. Within this context, this review revisits several hot topics for current inbred strains, discussing the latest cutting-edge results on mutation and genetic drift, and characterizing other sources of genetic heterogeneity such as heterozygote selection or contamination. Far from invalidating the usefulness of inbred mice in research, this review was an attempt to describe the different sources of allogenicity and warns about potential consequences on the genetic stability of mice.

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“…The high deviation between the two Beijing populations (Pop1 and Pop2) may result from this operation or hybridization between different populations. Recent study indicates that a continuous and unavoidable flow of genetic variability does exist in the B6 strain (Casellas & Medrano, 2008). Watkins-Chow & Pavan (2008) also predicts that genetic variations could exist within the individual frozen embryo stock which was used to replace the foundation stock every five generations to limit the genetic drift in the Jackson Laboratory (Taft et al, 2006), and persist in the population independent of any possible selection.…”

Section: Disscussionmentioning

confidence: 99%

Microsatellite Variation Within Three Populations of Inbred C57BL/6J Strain

Niu¹,

Liang²

2009

Zoological Research

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Abstract:The goal of this study was to investigate the genetic stability of the C57BL/6J (B6) inbred mouse strain maintained in different breeders. Three populations of B6, Pop1 and Pop2 purchased from Beijing and Pop3 purchased from Shanghai, were examined. Fifteen microsatellite loci reported to be polymorphic among inbred strains were amplified using FAM labeled primers and genotyped with ABI Prism 377 automated sequencer. Seven loci were found polymorphic, and all the loci were homozygous in all the three populations. The present study indicates that genetic variation occurs in different B6 populations although they are still inbred in each breeder. The mechanism of genetic variation is not well understood now, but it is very important to know the precise content of the B6 genome before use of this strain in research.

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Within-Generation Mutation Variance for Litter Size in Inbred Mice

Cited by 22 publications

References 46 publications

Simultaneous Estimation of Additive and Mutational Genetic Variance in an Outbred Population of Drosophila serrata

Simultaneous Estimation of Additive and Mutational Genetic Variance in an Outbred Population of Drosophila serrata

Inbred mouse strains and genetic stability: a review

Microsatellite Variation Within Three Populations of Inbred C57BL/6J Strain

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