Mutation Load: The Fitness of Individuals in Populations Where Deleterious Alleles Are Abundant

Agrawal, Aneil F.; Whitlock, Michael C.

doi:10.1146/annurev-ecolsys-110411-160257

Cited by 179 publications

(205 citation statements)

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“…We identify an active process of maintenance of variation at crucial genes for pathogen defense and chemical perception. We hypothesize that the lack of competitors reduced the impact of many deleterious mutations (67), and that the highly diversified diet of the brown bear may have compensated for the energy production problems in the Apennine population by facilitating a switch from omnivory to an almost completely vegetarian diet (68,69). In addition, we inferred a genetic component related to a behavioral change towards a less aggressive temperament, which potentially reduced the risk perceived by local human communities and thus limited persecution and attempts to eradicate the Apennine bear.…”

Section: Conclusion and Conservation Perspectivesmentioning

confidence: 99%

Survival and divergence in a small group: The extraordinary genomic history of the endangered Apennine brown bear stragglers

Benazzo

Trucchi

Cahill

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

147

125

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Survival and divergence in a small group: the extraordinary genomic history of the endangered Apennine brown bear stragglers 2 AbstractAbout 100 km east of Rome, in the Central Apennine mountains, a critically endangered population of approximately fifty brown bears live in complete isolation. Mating outside this population is prevented by several hundred kilometers of bear-free territories. We exploited this natural experiment to better understand the gene and genomic consequences of surviving at extremely small population size. First, we found that brown bear populations in Europe lost connectivity since Neolithic times, when farming communities expanded and forest burning was used for land clearance. In Central Italy, this resulted in a 40-fold population decline. The overall genomic impact of this decline included the complete loss of variation in the mitochondrial genome and along long stretches of the nuclear genome. Several private and deleterious amino acid changes were fixed by random drift; predicted effects include energy deficit, muscle weakness, anomalies in cranial and skeletal development, and reduced aggressiveness. Despite this extreme loss of diversity, Apennine bear genomes show non-random peaks of high variation, possibly maintained by balancing selection, at genomic regions significantly enriched for genes associated with immune and olfactory systems. Challenging the paradigm of increased extinction risk in small populations, we suggest that random fixation of deleterious alleles a) can be an important driver of divergence in isolation, b) can be tolerated when balancing selection prevents random loss of variation at important genes and c) is followed by or results directly in favorable behavioral changes. SignificanceA small and relict population of brown bears lives in complete isolation in the Italian Apennine mountains, providing a unique opportunity to study the impact of drift and selection on the genomes of a large endangered mammal and to reconstruct the phenotypic consequences and the conservation implications of such evolutionary processes. The Apennine bear is highly inbred and harbors very low genomic variation. Several deleterious mutations have been accumulated by drift. We found evidence that this is a consequence of habitat fragmentation in the Neolithic, when human expansion and land clearance shrank its habitat, and that retention of variation at immune system and olfactory receptor genes, as well as changes in diet and behavior, prevented the extinction of the Apennine bear.

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Section: Conclusion and Conservation Perspectivesmentioning

confidence: 99%

Survival and divergence in a small group: The extraordinary genomic history of the endangered Apennine brown bear stragglers

Benazzo

Trucchi

Cahill

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

147

125

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“…UTATIONS that sicken and kill segregate in populations and are created anew each generation (Agrawal and Whitlock 2012). The rate at which mutations appear and how these mutations interact to determine fitness tell us how maladapted populations are expected to be in comparison to some optimum (Poon and Otto 2000;Silander et al 2007).…”

mentioning

confidence: 99%

Accelerating Mutational Load Is Not Due to Synergistic Epistasis or Mutator Alleles in Mutation Accumulation Lines of Yeast

Jasmin

Lenormand

2015

Genetics

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Much of our knowledge about the fitness effects of new mutations has been gained from mutation accumulation (MA) experiments. Yet the fitness effect of single mutations is rarely measured in MA experiments. This raises several issues, notably for inferring epistasis for fitness. The acceleration of fitness decline in MA lines has been taken as evidence for synergistic epistasis, but establishing the role of epistasis requires measuring the fitness of genotypes carrying known numbers of mutations. Otherwise, accelerating fitness loss could be explained by increased genetic mutation rates. Here we segregated mutations accumulated over 4800 generations in haploid and diploid MA lines of the yeast Saccharomyces cerevisiae. We found no correspondence between an accelerated fitness decline and synergistic epistasis among deleterious mutations in haploid lines. Pairs of mutations showed no overall epistasis. Furthermore, several lines of evidence indicate that genetic mutation rates did not increase in the MA lines. Crucially, segregant fitness analyses revealed that MA accelerated in both haploid and diploid lines, even though the fitness of diploid lines was nearly constant during the MA experiment. This suggests that the accelerated fitness decline in haploids was caused by cryptic environmental factors that increased mutation rates in all lines during the last third of the lines' transfers. In addition, we provide new estimates of deleterious mutation rates, including lethal mutations, and highlight that nearly all the mutational load we observed was due to one or two mutations having a large effect on fitness.

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“…A number of factors can lead to a reduction in the mutation load (Agrawal and Whitlock 2012), two of which have been discussed in relation to the problem in humans. First, it has been suggested that many genetic deaths occur in the cell lineages leading to the gametes (Reed and Aquadro 2006) and prior to birth, since many pregnancies spontaneously abort at an early stage (Wang et al 2004).…”

mentioning

confidence: 99%

“…To prevent population decline x must be greater than 16 in humans if selection acts solely on absolute fertility differences. Agrawal and Whitlock (2012) have argued that x may substantially exceed 16, since human family sizes can be large in modern societies and males can potentially have many offspring by mating with multiple females. However, reproductive potential may have been much more limited in ancestral human populations.…”

mentioning

confidence: 99%

A Resolution of the Mutation Load Paradox in Humans

2012

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Current information on the rate of mutation and the fraction of sites in the genome that are subject to selection suggests that each human has received, on average, at least two new harmful mutations from its parents. These mutations were subsequently removed by natural selection through reduced survival or fertility. It has been argued that the mutation load, the proportional reduction in population mean fitness relative to the fitness of an idealized mutation-free individual, allows a theoretical prediction of the proportion of individuals in the population that fail to reproduce as a consequence of these harmful mutations. Application of this theory to humans implies that at least 88% of individuals should fail to reproduce and that each female would need to have more than 16 offspring to maintain population size. This prediction is clearly at odds with the low reproductive excess of human populations. Here, we derive expressions for the fraction of individuals that fail to reproduce as a consequence of recurrent deleterious mutation (u) for a model in which selection occurs via differences in relative fitness, such as would occur through competition between individuals. We show that u is much smaller than the value predicted by comparing fitness to that of a mutation-free genotype. Under the relative fitness model, we show that u depends jointly on U and the selective effects of new deleterious mutations and that a species could tolerate 10's or even 100's of new deleterious mutations per genome each generation.A LL organisms are subject to recurrent deleterious mutation, which cause some individuals to die or fail to reproduce. Deleterious mutations therefore impose a cost or load on the population. The evolutionary consequences of deleterious mutations were first studied by J. B. S. Haldane, who showed that the reduction in mean fitness in a diploid organism caused by recurrent semidominant deleterious mutation at a single locus is equal to twice the mutation rate (Haldane 1937). This led H. J. Muller to suggest that each new deleterious mutation ultimately leads to one genetic death, irrespective of the mutation's fitness effect (Muller 1950). Subsequently, the mutation load was more formally defined as the proportional reduction in mean fitness of a population relative to that of a mutation-free genotype, brought about by deleterious mutations (Crow 1970):where w is the mean fitness of the population at equilibrium and w max is the mean fitness of a deleterious mutation-free individual.Under viability selection, the mutation load is equivalent to the proportion of individuals that fail to survive and hence leave no descendants in the next generation. For example, if an individual carries 10 mutations, each reducing the chance of surviving to reproductive age by 10%, then this individual is expected to survive with probability (1-0.1) 10 = 0.35. If all individuals in the population have this genotype, then 65% of them would fail to have any descendants in the next generation. The load does not ha...

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Mutation Load: The Fitness of Individuals in Populations Where Deleterious Alleles Are Abundant

Cited by 179 publications

References 134 publications

Survival and divergence in a small group: The extraordinary genomic history of the endangered Apennine brown bear stragglers

Survival and divergence in a small group: The extraordinary genomic history of the endangered Apennine brown bear stragglers

Accelerating Mutational Load Is Not Due to Synergistic Epistasis or Mutator Alleles in Mutation Accumulation Lines of Yeast

A Resolution of the Mutation Load Paradox in Humans

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