- Background: Mutation load is expected to be reduced in hybrids via complementation of deleterious alleles. - While local adaptation of hybrids confounds phenotypic tests for reduced mutation load, it may be possible to assess variation in load by analyzing the distribution of putatively deleterious alleles. - engelmannii) hybrid complex, a group likely to suffer from high mutation load and in which hybrids exhibit local adaptation to intermediate conditions. - Results: As expected, we found that predicted deleterious alleles were at lower average allele frequencies than alleles not predicted to be deleterious. - Both the proportion of alleles predicted to be deleterious and the proportion of loci homozygous for predicted deleterious alleles were higher in P. - Relative to parental species, the proportion of alleles predicted to be deleterious was intermediate in hybrids, and the proportion of loci homozygous for predicted deleterious alleles was lowest.. - Conclusion: Given that most deleterious alleles are recessive, this suggests that mutation load is reduced in hybrids due to complementation of deleterious alleles. - Mutation load is the reduction in fitness caused by deleterious alleles segregating at mutation-selection balance in populations [1, 2]. - Decreased mutation load in hybrids may increase their fitness relative to parents [3–5]. - Because mutations are random and deleterious alleles may rise in frequency through genetic drift, mutation load in partially reproductively isolated groups is likely to result from largely distinct sets of alleles [6].. - Therefore, relative to parents, mutation load due to additive deleterious alleles should be intermediate in. - hybrids due to their intermediate number of deleterious alleles. - However, most deleterious alleles are thought to be at least partially recessive [2, 7–9], and mutation load due to recessive deleterious alleles should be lower in hybrids than in parental species due to their lower homozygosity of deleterious alleles. - Reduction of mutation load in hybrids may commonly contribute to hybrid zone dynamics. - However, the possi- bility that hybrids are also locally adapted to environ- mental conditions in contact zones confounds our ability to phenotypically detect reduced mutation load.. - However, since we have no theoretical expectation for the precise differ- ences in fitness between hybrids and parents in each environment that are caused by local adaptation, it is difficult to tell whether reduced mutation load has an additional effect on hybrid fitness, which should enhance their fitness across all environments.. - Here we introduce an alternative approach to assess whether mutation load is reduced in hybrid zones, which identifies bioinformatically predicted deleterious alleles that are segregating in populations and then compares properties of these alleles in hybrid and non-hybrid indi- viduals. - Traditionally, identifying the alleles underlying mutation load in natural populations has been very diffi- cult. - Most deleterious alleles contributing to mutation load tend to be of small effect and are kept at low frequency by purifying selection [2, 11], making their individual effects on fitness or phenotype too small to detect with reasonable sample sizes. - While not all alleles predicted to be deleterious by these methods will actually be so, and while some deleterious alleles may be missed, tests of functionally verified deleterious alleles have typically found both specificity and sensitivity to be between 70 and though specificity was lower in [18]) (see the Discussion regarding accuracy of specificity esti- mates). - The interior spruce hybrid complex is an ideal natural system to investigate the patterns of mutation load in hybridizing species. - We predict that these hybrids should also benefit from decreased mutation load. - Instead, we can test for a signature of reduced mutation load in hybrids at the genetic level.. - Conifers, in general, are known to suffer from high mutation load [32–34], and a reduction in load via hybridization may provide a substantial fitness benefit.. - Previous estimates of mutation load in conifers have been derived by comparing viable seed numbers per cone from self-pollination with those from unrelated crossings. - However, the deleterious alleles underlying their high mutation load have yet to be identified. - Furthermore, mutation load has not been estimated in Engelmann spruce or in white-Engelmann hybrids. - By identifying deleterious alleles in white spruce, Engelmann spruce and their hybrids, we are able to infer the relative severity of mutation load in the two species and their hybrids, and to better understand the effects of hybridization on load.. - We then determined the proportion of alleles that are putatively deleterious in individuals of each of the two spruce species and in hybrids, as well as the proportions of loci that are heterozygous or homozygous for putative deleterious alleles. - This information allowed us to test the following hypotheses: first, if putative deleterious alleles are actually deleterious, then we predict that they should. - occur at lower frequencies than non-deleterious alleles and be associated with a decrease in fitness (via a pheno- typic fitness proxy). - and second, we hypothesize that mutation load should be reduced in hybrids.. - While deleterious alleles may occasionally rise to high frequencies within populations at non-equilibrium condi- tions, it is very unlikely that the same allele would do so in each of two species. - This balanced accuracy has been shown to be very similar to that of other programs available for predicting deleterious alleles (tested using similar methods), including SIFT, PolyPhen2 and Mutation Assessor [16]. - Finally, here we compare the relative strength of mutation load across populations, rather than estimat- ing the absolute strength of mutation load. - Thus, while we recognize that some fraction of the predicted deleterious alleles are likely false positive, the specific rate. - Proportion of alleles predicted to be deleterious. - Effect of mutation load on a fitness proxy. - We found that the proportion of ancestry from Engelmann spruce, hereafter ‘ancestry proportion. - Below, to be concise, we refer to the ‘proportion of alleles at polymorphic loci. - positive linear relationship between the proportion of ancestry from Engelmann spruce and both the pro- portion of alleles that are non-deleterious minor al- leles (r 2 = 0.93, F p <. - 10 −15 ) and the proportion of alleles that are deleterious minor alleles (r 2 = 0.39, F p <. - proportion of ancestry from Engelmann spruce ≥90. - proportion of ancestry from Engelmann spruce ≤10. - proportion of ancestry from Engelmann spruce ≤60%) (Additional file 1: Figure S5). - Furthermore, we tested how the ratio of the proportion of alleles that are. - 3 Effect of deleterious alleles on a fitness proxy. - Quadratic regression of the proportion of ancestry from Engelmann spruce on total biomass (a) and linear regressions of those residuals on the proportion of alleles at polymorphic loci predicted to be deleterious (b) and the proportion of polymorphic loci predicted to be homozygous deleterious (c). - 4b) to the proportion of alleles that are minor and non- deleterious (response variable in Fig. - 4a) changed with the proportion of ancestry from Engelmann spruce.. - Both the proportion of loci that were homozygous for a non-deleterious minor allele and the proportion that were homozygous for a deleterious minor allele increased with. - The proportion of ancestry from Engelmann spruce is shown against the proportion of alleles at polymorphic loci that are non-deleterious minor alleles (a) the proportion of alleles at polymorphic loci that are deleterious minor alleles (b), the ratio of the proportion of alleles at polymorphic loci that are deleterious minor alleles to the proportion of alleles at polymorphic loci that are non-deleterious minor alleles (c), the proportion of polymorphic loci that are homozygous for a non-deleterious minor allele (d), the proportion of polymorphic loci that are homozygous for a deleterious minor allele (e) and the ratio of the proportion of polymorphic loci that are homozygous for a deleterious minor allele to the proportion of polymorphic loci that are homozygous for a non-deleterious minor allele (f). - Note difference in Y-axis scale among panels, especially for deleterious and non-deleterious alleles. - the proportion of ancestry from Engelmann spruce with positive quadratic curvature (r 2 = 0.77, F p <. - Intermediate hybrids had a 12% lower proportion of loci that were homozygous for a deleterious minor allele than white spruce individuals (Tukey HSD p = 0) and 21% lower proportion of these than Engelmann spruce individuals (Tukey HSD p = 0) (Fig. - The ratio of the proportion of loci that were homozygous for a deleterious minor allele (response variable in Fig. - We used the distribution of putatively deleterious alleles carried by individuals to infer the relative strength of mutation load across a natural hybrid complex. - This approach allowed us to test the prediction that mutation load is reduced in hybrids that are locally adapted to intermediate environments, a pattern that confounds our ability to test this prediction phenotypically.. - Here, we refrain from comparing num- bers or proportions of deleterious alleles per individual (reflecting the extent of mutation load) with those esti- mated for other taxa, due to differences in methods and cautions explained below. - However, inbreeding experi- ments have long suggested that conifers suffer from rela- tively high mutation load . - We recommend caution when interpreting absolute numbers and absolute proportions of deleterious alleles estimated bioinformatically in this and other studies.. - In support of the PROVEAN predictions, however, we find strong evidence that alleles predicted to be deleterious are at lower allele frequencies on average than those not predicted to be deleterious, suggesting that predicted deleterious alleles are enriched for truly deleterious al- leles. - Nonetheless, similar evidence that predicted deleterious alleles are enriched for truly deleterious alleles has recently been found in other systems as well, including Arabidopsis [17], maize [20], barley and soybean [22], sunflower [23] and humans suggesting that that these approaches are useful for identifying deleteri- ous alleles underlying mutation load.. - Genotyping error presents an underappreciated complication to studies identifying deleterious alleles bioinformatically. - Because we expect deleterious alleles to be at low frequencies, we cannot use a minor allele frequency cutoff when filtering SNPs to help eliminate rare genotyping errors, as is typically done in studies of the genetics of adaptation. - This represents an alternative explanation for the commonly reported pattern that predicted deleterious alleles are at lower frequencies.. - only a single time (the frequency class most likely to contain genotyping errors), we still found strong evidence that predicted deleterious alleles are at lower allele frequencies. - This suggests that while rare genotyp- ing errors are almost certainly present in the dataset, they are not driving the pattern, and instead, many real deleterious alleles have been identified.. - Ideally, we would like to confirm that predicted deleterious alleles indeed have a negative effect on a phenotypic fitness proxy. - Because most deleterious alleles are of small effect and are at low allele frequen- cies, detecting their individual phenotypic effects re- quires prohibitively massive sample sizes. - Here, we tested for cumulative effects of deleterious alleles (i.e.. - Because deleterious alleles tend to be strongly differenti- ated among species, their patterns are tightly correlated with those of ancestry. - This has perhaps led to low power for detecting an additional effect of mutation load on our phenotypic fitness proxy. - Relative amount of mutation load in white spruce and Engelmann spruce. - Our results suggest that Engelmann spruce carries a greater mutation load than white spruce. - Engelmann spruce indi- viduals tend to be burdened by more deleterious alleles (in both heterozygous and homozygous state) due to both higher diversity and higher frequencies of all rare alleles, in- cluding deleterious ones. - It may seem counterintuitive that the species with greater genetic diversity has greater mutation load. - In particular, if local population sizes are low and there is low dispersal between local popula- tions, then drift is strong relative to selection within local populations, allowing neutral and deleterious alleles to drift locally to high frequencies, while low dispersal maintains a high level of genetic diversity at the species level [53].. - While with increasing ancestry from Engelmann spruce, individuals have more deleterious alleles on average, we also find that the same individuals have proportionately fewer deleterious alleles relative to non-deleterious alleles (both in total and in homozy- gous state). - In other words, patterns of deleterious al- leles vary with ancestry proportion when correcting for patterns in non-deleterious alleles. - First, this provides evidence that patterns in deleterious alleles are distin- guishable from those of demography (as represented by non-deleterious alleles). - Relative amount of mutation load in parental species and their hybrids. - Hybrids are intermediate relative to parental species for the proportion of alleles that are deleterious. - Thus, if most deleterious alleles have additive effects, then hybrids should have an intermediate mutation load rela- tive to parental species. - However, evidence suggests that deleterious alleles tend to be (at least partially) recessive [2, 7–9]. - Here, we find that hybrids have a lower propor- tion of loci that are homozygous for deleterious alleles than either parental species. - While this pattern is also expected (and was found) for non-deleterious alleles, showing a decrease in the homozygosity of deleterious alleles provides direct evidence for the possibility of complementation in hybrids. - Even if complementation of deleterious alleles does not have a large enough effect to result in heterosis (i.e., hybrid fitness >. - When hybrids also benefit from local adaptation to their own environment, decreased muta- tion load due to complementation of deleterious alleles may give them a fitness advantage as well, though its effects on phenotypic fitness proxies would be insepar- able from those of local adaptation. - Studying mutation load at the genetic level has allowed us to infer that in- terior spruce hybrids, which are locally adapted to envir- onmental conditions that are intermediate to the parental species (Engelmann and white spruce), also benefit from reduced mutation load due to complemen- tation of deleterious alleles, given that most deleterious alleles are recessive.. - Here we showed that PROVEAN is a useful tool for identifying the genetic basis of mutation load in the in- terior spruce hybrid complex. - The set of putatively dele- terious alleles we identified allowed us to compare the relative strength of mutation load across the hybrid complex. - We found that Engelmann spruce suffers from greater mutation load than white spruce due to higher frequencies of rare deleterious alleles. - Given that dele- terious alleles tend to be recessive, we also find that hy- brids have lower mutation load than either of the parental species, due to complementation of deleterious alleles introduced by each of the parental species. - Along with bounded hybrid superiority, this reduced mutation load likely contributes to the high hybrid fitness previ- ously reported in this complex [31].. - Because these trees suffer from high mutation load, understanding the genetic basis mutation load and factors that contribute to its strength will help us with management and breeding of this important genetic resource.. - The mutation load in small populations.. - Mutation load: the fitness of individuals in populations where deleterious alleles are abundant. - The deleterious mutation load is insensitive to recent population history. - Engelmann spruce
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