Impact of mutation rate and selection at linked sites on fine-scale DNA variation across the homininae genome

Castellano, David; Eyre‐Walker, Adam; Munch, Kasper

doi:10.1101/452201

Cited by 5 publications

(9 citation statements)

References 87 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Interestingly, there is a negative, but very shallow, correlation between the fraction of weakly deleterious mutations (210 , S d # 21) and N e ( Figure 3D and Table 3). This is consistent with a recent work that found that the effect of linked selection (mainly background selection) on genetic diversity is very similar along the genomes of great apes (Castellano et al 2018b).…”

Section: Model Choicesupporting

confidence: 93%

Comparison of the Full Distribution of Fitness Effects of New Amino Acid Mutations Across Great Apes

Castellano

Macià²,

Tataru³

et al. 2019

Genetics

Self Cite

View full text Add to dashboard Cite

The distribution of fitness effects (DFE) is central to many questions in evolutionary biology. However, little is known about the differences in DFE between closely related species. We use .9000 coding genes orthologous one-to-one across great apes, gibbons, and macaques to assess the stability of the DFE across great apes. We use the unfolded site frequency spectrum of polymorphic mutations (n = 8 haploid chromosomes per population) to estimate the DFE. We find that the shape of the deleterious DFE is strikingly similar across great apes. We confirm that effective population size (N e) is a strong predictor of the strength of negative selection, consistent with the nearly neutral theory. However, we also find that the strength of negative selection varies more than expected given the differences in N e between species. Across species, mean fitness effects of new deleterious mutations covaries with N e , consistent with positive epistasis among deleterious mutations. We find that the strength of negative selection for the smallest populations, bonobos and western chimpanzees, is higher than expected given their N e. This may result from a more efficient purging of strongly deleterious recessive variants in these populations. Forward simulations confirm that these findings are not artifacts of the way we are inferring N e and DFE parameters. All findings are replicated using only GC-conservative mutations, thereby confirming that GC-biased gene conversion is not affecting our conclusions.

show abstract

Section: Model Choicesupporting

confidence: 93%

Comparison of the Full Distribution of Fitness Effects of New Amino Acid Mutations Across Great Apes

Castellano

Macià²,

Tataru³

et al. 2019

Genetics

Self Cite

View full text Add to dashboard Cite

show abstract

“…Interestingly, there is a negative, but very shallow, correlation between the fraction of weakly deleterious mutations (10 < S d ≤ 1) and N e (Figure 3 D, Table 4). This is consistent with a recent work that found that the impact of linked selection (mainly background selection) on genetic diversity is very similar along the genomes of great apes (Castellano et al 2018b). Table 5 E).…”

supporting

confidence: 93%

Comparison of the full distribution of fitness effects of new amino acid mutations across great apes

Castellano

Macià

Tataru

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

The distribution of fitness effects (DFE) is central to many questions in evolutionary biology.However, little is known about the differences in DFEs between closely related species. We use more than 9,000 coding genes orthologous onetoone across great apes, gibbons, and macaques to assess the stability of the DFE across great apes. We use the unfolded site frequency spectrum of polymorphic mutations (n = 8 haploid chromosomes per population) to estimate the DFE. We find that the shape of the deleterious DFE is strikingly similar across great apes. We confirm that effective population size (N e ) is a strong predictor of the strength of negative selection, consistent with the Nearly Neutral Theory.However, we also find that the strength of negative selection varies more than expected given the differences in N e between species. Across species, mean fitness effects of new deleterious mutations co varies with N e , consistent with positive epistasis among deleterious mutations. We find that the strength of negative selection for the smallest populations: bonobos and western chimpanzees, is higher than expected given their N e . This may result from a more efficient purging of strongly deleterious recessive variants in these populations. Forward simulations confirm that these findings are not artifacts of the way we are inferring N e and DFE parameters. All findings are replicated using only GCconservative mutations, thereby confirming that GCbiased gene conversion is not affecting our conclusions. 2 4 6 8 10 12 14 16All organisms undergo mutation. Studying the effect of mutations on fitness is fundamental to explain the patterns of genetic diversity within and between species and to predict the impact of population size on the probability of survival, or extinction of a species . The fitness effects of all new mutations that can occur in a given genome are described by the distribution of fitness effects (DFE). The allele frequency distributions or the site frequency spectrum (SFS) contains information to infer the DFE of new mutations. Current statistical methods infer the DFE while accounting for demography and other sources of distortion in the SFS (EyreWalker et al. 2006;Keightley and EyreWalker 2007;Boyko et al. 2008;Schneider et al. 2011;Galtier 2016;Kim et al. 2017;Tataru et al. 2017;Barton and Zeng 2018).The DFE of new deleterious amino acid mutations is assumed to be similar in closely related species, while the mean effect of those deleterious mutations (S d = 2N e s d ) is expected to increase as a function of the effective population size (N e ) (Kimura 1983; Ohta 1992). Very little is known about the variability in the DFE of new beneficial mutations across species as well as how this variability affects the estimates of the deleterious DFE. Most studies have described the DFE of new deleterious mutations of individual populations, while the study of the differences in the DFE between populations or species has remained unexplored. To our knowledge, Huber et al. (2017) is the first work that tries to ...

show abstract

“…Locally elevated mutation rate is a potential confound [53], however. Some evidence suggests that mutation rate correlates with substitution rates between species within long segments of the genome (~50 kb) [54], perhaps due to mutation pressure. However, the situation remains unclear, as other studies found that mutation rate does not explain variation in divergence between species [55,56].…”

Section: Discussionmentioning

confidence: 99%

Identifying branch-specific positive selection throughout the regulatory genome using an appropriate proxy neutral

2020

View full text Add to dashboard Cite

Background: Adaptive changes in cis-regulatory elements are an essential component of evolution by natural selection. Identifying adaptive and functional noncoding DNA elements throughout the genome is therefore crucial for understanding the relationship between phenotype and genotype. Results: We used ENCODE annotations to identify appropriate proxy neutral sequences and demonstrate that the conservativeness of the test can be modulated during the filtration of reference alignments. We applied the method to noncoding Human Accelerated Elements as well as open chromatin elements previously identified in 125 human tissues and cell lines to demonstrate its utility. Then, we evaluated the impact of query region length, proxy neutral sequence length, and branch count on test sensitivity and specificity. We found that the length of the query alignment can vary between 150 bp and 1 kb without affecting the estimation of selection, while for the reference alignment, we found that a length of 3 kb is adequate for proper testing. We also simulated sequence alignments under different classes of evolution and validated our ability to distinguish positive selection from relaxation of constraint and neutral evolution. Finally, we reconfirmed that a quarter of all non-coding Human Accelerated Elements are evolving by positive selection. Conclusion: Here, we introduce a method we called adaptiPhy, which adds significant improvements to our earlier method that tests for branch-specific directional selection in noncoding sequences. The motivation for these improvements is to provide a more sensitive and better targeted characterization of directional selection and neutral evolution across the genome.

show abstract

Impact of mutation rate and selection at linked sites on fine-scale DNA variation across the homininae genome

Cited by 5 publications

References 87 publications

Comparison of the Full Distribution of Fitness Effects of New Amino Acid Mutations Across Great Apes

Comparison of the Full Distribution of Fitness Effects of New Amino Acid Mutations Across Great Apes

Comparison of the full distribution of fitness effects of new amino acid mutations across great apes

Identifying branch-specific positive selection throughout the regulatory genome using an appropriate proxy neutral

Contact Info

Product

Resources

About