Interference Effects of Deleterious and Beneficial Mutations in Large Asexual Populations

Jain, Kavita

doi:10.1534/genetics.119.301960

Cited by 7 publications

(6 citation statements)

References 49 publications

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“…Our particular focus is on how long-term average frequencies of beneficial alleles at various site types depend on the number and distribution of site types within linkage groups, on the joint forces of selection and mutation bias, and in particular on the population size. Related analyses have been performed by John and Jain (2015), Jain and John (2016), and Jain (2019), but mostly under the assumptions of either an effectively infinite population and/or an infinite-sites framework, and even in these cases, achieving reasonably simple expressions has been difficult.…”

Section: The Modelmentioning

confidence: 99%

“…The overall process is further complicated by the fact that recurrent purging of deleterious mutations has general effects on effective population sizes, thereby influencing all other aspects of the efficiency of selection. There has been much research on these matters as well (Gerrish and Lenski 1998; Johnson and Barton 2002; Campos and Wahl 2010; Desai and Fisher 2007; Charlesworth 2013a; Good et al 2014; Pénisson et al 2017; Jain 2019), but almost all analyses have been restricted to the infinite-sites model, and often to populations that are effectively infinite in size with all mutations having equal effects.…”

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confidence: 99%

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The Divergence of Mean Phenotypes Under Persistent Directional Selection

Devi

Speyer

Lynch

2022

Preprint

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Numerous organismal traits, particularly at the cellular level, are likely to be under persistent directional selection across phylogenetic lineages. For such traits, unless all mutations affecting such traits have large enough effects to be efficiently selected in all species, gradients in mean phenotypes are expected to arise as a consequence of differences in the power of random genetic drift, which varies by approximately five orders of magnitude across the Tree of Life. Prior theoretical work examining the conditions under which such gradients can arise focused on the simple situation in which all genomic sites affecting the trait have identical and constant mutational effects. Here, we extend this theory to incorporate the more biologically realistic situation in which mutational effects on a trait differ among nucleotide sites. Pursuit of such modifications lead to the development of semi-analytic expressions for the ways in which selective interference arises via linkage effects in single-effect models, which then extend to more complex scenarios. The theory developed clarifies the conditions under which mutations of different selective effects mutually interfere with each others fixation, and shows how variance in effects among sites can substantially modify and extend the expected scaling relationships between mean phenotypes and effective population sizes.

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Section: The Modelmentioning

confidence: 99%

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confidence: 99%

The Divergence of Mean Phenotypes Under Persistent Directional Selection

Devi

Speyer

Lynch

2022

Preprint

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“…The process of interference between deleterious and advantageous variants has been mostly studied in haploid species (Jain, 2019;Johnson and Barton, 2002;Peck, 1994). In diploid species including humans, recessive deleterious mutations specifically have been shown to have the ability to slow down, or even stop the frequency increase of advantageous mutations that they are linked with (Assaf et al, 2015).…”

Section: A Possible Role Of Interference Of Deleterious Mutationsmentioning

confidence: 99%

Decreased recent adaptation at human mendelian disease genes as a possible consequence of interference between advantageous and deleterious variants

Moreno

Salazar‐Tortosa

et al. 2021

eLife

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Advances in genome sequencing have dramatically improved our understanding of the genetic basis of human diseases, and thousands of human genes have been associated with different diseases. Despite our expanding knowledge of gene-disease associations, and despite the medical importance of disease genes, their recent evolution has not been thoroughly studied across diverse human populations. In particular, recent genomic adaptation at disease genes has not been characterized as well as purifying selection and long-term adaptation. Understanding the relationship between disease and adaptation at the gene level in the human genome is hampered by the fact that we don’t know whether disease genes have experienced more, less, or as much adaptation as non-disease genes during the last ~50,000 years of recent human evolution. Here, we compare the rate of strong recent adaptation in the form of selective sweeps between mendelian, non-infectious disease genes and non-disease genes across 26 distinct human populations from the 1,000 Genomes Project. We find that mendelian disease genes have experienced far less selective sweeps compared to non-disease genes especially in Africa. This sweep deficit at mendelian disease genes is less visible in East Asia or Europe. Investigating further the possible causes of the sweep deficit at disease genes, we find that this deficit is very strong at disease genes with both low recombination rates and with high numbers of associated disease variants, but is almost non-existent at disease genes with higher recombination rates or lower numbers of associated disease variants. Because segregating recessive deleterious variants have the ability to interfere with adaptive ones, these observations strongly suggest that adaptation has been slowed down by the presence of interfering recessive deleterious variants at disease genes. This is further supported by population simulations that show that interference at disease genes is expected to be lower in East Asia and Europe. These results clarify the evolutionary relationship between disease genes and recent genomic adaptation, and suggest that disease genes suffer not only from a higher load of segregating deleterious mutations, but also from a transient inability to adapt as much, and/or as fast as the rest of the genome.

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“…Another possibility is that adaptation may be limited at disease genes due to deleterious mutations interfering with and slowing down advantageous variants. This process has been mostly studied in haploid species (Peck, 1994;Johnson and Barton, 2002;Jain, 2019). In diploid species including humans, recessive deleterious mutations specifically have been shown to have the ability to slow down, or even stop the frequency increase of advantageous mutations that they are linked with (Assaf et al, 2015;Uricchio et al, 2019).…”

Section: A Possible Role Of Interference Of Deleterious Mutationsmentioning

confidence: 99%

Decreased adaptation at human disease genes as a possible consequence of interference between advantageous and deleterious variants

et al. 2021

Preprint

View full text Add to dashboard Cite

Advances in genome sequencing have dramatically improved our understanding of the genetic basis of human diseases, and thousands of human genes have been associated with different diseases. Despite our expanding knowledge of gene-disease associations, and despite the medical importance of disease genes, their evolution has not been thoroughly studied across diverse human populations. In particular, recent genomic adaptation at disease genes has not been well characterized, even though multiple evolutionary processes are expected to connect disease and adaptation at the gene level. Understanding the relationship between disease and adaptation at the gene level in the human genome is severely hampered by the fact that we do not even know whether disease genes have experienced more, less, or as much adaptation as non-disease genes during recent human evolution. Here, we compare the rate of strong recent adaptation in the form of selective sweeps between disease genes and non-disease genes across 26 distinct human populations from the 1,000 Genomes Project. We find that disease genes have experienced far less selective sweeps compared to non-disease genes during recent human evolution. This sweep deficit at disease genes is particularly visible in Africa, and less visible in East Asia or Europe, likely due to more intense genetic drift in the latter populations creating more spurious selective sweeps signals. Investigating further the possible causes of the sweep deficit at disease genes, we find that this deficit is very strong at disease genes with both low recombination rates and with high numbers of associated disease variants, but is inexistent at disease genes with higher recombination rates or lower numbers of associated disease variants. Because recessive deleterious variants have the ability to interfere with adaptive ones, these observations strongly suggest that adaptation has been slowed down by the presence of interfering recessive deleterious variants at disease genes. These results clarify the evolutionary relationship between disease genes and recent genomic adaptation, and suggest that disease genes suffer not only from a higher load of segregating deleterious mutations, but also from an inability to adapt as much, and/or as fast as the rest of the genome.

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Interference Effects of Deleterious and Beneficial Mutations in Large Asexual Populations

Abstract: Linked beneficial and deleterious mutations are known to decrease the fixation probability of a favorable mutation in large asexual populations. While the hindering effect of strongly deleterious mutations on

Cited by 7 publications

References 49 publications

The Divergence of Mean Phenotypes Under Persistent Directional Selection

The Divergence of Mean Phenotypes Under Persistent Directional Selection

Decreased recent adaptation at human mendelian disease genes as a possible consequence of interference between advantageous and deleterious variants

Decreased adaptation at human disease genes as a possible consequence of interference between advantageous and deleterious variants

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