Background selection

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Background selection describes the loss of genetic diversity at a locus due to negative selection against deleterious alleles with which it is in linkage disequilibrium. [1] The name emphasizes the fact that the genetic background, or genomic environment, of a mutation has a significant impact on whether it will be preserved versus lost from a population. Background selection contradicts the assumption of the neutral theory of molecular evolution that the fixation or loss of a neutral allele can be described by one-locus models of genetic drift, independently from other loci. As well as reducing neutral nucleotide diversity, background selection reduces the fixation probability of beneficial mutations, and increases the fixation probability of deleterious mutations.

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Effect on neutral diversity

The degree to which neutral nucleotide diversity, which is quantified as the 'effective population size', is reduced due to background selection, depends on whether the neutral sites are linked to deleterious sites. [2] For unlinked sites, it is reduced by exp(-8Ush), where U is the genome-wide deleterious mutation rate, s is the selection coefficient of deleterious mutations, and h is the dominance coefficient. [1] [3] This corresponds to the probability that an individual cannot appreciably contribute to the next generation because its genetic load is too high. The reduction is smaller for large s because deleterious mutations are removed more quickly from the population. For linked sites, diversity is reduced by exp(-u/r), where u/r is the ratio of deleterious mutation to recombination within a genomic window surrounding the neutral allele of interest. [4] [5] This corresponds to the probability that a gene copy is able to escape via recombination from nearby deleterious alleles. Background selection at linked sites dominates when U<1, while background selection at unlinked sites dominates when U>1. [2]

Background selection contributes to a selective explanation of the positive correlation between local rates of recombination and polymorphism across the genome. In areas of high recombination, new mutations are more likely to ‘escape' the effects of nearby selection and be retained in the population. [6] . The same correlation is also produced by genetic hitchhiking. The two theories are easiest to distinguish in regions of low recombination. [7]

Failing to account for background selection can lead to errors in the inference of the demographic history of populations. [8] [9] [10]

Implications for asexual populations

Background selection in asexual populations produces Muller's ratchet, the accumulation of irreversible deleterious mutations. Background selection reduces the effective population size down to represent only those individuals with the fewest mutations, and sometimes this size stochastically falls to zero, producing one click of the ratchet. [4]

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Genetic drift, also known as random genetic drift, allelic drift or the Wright effect, is the change in the frequency of an existing gene variant (allele) in a population due to random chance.

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Molecular evolution is the process of change in the sequence composition of cellular molecules such as DNA, RNA, and proteins across generations. The field of molecular evolution uses principles of evolutionary biology and population genetics to explain patterns in these changes. Major topics in molecular evolution concern the rates and impacts of single nucleotide changes, neutral evolution vs. natural selection, origins of new genes, the genetic nature of complex traits, the genetic basis of speciation, the evolution of development, and ways that evolutionary forces influence genomic and phenotypic changes.

<span class="mw-page-title-main">Neutral theory of molecular evolution</span> Theory of evolution by changes at the molecular level

The neutral theory of molecular evolution holds that most evolutionary changes occur at the molecular level, and most of the variation within and between species are due to random genetic drift of mutant alleles that are selectively neutral. The theory applies only for evolution at the molecular level, and is compatible with phenotypic evolution being shaped by natural selection as postulated by Charles Darwin.

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<span class="mw-page-title-main">Muller's ratchet</span> Accumulation of harmful mutations

In evolutionary genetics, Muller's ratchet is a process which, in the absence of recombination, results in an accumulation of irreversible deleterious mutations. This happens because in the absence of recombination, and assuming reverse mutations are rare, offspring bear at least as much mutational load as their parents. Muller proposed this mechanism as one reason why sexual reproduction may be favored over asexual reproduction, as sexual organisms benefit from recombination and consequent elimination of deleterious mutations. The negative effect of accumulating irreversible deleterious mutations may not be prevalent in organisms which, while they reproduce asexually, also undergo other forms of recombination. This effect has also been observed in those regions of the genomes of sexual organisms that do not undergo recombination.

In evolutionary genetics, mutational meltdown is a sub class of extinction vortex in which the environment and genetic predisposition mutually reinforce each other. Mutational meltdown is the accumulation of harmful mutations in a small population, which leads to loss of fitness and decline of the population size, which may lead to further accumulation of deleterious mutations due to fixation by genetic drift.

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Genetic load is the difference between the fitness of an average genotype in a population and the fitness of some reference genotype, which may be either the best present in a population, or may be the theoretically optimal genotype. The average individual taken from a population with a low genetic load will generally, when grown in the same conditions, have more surviving offspring than the average individual from a population with a high genetic load. Genetic load can also be seen as reduced fitness at the population level compared to what the population would have if all individuals had the reference high-fitness genotype. High genetic load may put a population in danger of extinction.

Inbreeding depression is the reduced biological fitness that has the potential to result from inbreeding. The loss of genetic diversity that is seen due to inbreeding, results from small population size. Biological fitness refers to an organism's ability to survive and perpetuate its genetic material. Inbreeding depression is often the result of a population bottleneck. In general, the higher the genetic variation or gene pool within a breeding population, the less likely it is to suffer from inbreeding depression, though inbreeding and outbreeding depression can simultaneously occur.

Coalescent theory is a model of how alleles sampled from a population may have originated from a common ancestor. In the simplest case, coalescent theory assumes no recombination, no natural selection, and no gene flow or population structure, meaning that each variant is equally likely to have been passed from one generation to the next. The model looks backward in time, merging alleles into a single ancestral copy according to a random process in coalescence events. Under this model, the expected time between successive coalescence events increases almost exponentially back in time. Variance in the model comes from both the random passing of alleles from one generation to the next, and the random occurrence of mutations in these alleles.

Genetic hitchhiking, also called genetic draft or the hitchhiking effect, is when an allele changes frequency not because it itself is under natural selection, but because it is near another gene that is undergoing a selective sweep and that is on the same DNA chain. When one gene goes through a selective sweep, any other nearby polymorphisms that are in linkage disequilibrium will tend to change their allele frequencies too. Selective sweeps happen when newly appeared mutations are advantageous and increase in frequency. Neutral or even slightly deleterious alleles that happen to be close by on the chromosome 'hitchhike' along with the sweep. In contrast, effects on a neutral locus due to linkage disequilibrium with newly appeared deleterious mutations are called background selection. Both genetic hitchhiking and background selection are stochastic (random) evolutionary forces, like genetic drift.

In natural selection, negative selection or purifying selection is the selective removal of alleles that are deleterious. This can result in stabilising selection through the purging of deleterious genetic polymorphisms that arise through random mutations.

In population genetics, fixation is the change in a gene pool from a situation where there exists at least two variants of a particular gene (allele) in a given population to a situation where only one of the alleles remains. That is, the allele becomes fixed. In the absence of mutation or heterozygote advantage, any allele must eventually either be lost completely from the population, or fixed, i.e. permanently established at 100% frequency in the population. Whether a gene will ultimately be lost or fixed is dependent on selection coefficients and chance fluctuations in allelic proportions. Fixation can refer to a gene in general or particular nucleotide position in the DNA chain (locus).

The nearly neutral theory of molecular evolution is a modification of the neutral theory of molecular evolution that accounts for the fact that not all mutations are either so deleterious such that they can be ignored, or else neutral. Slightly deleterious mutations are reliably purged only when their selection coefficient are greater than one divided by the effective population size. In larger populations, a higher proportion of mutations exceed this threshold for which genetic drift cannot overpower selection, leading to fewer fixation events and so slower molecular evolution.

The McDonald–Kreitman test is a statistical test often used by evolutionary and population biologists to detect and measure the amount of adaptive evolution within a species by determining whether adaptive evolution has occurred, and the proportion of substitutions that resulted from positive selection. To do this, the McDonald–Kreitman test compares the amount of variation within a species (polymorphism) to the divergence between species (substitutions) at two types of sites, neutral and nonneutral. A substitution refers to a nucleotide that is fixed within one species, but a different nucleotide is fixed within a second species at the same base pair of homologous DNA sequences. A site is nonneutral if it is either advantageous or deleterious. The two types of sites can be either synonymous or nonsynonymous within a protein-coding region. In a protein-coding sequence of DNA, a site is synonymous if a point mutation at that site would not change the amino acid, also known as a silent mutation. Because the mutation did not result in a change in the amino acid that was originally coded for by the protein-coding sequence, the phenotype, or the observable trait, of the organism is generally unchanged by the silent mutation. A site in a protein-coding sequence of DNA is nonsynonymous if a point mutation at that site results in a change in the amino acid, resulting in a change in the organism's phenotype. Typically, silent mutations in protein-coding regions are used as the "control" in the McDonald–Kreitman test.

In genetics, when multiple copies of a beneficial mutation become established and fix together it is called soft sweep. Depending on the origin of these copies, linked variants might then be retained and emerge as haplotype structures in the population. There are two major forms of soft sweeps:

  1. A beneficial mutation previously separated in the population neutrally and therefore existed as multiple haplotypes at the time of the selective shift in which the mutation became beneficial. In this way, a single beneficial mutation may carry multiple haplotypes to an intermediate frequency, while itself becomes fixed.
  2. Another model happening when multiple beneficial mutations independently occur in short succession of one another — consequently, a second copy occur through mutation before the selective fixation of the first copy.

References

  1. 1 2 Charlesworth, B., M. T. Morgan, and D. Charlesworth. 1993. The effect of deleterious mutations on neutral molecular variation. Genetics. 134: 1289-1303.
  2. 1 2 Matheson, Joseph; Masel, Joanna (2 March 2024). "Background Selection From Unlinked Sites Causes Nonindependent Evolution of Deleterious Mutations". Genome Biology and Evolution. 16 (3). doi:10.1093/gbe/evae050. PMID   38482769.
  3. ↑ Charlesworth, D., B. Charlesworth, and M. T. Morgan. 1995. The pattern of neutral molecular variation under the background selection model. Genetics. 141: 1619-1632.
  4. 1 2 Charlesworth, Brian. 2012. The effects of deleterious mutations on evolution at linked sites. Genetics. 190: 5-22.
  5. ↑ Hudson, Richard R. and Norman L. Kaplan. 1995. Deleterious background selection with recombination. Genetics. 141: 1605-1617.
  6. ↑ Lewontin, R. C. 1974. The genetic basis for evolutionary change. Columbia Univ. Press, New York, NY.
  7. ↑ Innan, Hideki and Wolfgang Stephan. 2003. Distinguishing the hitchhiking and background selection models. Genetics. 165: 2307-2312.
  8. ↑ Ewing, Gregory B.; Jensen, Jeffrey D. (January 2016). "The consequences of not accounting for background selection in demographic inference". Molecular Ecology. 25 (1): 135–141. Bibcode:2016MolEc..25..135E. doi:10.1111/mec.13390. PMID   26394805.
  9. ↑ Pouyet, Fanny; Aeschbacher, Simon; Thiéry, Alexandre; Excoffier, Laurent (23 August 2018). "Background selection and biased gene conversion affect more than 95% of the human genome and bias demographic inferences". eLife. 7. doi: 10.7554/eLife.36317 .
  10. ↑ Johri, Parul; Riall, Kellen; Becher, Hannes; Excoffier, Laurent; Charlesworth, Brian; Jensen, Jeffrey D. (25 June 2021). "The Impact of Purifying and Background Selection on the Inference of Population History: Problems and Prospects". Molecular Biology and Evolution. 38 (7): 2986–3003. doi:10.1093/molbev/msab050. PMC   8233493 . PMID   33591322.
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