Reading 7b

Pseudogenes Establish a Canonical Rate of Neutral Evolution

The evolution of pseudogenes conforms to the assumptions and predictions of the neutral theory.

Null hypothesis

The hypothesis that there is no significant difference between specified populations, any observed difference being due to sampling or experimental error.

Status of the Neutral Theory

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Single-nucleotide polymorphism

A point in the genome at which some individuals have one nucleotide and other individuals have another. The researchers found lower standing diversity, measured as the fraction of individuals who are heterozygotes, for polymorphisms that involve amino acid changes versus polymorphisms that do not. These results imply that most single-nucleotide mutations that swap one amino acid for another are deleterious and held at low frequency by negative selection.

Negative (purifying) selection

Natural selection against deleterious mutations.

McDonald-Kreitman (MK) test

Based on the neutral theory's assertion that all standing variation at both silent sites and replacement sites consists of neutral alleles evolving by drift. If this assertion is true, then dN/dS between closely related species should be the same as the ratio of synonymous to nonsynonymous polymorphisms within species, pN/pS. Positive selection on nonsynonymous substitutions within species can elevate dN/dS above pN/pS because beneficial mutations rise quickly to fixation within populations. They thus contribute only briefly to polymorphism, but permanently and cumulatively to interspecific divergence. The researchers counted differences as fixed if they were present in all individuals from a particular species, and as polymorphisms if they were present in only some individuals from a particular species. Differences that were fixed in one species and polymorphic in another were counted as polymorphic. McDonald and Kreitman found that 29% of the differences that were fixed between species were replacement substitutions. Within species, however, only 5% of the polymorphisms in the study represented replacements. This is strong evidence against the neutral model's prediction. McDonald and Kreitman's interpretation is that the differences in replacement mutations fixed in different species are selectively advantageous

Empirical Research on Inbreeding

Because inbreeding can produce a large excess of homozygotes, Hardy-Weinberg analysis can be used to detect inbreeding in nature. Data revealing a deficit of heterozygotes and an excess of homozygotes may be evidence of inbreeding. In principle, a deficit of heterozygotes could result from selection against them and in favor of homozygotes. The appearance of a heterozygote deficit could also arise if the California otters, which Lidicker and McCollum treated as a single population, actually comprise two separate populations with different allele frequencies. Lidicker and McCollum consider these alternative explanations, however, and conclude that inbreeding is more plausible.

Silent Sites Change Faster than Replacement Sites in Most Coding Loci

Both kinds of substitution accumulated in a linear, clocklike fashion, but the rate of evolution for silent changes is much higher than the rate of evolution for replacement changes Silent changes are not exposed to natural selection on protein function, because they do not alter the amino acid sequence. New alleles created by silent mutations should thus increase or decrease in frequency largely as a result of drift. Replacement mutations, in contrast, change the amino acid sequences of proteins. If most of these alterations are deleterious, then most of them should be eliminated by natural selection without ever becoming common enough to be detected. In most coding sequences, substitution rates are higher at silent sites than at replacement sites. This result is consistent with the notion that molecular evolution is dominated by drift and negative selection.

Coalescence Applied

Coalescence models can be fit to data, yielding estimates for parameters such as population size.

Codon bias

Codon usage is highly nonrandom. It suggests that some synonymous mutations are not selectively neutral. It is strongest in highly expressed genes—such as those for the proteins found in ribosomes—and weak to nonexistent in rarely expressed genes. In addition, the suite of codons that are used most frequently correlates strongly with the most abundant species of tRNA in the cell. If a "silent" mutation in a highly expressed gene creates a codon that is rare in the pool of tRNAs, the mutation will be selected against. The selective agent is the speed and accuracy of translation. It explains the observation that silent changes do not accumulate as quickly as base changes in pseudogenes. Other synonymous mutations may experience selection as a result of their effects on mRNA stability or exon splicing

Silent-site (synoymous) mutations

DNA sequences changes that do not result in amino acid changes.

Pseudogenes

Functionless stretches of DNA that result from gene duplications. Because they do not encode proteins, mutations in pseudogenes should be neutral with respect to fitness. When such mutations achieve fixation in populations, it should happen solely as a result of drift.

Inbreeding

Inbreeding decreases the frequency of heterozygotes and increases the frequency of homozygotes compared to expectations under Hardy-Weinberg assumptions. If all the individuals reproduce by selfing, homozygous parents will produce all homozygous offspring while heterozygous parents will produce half homozygous and half heterozygous offspring. The frequency of heterozygotes has been halved every generation, and the frequency of homozgyotes has increased. We cannot predict the genotype frequencies by multiplying the allele frequencies. Although inbreeding does cause genotype frequencies to change from generation to generation, it does not cause allele frequencies to change. Inbreeding by itself, therefore, is not a mechanism of evolution.

Inbreeding depression

Inbreeding may lead to reduced mean fitness if it generates offspring homozygous for deleterious alleles. By increasing the proportion of individuals in a population that are homozygotes, inbreeding increases the frequency with which deleterious recessives affect phenotypes. Refers to the effect these alleles have on the average fitness of offspring in the population. δ = 1 - (ws/w0) where ws and wo are the fitnesses of selfed and outcrossed progeny, respectively. This definition makes levels of inbreeding depression comparable across species.

General Analysis of Inbreeding

Inbreeding that is less extreme than selfing produces the same effect as selfing—it increases the proportion of homozygotes—but at a slower rate.

Mechanisms of inbreeding avoidance

Mate choice, genetically controlled self-incompatibility, and dispersal. But under some circumstances, inbreeding may be unavoidable. In small populations, for example, the number of potential mates for any particular individual is limited.

Positive selection

Natural selection favoring beneficial mutations.

Neutral theory

Neutral mutations that rise to fixation by drift vastly outnumber beneficial mutations that rise to fixation by natural selection. Genetic drift, not natural selection, is the mechanism responsible for most molecular evolution. The rate of molecular evolution is, to a good approximation, equal to the mutation rate.

Hitchhiking (selective sweep)

Occur when strong positive selection acts on a particular amino acid change. As a favorable mutation increases in frequency, neutral or even slightly deleterious mutations closely linked to the favored site will increase in frequency along with the beneficial locus. These linked mutations are swept along by selection and may even ride to fixation. Note that this process occurs when only recombination fails to break up the linkage between the hitchhiking sites and the site under selection. Results in dramatic reductions in polymorphism as an occasional advantageous mutation quickly sweeps through a population.

Which Loci Are under Strong Positive Selection?

Positive selection seems to be particularly common in genes involved in biological conflict. Replacement substitutions appear to be particularly abundant in loci involved in arms races between pathogens and their hosts, in loci with a role in reproductive conflicts such as sperm competition and egg-sperm interactions, and in recently duplicated genes that have attained new functions. Positive selection has also been detected in genes involved in sex determination, gametogenesis, sensory perception, interactions between symbionts, tumor suppression, and programmed cell death as well as in genes that code for certain enzymes or regulatory proteins.

Background selection

Results from negative selection against deleterious mutations, rather than positive selection for advantageous mutations. Like hitchhiking, it occurs in regions of reduced recombination. The idea here is that selection against deleterious mutations removes closely linked neutral mutations and yields a reduced level of polymorphism. Causes a slow, steady decrease in polymorphism as frequent deleterious mutations remove individuals from the population.

Replacement (nonsynonymous) mutations

Sequence changes that result in an amino acid change.

Coalescence

The merging of genealogical lineages as we trace allele copies backward in time. Mathematical descriptions of coalescence provide an efficient means of simulating evolution by genetic drift. The term was coined by John Kingman, who found a way to simulate the coalescence of alleles in a population evolving backward in time by genetic drift. Among his method's virtues is that it requires no information about the rest of the population other than its size. The result is an evolutionary tree of genes—a gene tree or gene genealogy. Every one of the simulated gene trees is unique. We are modeling genetic drift, so the differences among trees are due to chance events. Randomly chosen individuals from a large population are likely to be more distantly related than randomly chosen individuals from a small population.

Coefficient of inbreeding

This quantity is symbolized by F, and is defined as the probability that the two alleles in an individual are identical by descent (meaning that both alleles came from the same ancestor allele in some previous generation). A1A1: p^2(1-F) + pF A1A2: 2pq(1 - F) A2A2: q^2(1 - F) + qF The same logic applies when many alleles are present in the gene pool. Then, the frequency of any homozygote AiAi is given by pi^2(1 - F) + piF And the frequency of any heterozygote AiAj is given by 2pipj(1 - F) where pi is the frequency of allele Ai and pj is the frequency of allele Aj . The last expression states that the fraction of individuals in a population that are heterozygotes (that is, the population's heterozygosity) is proportional to (1 - F). If we compare the heterozygosity of an inbred population, HF, with that of a random mating population, H0 , then the relationship will be HF = H0(1 - F) Anytime F is greater than 0, the frequency of heterozygotes is lower in an inbred population than it is in a random mating population.

Selection on Replacement Mutations

to find out whether replacements within a particular gene are deleterious, neutral, or advantageous, we can compare two sequences and calculate the rate of nonsynonymous substitutions per site (dN) and the rate of synonymous substitutions per site (dS). When sequences evolve by drift and negative selection, synonymous substitutions outnumber replacement substitutions. When sequences evolve by drift and positive selection, replacement substitutions outnumber synonymous substitutions. dN/dS < 1 when replacements are deleterious dN/dS = 1 when relecements are neutral dN/dS > when replacements are advantageous Positive selection causes replacement changes to spread through the population much more quickly than neutral alleles can spread by chance. In many examples, replacement substitutions outnumber synonymous substitutions—a signature of positive selection

7.3 Genetic Drift and Molecular Evolution

Early analyses of molecular evolution suggested that rates of change were high and constant through time. These conclusions appeared to be in conflict with what might be expected under natural selection.

Variation among Loci: Evidence for Functional Constraints

Rates of molecular evolution vary widely among loci because genes responsible for the most vital cellular function appear to have the lowerest rates of replacement substitutions. When functional constraints are lower, a larger fraction of replacement mutations are neutral with respect to fitness and may fix by drift.

Comparing Silent and Replacement Changes within and between Species

Replacement substitutions will outnumber silent substitutions only when positive selection has been strong.

Nearly Neutral Mutations

The nearly neutral model explains why, in some cases, rates of sequence change correlate with absolute time instead of generation time. There is a strong negative correlation between average population size in a species and its generation time. Species with short generation times tend to have large populations; species with long generation times tend to have small populations. As generation time goes up, population size, and thus |2Nes|, go down. As a result, a larger fraction of the mutations that arise—in particular, a larger fraction of the mildly deleterious mutations that are typically abundant in most species—are effectively neutral.

3 patterns of inbreeding depression

1. Inbreeding effects are often easiest to detect when plants undergo some sort of environmental stress. Selfed and outcrossed individuals had equal fitness when grown alone, but differed significantly when grown under competition. The strongest inbreeding effects on survival when an unplanned insect outbreak occurred. 2. Inbreeding effects are more likely to show up later in the life cycle—not, for example, during the germination or seedling stage. Maternal effects— specifically, the seed mother's influence on offspring phenotype through provisioning of seeds—can mask the influence of deleterious recessives until later in the life cycle. 3. Inbreeding depression varies among family lineages. Some families showed inbreeding depression; others showed no discernible effect of type of mating; still others showed improved performance under inbreeding.

Pedigree

A diagram showing the genealogical relationships of individuals.

Polymorphism

A locus at which different individuals in a population carry different alleles.

7.5 Conservation Genetics of the Florida Panther

A loss of allelic diversity under genetic drift appears to have caused inbreeding depression in Florida panthers.