Evolution Exam 2

Neutral Alleles

-Alleles whose fate is determined largely by genetic drift

Ages of LGT Regions in Ecoli

-Can estimate based on changes in GC content over time

Genome Rearrangement- Ciliates

-Ciliates are single cell eukaryotes with separate germline and somatic nuclei

Change in Repetitive element Content

-Human genome has a larger fraction of repetitive sequence

Mutation and Selection: Deleterious mutations

-Why some disease causing alleles are still seen- regenerating -mutation-selection balance

Selection and HW model

-new genotype frequencies after selection: A1A1= p^2w11/W A1A2= 2pqw12/W A2A2= q^2w22/W -Average fitness for all population (W): W= p^2w11+ 2pqw12+ q^2w22 -New allele frequencies: A1= (p^2w11 + pqw12)/W A2= (q^2w22 + pqw12)/W

Variation in size and gene content in Bactera

-not a lot of repetitive genes in genome of bacteria so most are protein coding, have a lot of protein coding genes -Variation in genome size due to difference in gene content -Deletional bias: more deletions than insertions

Values, Means and Variances

1. Phenotypic= genetic value + environmental value P=G + E 2. average P= average G + average E 3. varianceP= varianceG + VarianceE

Molecular Clock

Constancy of Amino acid substitution rates -Because substitution rates at neutral loci dont depend on pop size or other demographic parameters, proponents of neutral theory suggest that selectively neutral mutations arise at similar rates in diff taxa and that they should also be fixed at similar rates -Number of aa in genes approximately proportional to the time since diverged on the phylogenetic tree- closely related species have fewer differences, hypothesized that molecular evolution proceeds in a clocklike manner with amino acid seq changing at a constant rate over time and at the same rate in different lineages k=D/2t D= number of substitutions per sub site

LGT in Bacteria

Bacteria can colonize any environment, they evolved by acquiring DNA from those environments -Bacteria have gained a significant proportion of their genetic diversity through the acquisition of sequences from distantly related organisms. These lateral transfers have effectively changes the ecological and pathogenic character of bacterial species LGT: prokaryotic genomes are mosaics made of fragments from different sources -Basically genetically modified organisms. Salmon grows faster bc it has a gene from another species ---> no health effects. people are scared but bacteria is basically a GMO because its made of genes from other species

Heritability

Broad sense heritability (H^2) of a trait is the fraction of the total phenotypic variation that is due to genes -H^2= 1 if all variation was due to genes (not environment) -not useful for studying evolution, not useful to make predictions about how a pop will respind to natural selection Narrow sense heritability (h^2) proportion of phenotypic variation due to additive genetic variation, the fraction of the variation thats accessible to natural selection

Generating Linkage Disequilibrium

Can be generated by: 1. Selection on multilocus genotypes 2. Physical Linkage 3. Genetic drift 4. Migration (population admixture) 5. Assortative mating 6. Mutation There processes lead to overrepresentation or underrepresentation of specific haplotypes

Empirical Evidence: Functional Constraints

Clocks turn at different rates in different lineages Genes, sites of genomic regions with different functional constraints evolve at different rates -Higher rate if low functional constraint -Lower rate if high functional constraint -Different types of sites within a gene evolve at different rates: synonymous vs nonsynonymous sites

Genetic Drift and Genome Reduction in Bacteria

Comparison of orthologous genes from 42 species pairs of closely related bacteria with wide diversity of life styles and genome sizes -as size of prokaryptes increases so does amount of protein coding dna -significant negative correlation between level of genetic drift (using Ka/Ks as proxy) and genome size

Genetics of Quantitative Traits

Complex phenotypes usually affected by many genes act additively -with 3 genes, 8 gamete types, 64 genotypes, 7 different phenotypes -we don want to keep up with all those allele frequencies and fitnesses When many genes contribute additively to a trait, Mendelian inheritance produces a roughly normal distribution of phenotypes, (frequencies of each possible genotype when you cross every heterozygote) can summarize the key info using the normal distriubtion

Components of Fitness

Components of fitness are characteristics of an organism that affect its lifetime reproductive success -Total fitness can be decomposed into these components that represent natural selection acting at different times during the lifetime of the organism -Components: Gametic selection, fecundity selection, viability selection, sexual selection (may not help with surviving but helps with reproductive success)

Linkage Disequilibrium Coefficient (D)

D= observed-expected haplotype frequencies If f(A)=p1, f(a)=p2, f(B)= q1, f(b)= q2 then... Freq(AB)= p1q1+D Freq (Ab)=p1q2-D Freq(aB)=p2q1-D Freq(ab)=p2q2 +D D=f(AB) x f(ab) - f(Ab) x f(aB) -Maximum value when all chromosomes are AB or ab with frequency 0.5 (D=.25) -Minimum value when all chromosomes are Ab or aB with frequency 0.5 (D= -0.25) -If D=0 the pop is in linkage equilibrium

Neutralist-selectionist controversy

Debate about whether drift or selection is the primary driver of evolutionary change in the subset of mutations that reach a high freqency in pops -He didnt reject Advantageous mutations, just that theyre rare

Exon Shuffling

Ectopic recombination of exons and domains from different genes -many current genes arose through the rearrangement of exons into new combinations. -19% of euk exons originated via exon shuffling

A "Selective Sieve"

Efficiency of selection depends on Ne -Ne large, selection is efficient, deleterious mutations are eliminated (sieve with many small wholes) -Ne small, selection is less efficient, slightly deleterious mutations remain as polymorphism and may fix (sieve with less but bigger wholes, more mutations can pass through)

Quantitative Genetics Important People

Fisher invented statistical idea of variance -1918 "correlation between relatives on the supposition of mendelian inheritance" -invented analysis of variance Wight Jay Lush- 1945 animal breeding plans Doublas Falconer- 1960 Intro to Quant. Genetics

Negative Frequency Dependent Selection

Fitness associated with a trait decreases as the frequency of that trait increases in a pop Phenotype favored when rare -allows variability to be maintained- when A1 allele starts at a high freqy phenotype P1 is common. It has low fitness and A1 declines in freq, when A1 starts at a low freq phenotype P1 is rare. it has a high fitness and A1 increases in freq, A1 eventually reaches an intermediate frequency -Example: right handed and left handed fish

Positive Frequency Dependent Selection

Fitness associated with a trait increass as the frequency of the trait increase in a pop -Phenotype favored when common -Does not maintain variation- when A1 starts above a critical threshold freq, phenotype P1 is common and has an advantage then goes to fixation, When A1 starts below threshold, phenotype P1 is rare and has a disadvantage. A1 is lost from the pop

Mutation as an evolutionary force

Genetic Mutation generates the variation on which natural selection acts, its undirected- occurs randomly with respect to its effects on organisms fitness -Mutation from A to a at a rate u: rate at which one allele becomes the other -If mutation is the only force acting then the frequency of A decreases over time -change in one generation: p'=p-up up= the fraction that have mutated -frequency of A after t generations: p(t)=p0e^(-ut) p0= the starting frequency e= the base of the natural log -Mutation alone changes allele frequencies at a slow pace, as directional change thats predictable. -More powerful when paired with other forces

Summary of Effects of Population size

Genetic drift- slow in large Ne. fast in small efficiency of selection- high in large low in small Number of new mutations- large in large, small in small Time to fixation: neutral- long in large and short in small prob of fixation: neutral (1/2N)- lower in large higher in small Prob of fixaiton: selected (2s)- independent in both

Genome-wide Estimates

Genome-wide estimates for alpha for different organisms- results suggst that in many species a substantial fraction of amino acid differences between species have been fixed by selection

Overdominance and Underdominance Allele Frequencies

Genotype A1A1 A1A2 A2A2 Overdominance 1-s 1 1-t Underdominance 1+s 1 1+t w11 w12 w22 p*= w22-w12/(w11-2w12+w22) ----> p*= t/(s+t) and q*= s/(s+t)

Change in chromosome structure in Primates

Human vs chimp: 1 fusion and at least 9 visible inversions

Why do we care about LD? 4

Important to understand periodic selection and long-term persistence of bacterial resistance to antibiotics -A beneficial mutation arises and sweeps to fixation, another beneficial mutation arrises and it in turn sweeps to fixation and the process continues

Linkage Disequilibrium via Migration

Inital haplotypes are coupling after migration, ab will occur on the AB only land so there will be a statisitcal association between A and B

Mutation-Selection Balance

Joint effects of mutation and selection -A mutates to a at u rate- effect is the frequency of a increases -Selection acts against a, frequency of a decreases -allows deleterious recessive alleles to persist -Recessive deleterious allele: A ---> a, at rate u q*= square root of u/s -Dominant deleterious allele: A ---> a at rate u p*= u/s -Lethal dominant allele: A <---- a at rate u p*=u -Several human diseases are good examples of this equilibrium between mutation and selection: recessive deleterious: cystic fibrosis, dominant deleterious: hungtingtons disease

The Normal Distribution

Just 2 parameters- used to study phenotypic evolution -Mean: X -Variance: sigma^2 (standard deviation: sigma) -Graph has 1 peak if two pops hve same mean but different variance, graph with 2 peaks if two pops have same variance but diff means -Evolution of mean phenotype depends on genetic variance and natural selection

Selection For Lactose Tolerance

LD around lactose gene, haplotypes around ancestral allele are very short, haplotypes around derived allele are long indicating recent strong selection for this allele

Mutation and Drift: The Neutral Theory

Look at how DNA or RNA sequences change over time and how the aa sequence that compose proteins changes over time -The null hypothesis to study evolution on a molecular level

The origin of New Genes

Main mechanisms: 1. LGT 2. Gene duplication 3. Exon Shuffling 4. Retroposition 5. Gene fusion/fision 6. De novo origination

LGT detection: Abrupt changes in GC content

Measure G+C content in different genes. If GC content at first and third codon positions is two or more s.e higher or lower than the respective means for all genes in the genome, this likely reflects LGT. Also use codon bias. -This approach underestimates LGT. why? -Transfer from organisms with similar GC content are not detected -Only detects recent transfer because mutational pressure will bring GC content to approach that of the new genome

Problem with Mendals Laws and Darwins Theory

Mendal laws seemed to only apply to discrete traits, those showing large difference between phenotypes -Mendelians: evolution as saltational process acting on discrete variation, large mutations leads to large changes in phenotype Darwin's ideas focused on continuous variation, that lead to small and gradual changes in phenotypes over time -Biometricians: evolution as gradual process acting on continuous variation

Genome rearrangements in Eukaryotes

Most species possess a nearly identical copy of their genome in every cell -Except immune cells- see lots of variation in sequence involved in recognizing forgien sequences, expect to see these differences in humans Some species undergo extensive genome rearrangements in some cell somatic lineages- programmed genome rearrangements -The rearrangements result in the selective removal of repetitive sequences, entire chromosomes or single copy genes in somatic cell lineages (not in germline)

LGT in Eukaryotes

Multiple events of LGT between bacteria and animals have been uncovered by genomic data -Eukaryotes are chimeras, the result of ancient endosymbiosis, LGT gave eukaryotes new metabolic capabilities

Molecular Evolution and Natural Theory

Neodarwinian view was prevelant in the 1960's 1. Natural selection is the major force driving the evolutionary process 2. Gene substitutions (fixation of alleles) occurs through selection 3. Polymorphism is maintained by balancing selection

Neutral Theory Common Mistake

Neutral theory proposes most substitutions are neutral NOT that most mutations are neutral

Inferring selection in DNA sequences

Neutral theory: -null hypothesis. tells us what to expect if mutation and drift have been only mechanisms of evolution at the molecular level -allows comparing observed patterns of variation to expected patterns under neutrality -departures from expectations suggest that natural selection has played a role shaping variation

Positive Selection

Nonsynonymos occur more rapidly because of selection compared to synonymous substitutions that occur from drift

Estimating Heritability

Parent offspring regression: -mean of trait in mom and dad for familyx ---> Px -mean of trait in offspring of familyx ----> Ox slope of graph= heritability -more variance is genetic, higher h^2 -genetic variance in phenotypic traits is required for evolution

GC Content

Percent of Gs and Cs in genome -Varies widely across organisms -Range in cellular organisms: 13-75%

Polygenic Traits: Epistasis

Phenotype depends on context -In mice that are DD at the Agouti locus, the different Mc1R variants have no effect on phenotype -In mice that are DL or LL at the agouti locus, the alleles at the Mc1R locus influence phenotype -Because the effect of alleles at the Mc1R locus depends on their context- namely which alleles are present at the agouti locus- there is epistasis between the Mc1R and agouti loci -Alleles interact in a non-additive way -The phenotypic effects of alleles at one locus depend on the context that is set by allele at another locus. Natural selection then operates on allele combination that determine particular phenotypes

Empirical Evidence: the Molecular Clock

Rate at which two lineages diverge over time equals the rate at which two lineages accumulate mutations -Margolisash proposed: If genetic changes occur at a constant rate across lineages members of one clade should be equidistant to members of another clade- genetic equidistance principle If two species diverged t generations (or years) ago and neutral mutations happen at rate u per generation (or year) the expected divergence (D) between 2 neutral sequences from the two species is D=2ut underestimates the amount of substitutions because it misses cases where two or more subs have occurred on the same site

Selection Coefficient

Relative fitness A1A1= 1 (w11), A1A2= 1 (w12), A2A2= 1-s (w22) -s is the selection coefficient, measures the selective disadvantage of genotype A2A2 relative to genotypes A1A1 and A1A2 -s= 1-w22

Codon Bias

Selection on synonymous variation -the non random usage of synonymous codons in coding DNA -Differential synonymous codons are used at different frequencies in different organisms because of selection -codon bias matches tRNA frequencies to improve translational efficiency -codon bias increases with level of gene expression -suggests advantage of having increased translational efficiency in highly expressed genes -If codon bias is result of selection- expect positive correlation

The Breeder's Equation

Selection reponse= h^2 x selection differential R=h^2S h^2=R/S we can use this equation to predict response to selection -if correlation between parent and offspring phenotypes is high. high heritability therefore high selection response -If correlation between parent and offspring phenotypes is low . low heritability therefore low selection response

Purifying Selection

Selection to maintain the currently common allele despiste occasional deleterious mutations dN/dS <1 -common exceptions: immunity genes, parasite antigens, reproductive proteins- evolve fast, strong evidence of positive selection, Why? overeresented in genome

Adaptive Landscapes

Sewell Wright Selection as a hill-climbing processes Provides a way to think about how phenotypes or genotypes change over evolutionary time as a consequence of natural selection -immediate allele frequency is favored, -For two loci mean fitness of population depends on specific combinations of allele frequencies at the two loci -adaptive landscapes are a useful metaphor for thinking about evolution at multiple loci -observe adaptive landscape for coloration and antipredator behavior in garter snakes- behavioral differences in avoiding predation in four different colored snakes -Adaptive landscape for snakes- high fitness snake that reverses and is unstriped also high fitness, striped snake that doesnt reverse, -Because genes at different loci interact the adaptive landscape can have multiple peaks and valleys- a large population typically moves "myopically" uphill to a local fitness maximum, a small pop can drift across fitness valleys and reach a global fitness maximum -Selection drives population up the hill, genetic drift- particular combos that may not be adaptive can move across valleys -Phenotypic evolution is a gradual hill climbing proces, pops evolving to reach local fitness peaks -gradual fitness change due to mutations of small effect, large scale phenotypic change due to a single mutation of large effect

Quantitative Genetics

Study of the genetics of continuously varying characters -Most phenotypic traits vary continuously (height, weight, shape, color etc) -Even some countable characters vary continuously (number of bristles in drosophilia)

Molecular Techniques like Amino Acid Sequencing, Protein Electrophoresis Lead to

The development of enzyme electrophoresis provided researchers a ready way to uncover cryptic molecular variation- differences in aa seq that dont manifest themselves in phenotypic differences 1. Polymorphism measure using protein electrophoresis were to big to be explained by selection- Lewontin- classic view is wrong -Saw there was too much variation so classic view is wrong but there was too much to be explained by selection. When heterozygotes mate they can have homozygous offspring so they would have lower fitness which cant be maintained by selection 2. Rate of amino acid sequence divergence across diverse groups of organisms was too constant ("Molecular Clock") to be explained by selection -Sequenced amino acid proteins from different organisms and variation between them. Knew the times of divergence based on fossils. the very constant rate observed cant be explained by selection. Proposed molecular clock. Natural selection cant be the whole story. not enough selection going on to account for this much variation

Response to Selection: Selection Response (R)

The difference between the mean of the offspring of the selected parents and the mean of the parental generation

Response to Selection: Selection Differential (S)

The difference between the mean of the selected parents and the mean of all the population

Fitness

The fitness of a genotype is the average per capita lifetime contribution of individuals of that genotype to the population after one or more generations. can be measured as the average number of offspring produced- measured relative to other genotypes

Recombination

The frequency of recommbination between two genes is proportional to the distance between the genes -if Genes A and B are far apart- crossing over more likely -B and C close together, crossing over less likely

Linkage Disequilibrium

The loci are in linkage disequilibrium if random association among two loci is not obvserved -Haplotype frequencies differ from the products of allele frequencies

The G-Value Paradox

The number of protein coding genes doesnt scale with organismal complexeity -Little relationship between gene content and organismal complexity -What matters may be how genes are connected and deployed -larger genome doesnt mean more genes

Allele Frequency Change Under Directional Selection

Type of independent selection where one allele is consistently favored over the other, selection drives allele freq in a single direction toward an increasing freq of favored allele which becomes fixed -changes in allele frequency under selection are predictable -The larger the selection coefficient the stronger the action of natural selection. As a result allele freq change faster and A1 allele approaches fixation earlier -Rate of change depends on the strength of selection

Syntenic Dot Plots

Used for detecting genome rearrangements -Looks at inversions -Cant use when only fragments of DNA are available for sequencing

Why Care about LD? 1

Useful to identify genomic regions that have experienced recent positive selection -if selection is acting at locus A does it affect evolutionary dynamics of locus B? depends on if its close enough

Why do we care about LD? 2

Useful to map genes involved in any trait of interest: QTL mapping, association mapping -Genetic mapping works because of presence of LD between markers and genes underlying phenotypes

Frequency Independent Selection

Where the fitness associated with a trait is not directly dependent on frequency of the trait in a pop

Estimating Fraction of aa Substitutions fixed by selection

alpha= 1- [(pN/pS)/(dN/dS)] -in neutrality alpha= 1-1= 0

Drift and Selection

depends on strength of selection and pop size -Dynamics of new mutations -Rapid fixation, little contribution to polymorphism for adventageous mutations, selected -Slow fixation, greater contribution to polymorphism, for neutral mutations. neutral

Retroposition and gene fusion

first step: duplication Second step: retroposition and gene fusion -1% of human DNA is retrotransposed to new locations

Polymorphism and Divergence Tests

neutral theory: -rate of neutral substitutions equals the mutation (u) -expected heterozygosity (polymorphism) is 4Nu/(1+4Nu) Prediction -Positive correlation between levels of divergence and polymorphism: both depend on mutation rate (u) -genes diverging fast should show a lot of variability within correlation

Selective Sweep (Hitchhiking)

selective sweep:When an allele goes to fixation as a result of strong natural selection alleles at nearby loci are carried along to high feq as well because there is limited opportunity for recombination to occur between these loci and the selected loci Genetic Hitchhiking: a hitchhiking allele rides along with a nearby beneficial allele to which it is linked and this it increases in frequency even though it may be neutral or even deleterious itself -Alleles that are closely linked to a locus under selection may change frequencies because of the linkage to a selected allele Uses: detecting selection in DNA sequences -Haplotype icreases in freq. LD increases, if fixed: selective sweep region and strong LD

Empirical Evidence: Hominid Evolution and Molecular Clock

-Immunological evidence -First test that didnt use sequencing- widely ridiculed at first -Allan Wilson and Vincent Sarich -Rate of immune response- estimate distance of relation of organisms, less response more closely related

Frequency Dependent Selection

-Relative fitness of a phenotype (genotype, allele) changes depending on the freq of the phenotype

Antagonistic Selection

-Selection acting in opposite directions -Maintains variability -Ex: Goldenrod gall fly- variability in gall size, wasp attacks smaller galls, fly attacks bigger gals

How is LGT Detected?

1. Nucleotide composition-based methods: atypical G+C content or codon usage suggest LGT 2. Conflicting gene phylogenies suggest LGT (different from species tree) 3. Differences in genomic gene content, some genes present in some closely related lineages but absent in basal lineages suggest LGT

Why do we care about LD? 3

Important to understand patterns of genome variation -Human variation: LD- distribution of variation in the human genome could be thought of as a mosaic of haplotype blocks determined by recombination hotspots- small regions of the genome that are particularly prone to serving as locations of crossover -Haplotype blocks: regions in which there is little evidence of historical recombination -difference among populations: more and larger blocks in european/asian pops

In Neutral Theory, Rate of substitution of neutral mutations is Independent of Population Size

The substitiution rate equals the mutation rate and is therefore independent of pop size. New mutations arise at a smaller rate each generation in smaller populations due to less indiviudals meaning less opportunity for mutation to arise but they fix at a higher rate because genetic drift is faster in smaller populations. In large pops many more mutations are produced each generation but they will fix at a lower rate because drift is slower in large populations. The two effects cancel each other out.

Linkage Disequilibrium Via Natural Selection

"Supergene" alleles and mimicry polymorphism in butterflies- very close together on chromosome, color polymorphism controlled by large region with up to 18 genes in strong LD -only aabb individuals are unable to produce the molecule and only they manifest the disease, as a result selection operates against the a allele but only when its part of the ab haplotype AND is paired with a second ab. no other haplotype is selected against, there will be a dearth of of ab haplotypes relative to what would be expected given the frequency of a and b alleles. -two pathways to get disease: at least one functional pathway present in each and every blue box, no disease -No functional pathway in 1 orange block- disease -ab less common than expected

The Mcdonald and Kreitman Tests

(tree tests) -Map difference either in allele substitutions between species or allelic polymorphisms within species and compare rates of synonymous and nonsynonymous -pN/pS(polymorphisms) =dN/dS (fixed) -ratios within and ratios between should be the same Species 1 A T 1 A C 1 A T 2 G T 2 G T 2 G T between species Within species -dN/dS >>> pN/pS- suggests directional selection (adaptive protein divergence) -dN/dS= pN/pS- suggests neutral evolution -dN/dS <<< pN/pS- suggests purifying selection (excess of mildly deleterious amino acid polymorphisms)

Types of natural selection on Quantitative traits

- directional selection -stabilizing selection -disruptive selection

Fitness Effects of New Mutations: Hypothetical distribution

-A lot of deleterious or neutral mutations -Kimura believes the neutral alleles are playing the most important role -A fraction of all mutations occurring at a genomic region are effectively neutral v=d + a + u d= deleterious mutations a=advantageous mutations u= neutral mutations or synanomous substitutions

Coat color and Viability Selection

-A1 is dominant associated with dark coloration -A2 is recessive, associated with light coloration -Probability of survival of the light colored pocket mice in the dark lava fields is 60-80% of that of the dark colored pocket mice. How should frequencies of two alleles change due to natural selection?

Viability Selection

-Allele frequency change under directional selection -Basic HW model can be modified to include selection -useful to predict changes in gene frequencies across multiple generations of selection

LGT fungi to Eukaryotes

-Animals dont make carotenolds, they get them from their diet. Required for several functions, ranging from ornamentation to antioxidants and immune system modulators to precursors for visual pigments. -Carotenoid bisysnthesis genes found in Aphid genome. genes fall in clade of fungi. genes part of large scaffolds with many insect genes -Single transfer with duplications. Genes expressed

Migration-Selection Balance

-Balance between migration and selection allows maintaining polymorphism -Gene flow and selection are acting in opposite directions -If theres selection against A in pop 2, the allele freq arrives at an equilibrium freq set by the balance between migration and selection

Fluctuating Selection

-Change in the direction of selection in variable environments -coat color and background -Variability Maintained

Reasons for Neutrality

-Degeneracy of the genetic code: synonymous vs nonsynonymous changes -At most loci, synonymous substitutions are more common -At a few loci, synonymous and nonsynonymous substitutions have comparable frequencies

When is Selection More Important Than Genetic Drift?

-Depends on the magnitude of the selection coefficient (s) and the effective pop size (Ne) -If 2Ne|s| < 1 genetic drift is more importnant (|s| < 1/2Ne) -If 2Ne|s| > 1 selection is more important (|s| > 1/2Ne) -Advantageous alleles with |s| < 1/2Ne behave as effectively as neutral alleles -In small pops, more mutations behave as neutral, more slighly deleterious mutations can fix by drift in small pops but most are elminated by selection in large pops

Neutral Allele Frequency Changes under Drift and Mutation

-Every individual has the same allele copy- there is no polymorphism -Every individual has the same allele copy but now a mutation has created a new allele- there is polymorphism -Allele 2 increases in frequency due to drift- there is polymorphism -Allele 2 increases in frequency until it gets fixed in the population- a substitution has occurred, now everyone has it -Imagine process takes place over and over again- incremental accumulation of genetic differences -A different mutation has created a new allele- there is polymorphism -A different mutation has created a new allele that increases in frequency by drift- there is a polymorphism -Allele substitution and polymorphism are two facets of the same phenomenon

Clines

-Evidence of selection -clines in allelic frequency reflect a balance between selection and migration

People Involved in this Discovery

-Fisher- 1930, the genetical theory of natural selection -Wright- 1931, evolution in mendelian populations -Haldane- 1932, the causes of evolution -Dobzhansky- 1937, genetics and the origin of species

Motif Multiplication and Exon Loss

-Gene function may be altered through the multiplication of motifs in an ancestral gene and/or loss of exons -Notothenioid fishes- live in very cold antarctica at temps at which most vertebrates blood would freeze -Antifreeze Glycoprotein (AFGP) genes: encode short polypeptides important to break up ice crystals and avoid blood freezing. Genes expressed in stomach and pancreas. genes originated 2.5 MYA -AFGP arose through duplication followed by motif multiplication and exon loss- AFGP appears to be derived (via motif multiplication and exon loss) from trypsinogen gene

Metagenomics

-Genomic analysis applied to entire communities of microbes bypassing the need to isolate and culture individual microbial species -The vast majority of the microbial world has been inaccessible to science because merely a miniscule fraction (<1%) of microbial species on Earth can be cultured. Metagenomics provides access to that diversity -Applications in Human health, Global Change (effect of microbes in carbon cycle), Agriculture, Environemntal Remediation, Bioenergy, Forensics

Patterns in Eukaryotes

-Highly significant negative correlation between genome size and population size (scaled by mutation rate) -difference in genome size may be the result of non-adaptive processes: faster accumulation of non coding DNA in small pops -Pop genetic processes seem to play a major role in explaining genome size variation in eukaryotes -Larger genomes tend to have a lower proportion of coding DNA than smaller genomes. -The species with the larger effective population size is expected to have the smaller genome. In larger populations, selection is expected to be able to remove deleterious mutations with even a small effect on fitness. Thus, a slightly deleterious noncoding or repetitive region of the genome can be more quickly removed from a genome, thereby resulting in a genome of smaller size.

Mutation Equilibrium

-If mutations occur in both directions, A to a= u and a to A= v -If p is the frequency of A, the equilibrium frequency is v/v+u or p'=p(1-u)+qv -operates far more slowly than natural selection, can take tens of thousands of generations for allele freq to approach equilibrium

Population Genetics of Multiple Loci

-If selection is acting at locus A, it can affect evolutionary dynamics of locus B by linkage

Effective Neutrality

-In finite pops natural selection cant operate effectively on mutations that have extremely small fitness consequences, even if alternative alleles have an effect on fitness and function thy can be effectively neutral if these effects are sufficiently small -an allele will be effectively neutral under same conditions that favor drift over selection: when the selective coefficent S is much smaller than 1/2Ne

Response to Artificial Selection in Corn

-In the pop selected for high oil content average oil content has increased steadily over the entire duration of the experiment, in pop selected for low oil content average oil content has decreased steadily -At start of experiment 1896 corn oil ranges from 4 to 6%, by 1988 the pop selected for low oil had 2% content, by 2004 the pop selected for high oil content had over 20% -Heritability for oil has declined but still not zero , heritability is a statistical property of a pop not a general fact about the genetic basis of a trait

Linkage Disequilibrium and Recombination

-LD can be reduced by recombination -Under random mating and no selection, linkage disequilibrium is reduced each generation. Rate of decay depends on recombination rate (r): D'=D(1-r) -Further apart higher recombination rate

LD varies

-LD varies greatly across the genome -LD decays with physical distance -LD decays rapidly even in species with almost exclusive self-fertilization

General Patterns of Genome Size in Eukaryotes

-Large interspecific variation in genome size -Variation in genome due to differences in non-coding DNA -Proportion of genome occupied by protein-coding DNA decreases with genome size but proportion occupied by Transposable Elements (TEs) increases with genome size Transposable elements: small genetic elements capable either of catalyzing their own movement within the genome or of moving with the assistance of other transposable elements

The C-Value Paradox

-Little relationship between genome size and organismal complexity -Cell size increases with genome size in vertebrates- cells must be larger to pack genome

Underdominance

-Lower heterozygote fitness- pop can reach unstable allele frequency equilibrium but most likely one allele will fix -When A1 allele starts above a critical threshold frequency it goes to fixation, when A1 allele starts below this frequency it is lost from the pop -Unstable polymorphism -Not many examples exist

Synonymous Substitutions

-Many molecular changes dont cause changes in the phenotype -many changes in protein coding DNA seq dont cause changes in aa seq corresponding protein -There is redundancy, most aa are coded by several different codons (usually differ in third position) these are synonymous or silent, they will be neutral -Substitutions are more common at silent sites than at non silent sites

The Human Microbiome

-Microbiome: multi-genus/species community of bacteria that exists within a defined environmental domain -Humans are born without any microorganisms -Colonication of skin, oral/respiratory tract, genitourinary system and gastrointestinal tract begins immediately at birth -Our adult bodies contain 10 times more microbial cells than human cells -Shifts in the pop of microbial communities may be associated with disease: Inflammatory Bowel disease, Obesity, Cardiovascular disease, Eczema etc -Opportunity to develop new approaches to therapy by focusing on microbiome

The Neutral Theory of Molecular Evolution

-Motoo Kimura purposed neutral theory At the molecular level of DNA seq or aa seq: 1. most of the variation present within a pop is selectively neutral 2. most of the changes in DNA or aa seq over time and thus many of the molecular differences between species are selectively neutral -The majority of molecular changes in evolution are due to random fixation (drift) of selectively neutral alleles (alleles fate is determined by drift not selection) -Concerned wth allelic substitutions- which occurs when a new allele arises by mutation and is subsequently fixed in the pop

Divergence Tests

-Natural selection on amino acid substitutions -comparing rates of substitution at nonsynonymous and synonymous sites: -Number of nonsynonymous substitutions per nonsynonymous site Ka (dN) -Number of synonymous substitution per synonymous site Ks(dS) -Under neutrality: Ka=Ks -Purifyig selection dN/dS <1 -Neutral Evolution dN/dS =1 -Positive Selection dN/dS > 1

Drift and Selection: Fixation Probability

-New neutral Mutation: P= 1/2N -New selected mutation p = 2s (for large N and small, positive s) -Beneficial allele is more likely to get fixed than the neutral but still has a high probability of getting lost

Polygenic Traits: Additive Effects

-Nilson-Ehle wheat cross (1908) -Red-kernel (dark) individuals crossed with white-kernel (light) individuals produce F1 offspring with intermediate kernel color -The F1 offspring all triple heterozygotes are then crossed to produce a range of color variants in the F2 generation of offspring -Additive effects of multiple genes leads to the phenotype -ie the more dominant genes the darker the kernel, AABBCC- darkest, aabbcc- lightest

Antibiotic Use and Linkage

-Observed no reduction of resistance to antibiotic after reduction of usage -Explanation has to do with interactions between different genes -Compensatory mutations arise at other loci in resistent bacterial strains but they dont reduce resistance they reduce or eliminate the fitness costs associated with the resistant phenotype -Due to compensatory mutations that increase fitness in the absence of the antibiotic- evolution at multiple loci Sensitive uncompensated: fitness high with no antibiotic present, low when its in use Resistant uncompensated: fitness the same for both around average, still has fitness costs Resistant compensated: Fitness high both when no antibiotic is present and when its in use, cost of fitness reduced

Noncoding Regions

-Only small fraction of genome encodes the seq of proteins, there rest is untranslated (doesnt mean it lacks function).

Reasons for Neutrality: Pseudogenes

-Pseudogene: nonfunctional DNA sequences homologous to active or previously active genes -Any mutation in pseudogene should have no effect because theyre nonfunctional; tend to be neutral

Allele Frequency Change Also Depends on Dominance

-Rate of change also depends on dominance -A1 approaches fixation most rapidly in incomplete dominance somewhat less rapidly in dominant case and much more slowly in recessive case -Dominant advantageous change slowly in frequency when common, recessive advantageous change slowly in frequency when rare -Selected alleles will eventually fix in the population -Doesnt mean that selection ONLY leads to loss of variation

Chimp Sex chromosomes

-Remarkable level of rearrangements in the Y observed -2/3 genes lost from chimp Y since last ancestor: unexpected given old age of these sex chromosomes. observations are not consistent with thoeyr of gradual decay of gene content

Modern Synthesis

-Resolved conflict between Mendelians and Biometricians. Continuous characters are the result of many discrete loci of small effect -Consensus: gradual evolution results from small genetic changes acted upon by natural selection -Microevolutionary processes lead to macroevolution- ie origin of new species and higher taxa

Sex Chromosome in Diptera

-Sex chromosomes have evolved many independent times from different autosome ancestors

The Evolution of Sex Chromosomes

-Sex chromosomes have evolved multiple independent times. They are fascinating cases of convergent evolution -Sex chromosomes are thought to have evolved from ordinary pairs of autosomes that stopped recombining with each other after acquiring a sex-determined role -Accumulation of sexually antagonistic genes (ie genes that are beneficial in one sex but detrimental in the other) linked to the sex-determining genes favors the evolution of suppression of recombination between the nascent sex chromosomes

The Human Sex Chromosome

-Shredding of genetic material in the human Y chromosome

Sickle Celle

-Sickle cell allele is common where malaria is endemic and rare elsewhere -High sickle cell observed in places with high malaria- people with sickle cell partially protected against malaria, the absence of malaria is a strong selection against but with malaria. protection of malaria comes with cost of more sickle cell in pop -Example of overdominance

Mutation and Selection: Beneficial mutations

-Steplike dynamics predicted by model in which successive beneficial mutations sweep through a pop by natural selection

Polymorphism Tests

-Tests based on the distribution of allele frequencies -Tests based on patterns of linkage disequilibrium -Tests based on difference in allele frequency among pops. finding Fst outliers

Linkage

-The observation that two genes are not transmitted independently -Genes physically near each other on a chromosome will not assort randomly during meiosis

LGT in Eukaryotes: Protosynthetic proteins in sea slugs

-The sea slug acquires plastids from its algal food source -Photosynthesis still occurs in sea slug after the algal nucleus and cytoplasm are digested -psbO(a protein) is actively expressed in sea slug and seq of psbO is identical between the sea slug and algal food source -Why dont we see more photosynthesis in animals? wouldnt it have a large advantage? another example is spotted salamander- has chloroplasts

Divergence Problem

-Using dN/dS to infer selection is overly conservative and can lead to underestimation of positive selection because dN/dS ratio is averaged over complete sequence

Variation in Size

-Varies between domains of live, Archaea, Bacteria and Eukaryotes and within eukaryotes

Overdominance

-When there is higher heterozygote fitness- pop can reach allele frequency equilibrium -When A1 starts at high freq, its freq declines, when A1 starts at low freq, its freq increases, A1 eventually reaches an intermediate freq that doesnt depend on the initial frequencies, so long as both alleles are present in the pop -Stable polymorphism

Pleiotrophy

-a single gene can have effects on multiple aspects of phenotype

Patterns of Gene duplication

-age distribution of duplicates- know how to interpret graphs. compare genes and identify which are cloesest if duplicated it will match, lots of duplicates get lost -If theres a thick peak means a particular time with lots of duplications- caused by positive selection? WHAT COULD CAUSE A LOT OF GENE DUPLICATION AT SAME TIME? -Tabulation of results of those analyses for mulitple species half life of a duplicated gene in humans: 7.5MY, in flies 3.2 MY, in yeast 1 MY

Nonsynonymous Substitutions

-do change the aa seq -Many are not neutral because they change the way the protein functions, some changes have fitness consequences, some have minimal effects on fitness

Genome Evolution

-evolution of genome size -evolution of genome structure -lateral gene transfer -metagenomics the microbiome -origin of new genes genome content and structure change, sometimes very rapidly

Adaptive Landscape Features

-fitness peaks- combinations of traits associated with the greatest fitness values -fitness valleys- regions of lower fitness

Linkage Disequilibrium

-hitchhiking (selective sweep)- haplotype increases in frequency, LD increases. if fixed: selective sweep, reduction of variation in surrounding region and strong linkage disequilibrium -during selective sweep haplotype carrying beneficial mutation increases in freq leads to increased LD

Drift and Selection: Efficiency depends on the Ne

-selection is more efficient in large pops -In small pops, drift can be a stronger force -Drift can lead to reduction in adaptation in small pops and can lead to loss of beneficial mutations -Important to consider when predicting what will happen

Neutral Theory Summary

1. Only tries to explain evolution at the molecular level 2. Proposes that most evolution at the molecular level- has been non adaptive. only a small fraction is adaptive 3. Natural selection is still the most important mechanism driving organismal adaptation 4. Neutrality does not imply strictly equal fitness for all alleles. it means that the fate of the a neutral allele is determined largely by drift (selection may be operating but it may be too weak to offset the effect of drift 5. Most new mutations are deleterious and are thus quickly eliminated by natural selection 6. Most mutations remaining in populations are neutral with respect to fitness. these mutations are the ones that we can see as sequence polymorphism or divergence

Maintenance of Genetic Variation Through Selection

1. Overdominance- ex. sickle cell 2. Frequency dependent selection- ex. right and left handed fish 3. Antagonistic selection- ex gall size 4. Fluctuating selection: ex. melanism in rock pocket mice -Spatial heterogeneity -Temporal or environmental variability All are examples of balancing selection, the process by which multiple alleles are maintained in a pop by natural selection

Tests for neutral model

1. Patterns of sequence variation BETWEEN species: Divergence Tests- data from more than one species. one sequence per species/locus -how they diverge from each other 2. Patterns of sequence variation WITHIN species: Polymorphism Tests-data from single species. multiple sequences per locus 3. Comparison of WITHIN AND BETWEEN species variation: Polymorphism and Divergence Tests- data from two species (or more). multiple sequences per species/locus -combines the two types

Expected Patterns Under Neutrality (drift and mutation)

1. Rare alleles that are young (just arose) and thus have high LD with other loci 2. Rare alleles that are old and thus have low LD with other loci 3. Common alleles that are old and thus have low LD with other loci NOT EXPECTED: common alleles that have high LD with other loci- Under neutrality, new alleles should be rare (not common) because they are the result of a recent mutation. If the neutral alleles are old one should not see high LD with other loci as recombination would have had enough time to mix alleles and reduce LD. Thus, common alleles that are young and that have with high LD with other alleles are not expected under neutrality, they represent new mutations (young) that have risen rapidly in frequency due to natural selection (leading to high LD).

Two Hypotheses About Genetic Variation

1. The classic view -Morgan: individuals homozygous for the "wild" type allele were most common. Wild type allele due to deleterious mutations. Not a lot of variation in populations -Native wild types will be fixed and mutants are rare, variation fixed by selection 2. The Balance View -Dobzhansky: a lot of variation in populations. Most individuals heterozygous. Variation maintained by balancing selection (heterosis) -Based on variation observed in wild and looking at different traits, proposed that most are heterozygous at every locus and that heterozygotes have higher fitness

Neutral Theory: Theoretical Principles 1

1. The probability of fixation of a neutral allele equals its frequency: -Frequency of new neutral mutation in a population of N diploid individuals= 1/2N -Probability of fixation= 1/2N (its frequency) -Probability of new mutant allele being lost in one generation: (1-1/2N)^2N which is basically e^-1= 0.368 -High probability a new mutation will get lost in one generation

Quantitative Genetics Main Points

1. Those phenotypic traits are controlled by multiple genes each one of small effect- bc of small effect many different genotypes have the same phenotype 2. The environment influences the phenotype -norm of reaction: array of phenotypes that result from a given genotype across a range of environmental conditions , ex: plant planted at different altitudes- phenotypic difference even though genes are the same Quantitative traits are determined by combined influence of the genotype at many loci and the environment

Neutral Theory: Theoretical Principles 2

2. The rate at which neutral mutations are fixed in populations (rate of substitutions) equals the neutral mutation rate (u) -The number of new neutral mutations per generation in a population of N diploid individuals = 2Nu -Probability of fixation of a new mutation= 1/2N -Rate of substitution: number of new mutations times the probability that one of them will fix: 2Nu x 1/2N= u -Allows to predict the molecular clock -Completely independent of population size- two effects associated with pop size cancel each other

Neutral Theory: Theoretical Principles 3

3. At mutation-drift equilibrium (when the number of lost alleles through drift equals the number of alleles gained through mutation), the expected equilibrium level heterozygosity (H) is: H= 4Nu/(1+4Nu) -Equilibrium level of variation is higher in a large population than in small one. -Larger populations are expected to have more genetic variation

Neutral Theory: Theoretical Principles 4

4. Among the newly arising neutral alleles that will eventually be fixed, the average time to fixation is 4N generations -The larger the pop size the longer it takes for a given mutation to get fixed therefore larger populations should harbor more polymorphism (variation)

Lateral Gene Transfer

A process in which an organism transfers genetic material from another cell that is not its offspring. Transfer of genetic material between different evolutionary lineages. Acquisition of foreign DNA. Contrasts with mechanism of vertical inheritance of genetic material -Important in Prokaryote evolution -Necessary to explain origin of eukaryotes (primary endosymbiosis) - where certain euk features came from -Not as common an event in eukaryotes -Network of life: tree like representation of evolutionary history not completely correct. no species trees only gene trees mechanisms- transformation, transduction, conjugation

Haplotype

A set of alleles from different loci that are transmitted together (typically located in the same chromosome) -Genotype frequencies will be slightly different than expected if there is random association between the two alleles from the two loci

LGT detection: Phylogenetic Incongruency

Anomalous position of gene in phylogeny -Expect: genes from 1 group of bacteria would be more closely realted -see: Archaea gene that is closer to a bacteria gene -so must have laterally transfers from bacteria to archaea

Evidence of Selective Sweep

At G6PD in humans -G6PD deficiency, acute hemolytic anemia common in regions with malaria hundreds of alleles few reach frequencies >1% -G6PD allele in strong LD and high frequency (18%). inferred recent selective sweep