teoría genética de poblacionescimi.ccg.unam.mx/~vinuesa/tlem09/docs/1introduccionfin2.pdfmuy...

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TLEM09 Dr. Luis Eguiarte 1

Taller Latinoamericano de EvoluciónMolecularGenética de Poblaciones yEVOLUCION MOLECULARLuis E. Eguiarte, Valeria SouzaEnrique Scheinvar y JaimeGascaDepartamento de Ecología EvolutivaInstituto de Ecología, UNAM TLEM09 Dr. Luis Eguiarte 2

Nueva Guía Mínima paraprincipiantes a la Genética dePoblaciones

Luis E. Eguiarte, Valeria SouzaEnrique Scheinvar y Jaime Gasca


La evolución es el corazón de la biologíamoderna.

Debido a los métodos para obtener datosmoleculares y a los genomas que se estáncompletando, la Evolución Molecular se estádesarrollando impresionantemente, y suimportancia es central para interpretar yanalizar correctamente los datos provenientesde proyectos genómicos y sus derivados (i.e.,metagenómica, proteómica, bioinformática,etc.). TLEM09 Dr. Luis Eguiarte 4

En estas sesiones vamos a revisarmuy brevemente la teoría de laGenética dePoblaciones que dafundamento a la Evolución Molecular,y algunas de sus aplicacionesempíricas en el análisis de datosrelevantes para resolver problemasevolutivos y ecológicos.

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OBJETIVOS DE LA SECCION

Que alumnos con experienciaprevia en genética se familiariceny entiendan la teoría básica y laaplicaciones fundamentales deGenética de Poblaciones y surelación con la EvoluciónMolecular y los avances recientescomo coalescencia y filogeografía


Programa10:00 1)Introducción a la Genética de Poblaciones10:45 2) Hardy-Weinberg y estimación de las frecuencias alélicas y lavariación genética Luis Eguiarte

11:50 3) Selección Natural Luis y Valeria12:30 4) Deriva Génica y el tamaño efectivo de las poblaciones13:00 5) Flujo génico y estructura de las poblaciones Luis Eguiarte

15:00 Programa TFPGA: frecuencias alélicas, H, P, estadísticos F16:00 Programa DnaSP para datos de secuencia: pi, theta, D deTajima, selección.

Jaime Gasca y Enrique Scheinvar17:15 Structure Jaime Gasca y Enrique Scheinvar / LCG

Jueves 2 de Julio10:00 6) Endogamia, Luis10:30 7) Mutación Valeria Souza11:00 8) HGT, Valeria Souza11:50 9) Genética de poblaciones molecular Luis12:30 10) Varios genes Valeria Souza


Primera Sesión :Introducción a la GENÉTICADE POBLACIONES

como el fundamento de la EvoluciónMolecular


Construction of Molecular Evolution fromPOPULATION GENETICS (= MICROEVOLUTION)How behaves the genetic variation in the population (withinspecies).Is the study of the evolutionary forces that change thespecies in time.

Ecology EvolutionPopulationGenetics

Genetics

Evolutionary Ecology

MolecularEcology

MolecularEvolutionDevelopmentalgenetics

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Molecular Evolution: Darwin + Kimura:

+1) Present organisms are the result of an

evolutionary process, and all arerelated in the great phylogenetic tree.

2) Evolution is gradual3) Evolution is the result of the process of

Natural Selection

Motoo Kimura (1924-1994):There are large levels of geneticvariation, but it is neutral for naturalselection, and if there is any NS it ispurifying.Balance between Genetic Drift andMutation (that makes that thegenetic variation is lost or fixed) TLEM09 Dr. Luis Eguiarte 10

Motoo Kimura (1924-1994):Teoría Neutra: variación genética dentro de una especie


But to understand theideas and concerns ofKimura, we need first toreview the principles ofPopulation Genetics, both“classic” and “molecular”.


Classic Population Genetics:Deals with the behavior of“simple” (mendelian) genesin a population...

The basic model considersone locus with only twoforms, two alleles:A & a

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The allelic frequencies p & q vary within andamong populationspp frequency of allele Afrequency of allele A qq frequency of allelefrequency of allele a a

AaAA AA

AA

AA

AA

AAAA

AA AA

AA

AA

AA

AA

AA aa

AA

AA

AA

aa

AA

AA AA

Aa

Aa

Aa

Aa

Aa

Aa

Aa

AaAa

Aa

Aa

Aa Aa

Aa

Aa

AaAa

Aa

Aa

Aa

Aa

aa

aaaa

aa aa

aa

aaaaaa

aa

aa

aaaa

aa

aa

aa

Species

populations


N individuals

N individuals

N individuals

Time 0

Time 1

Time t

Frequencies de A= p0

Frequencies de A= p1

Frequencies de A = pt

EvolutionChange in the allelefrequencies in time(T. Dobzhansky, 1941)

Hardy-WeinbergEquilibrium:In a ideal population(large, sexualreproduction, diploid,random mating amongindividuals), theallelic frequencies do NOTchange


The Evolutionary Forces violate the equilibrium of Hardy-Weinberg and in consequence change the allelic frequencies (and then generate Evolution).

Genetic drift, Natural selection, Migration, Mutation

Other evolutionary process do not change the allelic frequencies, but are relevant:

Mating systems/ inbreedingRecombination


A little bit ofhistoryRonald A.Fisher(1890-1962)Genetical Theory ofnatural Selection(1930)Natural selectionis the moreimportant force.

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Sewall Wright(1889-1988)Evolution in Mendelianpopulations (1931)

Fundamental role ofGenetic Drift(random processes)Shifting balanceShifting balance(Adaptive topography)


J.B.S.Haldane(1882-1964)The Causes ofEvolution (1932)

An intermediatepoint of view, notonly Selection,not only Drift...


The initial motivation ofFisher, Wright andHaldane was to showthen Darwin andWallace ideas werecompatible withMendelian GeneticsNatural Selection:Differential survival andreproduction TLEM09 Dr. Luis Eguiarte 20

La Selección Natural según Darwin yWallace

a) Existe variación en las poblacionesnaturales

b) Esta variación incluye caracteresrelevante para la sobrevivencia y lareproducción

c) Parte de esta variación es heredable.

d) Si se cumplen los puntos anteriores,tenemos automáticamente un proceso deSelección Natural que adapta a losorganismos

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Darwin & Wallace had no idea on the basis ofheredity...

Fisher, Haldane & Wright show that NaturalSelection could be understood consideringdifferences in the fitness (“efficiency”) of the differentgenotypes:one locus, two alleles: AA, Aa, aafitnessfitness ( (adecuaciónadecuación))= W.We can predict well the behavior of the alleles inpopulations in cases with Mendelian inheritance andclear-cut patterns in W.


Biston betularia: color, 1 locus, 2 alleles


ciudadbosque


Selección a favor delrecesivo (polillas claras)

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Different kinds of Natural Selection

Natural Selection Viability

Gametic Selection

FecunditySelection

Sexualselection

Frequency-dependant Denso-dependent


Modes o kinds of selection:1) Stabilizing or Balancing 1) Stabilizing or Balancing (one locus two alleles)Eliminates both tails in the distribution

2) Directional 2) Directional (Biston betularia) o puryfing (if it elliminatesthe products of mutation /genetic load)

Eliminates one of the tails.

t

t


3) Disruptive selection3) Disruptive selectionEliminates the modal categories, the tails higher W

latter we will see with morecare each Mode of selection...

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Wright: Genetic drift

Random changes in the Allelic frequencies,due the the finite sizes of populations...Stronger in smaller populations!

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Generations

Alle

lic fr

eque

ncy

p

1

0.5

0

NNee =9=9

10 200

Alle

lic fr

eque

ncy

p

1

0.5

0

10 200 Generations

NNee =50 =50

Genetic DriftThe smallersmaller theNe, the changesare moreviolent and thepopulationsdiverge andgeneticvariation is lostat a faster rate.


Large original population, N Time 0

Frequency de A1 = p0

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4 5 67

8

91Small Population

(Size n) Time 1

Frequency de A1

Time0.0

0.5

1.0

p0

Increases the variance in the allelicfrequencies among populations (=genetic differentiation)

Reduces the genetic diversity withineach population,

Increase inbreeding, due to the smallsize of the populations

Genetic Drift

S. Wright basic model


Genetic DriftH= expected heterocigosity, a measure ofgenetic variationHHtt = ( 1- 1/2 = ( 1- 1/2 NNee))

tt HHooif Ne =1, the genetic variation decreases by1/2H in one generationif Ne = infinite, Ht=Ho; no changes

with enough time and Ne is finite Ht= 0:there is always some decrease in geneticvariation due to drift! (but low if Ne is large)


Genetic Drift:Differentiation among populations

Vqt = poqo [1-(1-1/2 Ne ) t ]

if Ne infinite, Vqt =0, no divergenceamong the populationsif t is very large, Vqt = poqo.The differentiation is faster/ larger if thepopulations are small(“less than 100 individuals”)

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Effective population size Ne:

The size of an ideal population that wouldexperience the same effects due to geneticgeneticdriftdrift than the actual population studied.

Generally assumed to be similar to the numbersimilar to the numberof reproductive adultsof reproductive adults, but it is more complex....


Genetic Flow:In population genetics it is considered a synonymof migration.migration.

The incorporation of genes into the gene poolof one population from one or more otherpopulations(Futuyma, 1986).

m= migration rate,probability that a randomlychosen gene in any subpopulation comes fromcomes froma migranta migrant.


Effective population size Ne is usually studied atthe same time that the gene flow:

NNee mm = number of migrants per = number of migrants pergeneration.generation.

If Ne m is large (larger than 1) the differentpopulations behave as a single unit: no divergence due todrift.

If Ne m is low (smaller than 1): each populationevolves independently by genetic drift.

A single effective migrant per generation isenough to inhibit any genetic divergence amongpopulation


How are the levels of GeneticVariation in Natural Population?

Models of the GeneticStructure of the Populations T. Dobzhansky (1955): from hisexperiments and data on drosophila flies heproposed the “balance model”:the population and even theindividual rich in genetic variation,heterozygous in most loci,maintained by balancing selection(advantage of the heterozygotes)

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“balanced model”each individual heterozygous for most ofthe loci...high level of genetic variation in thepopulationsmaintained by Natural Selection!


“ classic model” H.J.Mullerlow genetic variation inpopulations, almost “pure”...the variation is due to deleteriousmutation, and is eliminated veryfast and constantly by thepurifying selection


Levels of Genetic Variation in Natural PopulationsLewontin y Hubby (1966): average H= 0.12 y P= 30%in 18 loci in D. pseudoobscura... similar high levels in mostorganisms!!!:

Superficially seem to support the Balanced Model of T.Dobzhansky: neodarwinians happy!!!


Monocotiledóneas

Distribución regional

A. striata

A. striata spp. striata

A. striata ssp. falcata

A. cupreata

A. potatorum

A. xylonacantha

A. celsii albicans

A. hidalguensis

A. difformis

A. subsimplex

A. cerulata

A. deserti

A. lechuguilla

A. victoriae-reginae

Yucca filamentosa

Manfreda brachstachya

Perennes longevas

Perennes de vida corta

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

0.5

0.1 0.15 0.2 0.25 0.3 0.35 0.4 0.45 0.5

Fst

Heterocigosis

Agaves wild population are rich in genetic variation, have low genetic differentiation:Long lived perennial (somatic mutations accumulate), mating systems (out-crossers), long distance pollination by bats... Speciation mediated by allopatry andecological adaptation (physiology, reproductive ecology)

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He, expected heterozygosity P, percentage of polymophic loci

** * *

*

*

* * **

Genetic Variation in A. cupreata y A. potarorum


But the data were not conclusive (couldsupport any of the models)! 12 years latter,

Kimura Genetic Club Meeting Fukuoka,November 1967 (Nature, 1968):

Kimura two observationsa) The rate of evolution in proteins is almost

constant and high. (Zuckerkandl E. y L. Pauling(1962, 1965) Molecular Clock).

b) High levels of genetic variation in proteins(Lewontin y Hubby (1966)) (too high to be maintained only by balancing selection)


Constancias Tasas Kimura 1967:The evolutionary rates of proteins are

constant and too high to beexplained by selection (hemoglobin,cytochrome c, triosaphosfatedehydrogenase vertebrates)

An Amino acid substitution every 28 x 106 years, ifevery protein is formed by 100 aa, and thegenome of a mammal is 4 x 109 pb: a rate of onesubstitution per genome every 2 years: veryhigh to be explained by selection TLEM09 Dr. Luis Eguiarte 44

Kimura (Nature, 1968):

Kimura used Haldane (1957) conceptof “cost of selection”: It is necessaryto eliminate ca. 30 the size of thepopulation to change one allele forother by selection...

He suggested a maximum rate fornatural population of one changeevery 300 generations (s= 0.1)

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Cost of selection: eliminate ca. 30 the size of thepopulation to change one allele for other by selection...Maximum rate for natural population of one change every 300generations (s= 0.1)

The intensity of selection involve in themolecular change, if due to selection, would be100 of times higher....

If Ne ca. 500,000, it would have been necessarythat each parent leaves 3.27 x 10 6descendants to maintain the observedmolecular substitution rates...


KIMURA: Segregational Load.If all the variation is maintained by BalancingSelection:

If there are 2,000 polymorphic genes(reasonable, considering a total genome of 13,000genes and a polymorphism of 30%), and each genehas only and advantage of s=0.01The total fraction of eliminated individuals should be0.9999546, each adult should leave a progeny of22,000 to maintain the population (at constant size). I.e., we should be several times dead to maintainedthe observed genetic variation (if all due to balancingselection).


KIMURA: Genetic Variation.

Segregational Load.If all the variation is maintained by Balancing Selection:

If there are 2000 polymorphic genes (reasonable,considering a total genome of 13,000 genes and apolymorphism of 30%), and each gene has only andadvantage of s=0.01The total fraction of eliminated individuals should be0.9999546, each adult should leave a progeny of 22,000to maintain the population (at constant size).

I.e., we should be several times dead to maintained theobserved genetic variation (if all due to balancingselection).


Then what is happening?

To account to the levels of geneticvariation it is possible to suggestcomplex models of naturalselection, involving variable W,frequency dependence, each physicaldeath involving the elimination of manygenes, etc. Milkman, Maynard Smithand others...

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Then what is happening?To account to the levels of genetic variation it is possibleto suggest complex models of natural selection, involvingvariable W, frequency dependence, each physical deathinvolving the elimination of many genes, etc.

Or a more simple solution: What if themolecular evolution is controlled by abalance between mutation and drift?I.e., extend Wright´s ideas to theMolecular World (no only Mendel´s)


A simple solution: What if the molecularevolution is controlled by a balance betweenmutation and drift?I.e., extend Wright´s ideas to the MolecularWorld (no only Mendel´s)


W K


Kimura 1968, Evolutionary rate at themolecular level: Balance mutation- driftGenetic variation is the balance betweenmutation, that produces the variation, andgenetic drift, that eliminates the variation.Thus H is higher if we have larger v or N,

Infinite Alleles Model: IAM (for isozymes,microsatellites): each mutation produces a new allele:Heterozygosity = 4Nv / (4Nv +1)

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Infinite Alleles Model: IAM each mutationproduces a new allele:

Heterozygosity = 4Nv / (4Nv +1)

H= 0.12 and v= 1.5 x 10 -5 (Drosophila)

a Ne of 2,300 can maintain thepolymorphism without any selectionH=0.35 would need a Ne of 9,000.

H is higher if we have larger v or NTLEM09 Dr. Luis Eguiarte 54

Kimura (1969, 1971): Infinite SitesModel (ISM)Each mutation occurs in a different sitein the sequence, adequate for DNA.

k= substitution rate = 2Nvu

N= effective population sizev= mutation rateu= probability that an allele is fixed


Kimura Infinite Sites Model (ISM)Each mutation occurs in a different site in the sequence, adequate forDNA.

k= substitution rate = 2NvuN= effective population sizev= mutation rateu= probability that an allele is fixed

Selection: u = 2s (result of Fisher, 1930)k= 4Nsv: thus, to be constant k, we need thatNe , s and v always produce the same result!Not very likely...Higher rate of evolution if higher selection, Neor mutation rate... TLEM09 Dr. Luis Eguiarte 56

Kimura (1969, 1971): Infinite Sites Model (ISM)k= susbtitution rate = 2NvuN= effective population sizev= mutation rateu= probability that an allele is fixed

if there is no selection, the probability of fixation is thesame that the initial allelic frequency u = 1/2N(result of Wright 1931)

k= 2Nv/2N = vthe rate of evolution must be equal to the mutationrate!k=v!!!!In completely neutral genes, the substitution rate should be the same (ifmutation rates are similar).All this directly generates molecular clock!

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Kimura y Otha (1969):

How long take amutation to fixate

t= 4Ne(= total coalescent time...) with a standard deviation ofca. 2.5Ne

Ne smaller

but equal substitutionrates (k)

Ne larger


Kimura Neutral Theory: Similar to Muller´s ClassicModel:neutral genes, the main role of selection is to eleminate thedeleterious mutants, as PURIFYNG SELECTION....Thus Lewontin(1974, The genetic basis of evolutionary change)called the neutral theory the NEO- CLASSIC MODEL


Kimura´s neutral theoryIt should be considered as the NULL MODEL,

that describe the evolutionary behavior interms of population genetics when there isno selection

Is the corner-stone of the study of MolecularEvolution

But the really interesting thinghappen when it is not followedby our data!


But Kimura´s neutral theory does not workfor all molecular data.

The really interesting thing happen when it isnot followed by our data!

Heterogeneity in substitution rates among lineages, in time and amongIn general we have less geneticvariation than expected by IAMThere are ample evidences andsignals in the sequence that indicatesdifferent kinds of selection: purifying,balancing and directional!

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In species/populationwith a largeNe we havefar lessgeneticvariation thanthe predictedby InfiniteAlleles Model

Predicted

Observed!!


Fin Primera Parte

teoría genética de poblacionescimi.ccg.unam.mx/~vinuesa/tlem09/docs/1introduccionfin2.pdfmuy...

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