1introduccion Genpoblaciones

Taller Latinoamericano de Evolución Nueva Guía Mínima para
Molecular
principiantes a la Genética de
Genética de Poblaciones y
Poblaciones
EVOLUCION MOLECULAR
Luis E. Eguiarte, Valeria Souza
Enrique Scheinvar y Jaime
Gasca Luis E. Eguiarte, Valeria Souza
Enrique Scheinvar y Jaime Gasca
Departamento de Ecología Evolutiva
Instituto
TLEM09
de Ecología, UNAM
Dr. Luis Eguiarte 1 TLEM09 Dr. Luis Eguiarte 2
La evolución es el corazón de la biología En estas sesiones vamos a revisar

moderna. muy brevemente la teoría de la
Debido a los métodos para obtener datos Genética de

moleculares y a los genomas que se están
completando, la Evolución Molecular se está
Poblaciones que da
desarrollando impresionantemente, y su fundamento a la Evolución Molecular,
importancia es central para interpretar y y algunas de sus aplicaciones
analizar correctamente los datos provenientes empíricas en el análisis de datos
de proyectos genómicos y sus derivados (i.e., relevantes para resolver problemas
metagenómica, proteómica, bioinformática, evolutivos y ecológicos.
etc.).
TLEM09 Dr. Luis Eguiarte 3 TLEM09 Dr. Luis Eguiarte 4
1
Programa
OBJETIVOS DE LA SECCION 10:00 1)Introducción a la Genética de Poblaciones
10:45 2) Hardy-Weinberg y estimación de las frecuencias alélicas y la
variación genética Luis Eguiarte
Que alumnos con experiencia 11:50 3) Selección Natural Luis y Valeria

12:30 4) Deriva Génica y el tamaño efectivo de las poblaciones
previa en genética se familiaricen 13:00 5) Flujo génico y estructura de las poblaciones Luis Eguiarte
y entiendan la teoría básica y la 15:00 Programa TFPGA: frecuencias alélicas, H, P, estadísticos F

16:00 Programa DnaSP para datos de secuencia: pi, theta, D de
aplicaciones fundamentales de Tajima, selección.
Jaime Gasca y Enrique Scheinvar
Genética de Poblaciones y su 17:15 Structure Jaime Gasca y Enrique Scheinvar / LCG
relación con la Evolución Jueves 2 de Julio

10:00 6) Endogamia, Luis
Molecular y los avances recientes 10:30 7) Mutación Valeria Souza
11:00 8) HGT, Valeria Souza
como coalescencia y filogeografía
TLEM09 Dr. Luis Eguiarte 5
11:50 9) Genética de poblaciones molecular Luis
12:30 10) Varios genes Valeria Souza
Primera Sesión : Construction of Molecular Evolution from

POPULATION GENETICS (= MICROEVOLUTION)
Introducción a la GENÉTICA How behaves the genetic variation in the population (within
species).
DE POBLACIONES Is the study of the evolutionary forces that change the
species in time.
Evolutionary
Ecology Ecology
como el fundamento de la Evolución Evolution
Molecular Population
Genetics
Molecular
Molecular Genetics Evolution
Ecology Developmental
genetics
2
Molecular Evolution: Darwin + Kimura: Motoo Kimura (1924-1994):
Teoría Neutra:
variación genética dentro de una especie
+
1) Present organisms are the result of an Motoo Kimura (1924-1994):
evolutionary process, and all are There are large levels of genetic
related in the great phylogenetic tree. variation, but it is neutral for natural
2) Evolution is gradual selection, and if there is any NS it is
3) Evolution is the result of the process of purifying.
Natural Selection Balance between Genetic Drift and
Mutation (that makes that the
TLEM09 Dr. Luis Eguiarte genetic variation is lost or fixed)
9 TLEM09 Dr. Luis Eguiarte 10
Classic Population Genetics:

But to understand the
ideas and concerns of Deals with the behavior of
Kimura, we need first to “simple” (mendelian) genes
review the principles of in a population...
Population Genetics, both
The basic model considers
“classic” and “molecular”.
one locus with only two
forms, two alleles:
A&a
3
The allelic frequencies p & q vary within and Evolution
N individuals Time 0
Change in the allele
among populations Frequencies de A= p 0
frequencies in time
p frequency of allele A q frequency of allele a (T. Dobzhansky, 1941)
Species N individuals
Time 1 Hardy-Weinberg
Frequencies de A= p 1 Equilibrium:
In a ideal population
populations AA
Aa
aa
(large, sexual
Aa aa
Aa reproduction, diploid,
AA
Aa
AA A
a
a AA
aa
Aa
aa random mating among
A AA Aa
aa
AA
Aa
Aa
A
Aa aa
aa
AA
Aa Aa
individuals), the
A AA
AA
AA AA Aa
AA
AA
Aa
AA N individuals Time t allelic frequencies do NOT
aa Frequencies de A = p t
Aa
Aa
AA Aa
Aa
AA
aa
aa
aa
aa
change
Aa aa AA
AA Aa aa aa
AaAa aa
Aa aa
The Evolutionary Forces violate the equilibrium of Hardy- A little bit of

Weinberg and in consequence change the allelic frequencies history
(and then generate Evolution).
Ronald A.
Genetic drift,
Natural selection, Fisher
Migration, (1890-1962)
Mutation Genetical Theory of
Other evolutionary process do not change the allelic natural Selection
frequencies, but are relevant: (1930)
Mating systems/ inbreeding
Recombination
Natural selection
is the more
TLEM09 Dr. Luis Eguiarte 15 TLEM09 Dr. Luis Eguiarte
important force. 16
4
Sewall Wright J.B.S.
(1889-1988)
Evolution in Mendelian
Haldane
populations (1931) (1882-1964)
The Causes of
Fundamental role of
Genetic Drift
Evolution (1932)
(random processes)
An intermediate
Shifting balance
(Adaptive topography) point of view, not
only Selection,
not only Drift...
The initial motivation of La Selección Natural según Darwin y

Wallace
Fisher, Wright and
Haldane was to show a) Existe variación en las poblaciones
then Darwin and naturales
b) Esta variación incluye caracteres
Wallace ideas were
relevante para la sobrevivencia y la
compatible with reproducción
Mendelian Genetics c) Parte de esta variación es heredable.
Natural Selection: d) Si se cumplen los puntos anteriores,

tenemos automáticamente un proceso de
Differential survival and Selección Natural que adapta a los
organismos
TLEM09
reproduction
Dr. Luis Eguiarte 19 TLEM09 Dr. Luis Eguiarte 20
5
Biston betularia: color, 1 locus, 2 alleles
Darwin & Wallace had no idea on the basis of
heredity...
Fisher, Haldane & Wright show that Natural

Selection could be understood considering
differences in the fitness (“efficiency”) of the different
genotypes:
one locus, two alleles: AA, Aa, aa
(adecuación))= W.
fitness (adecuación
We can predict well the behavior of the alleles in
populations in cases with Mendelian inheritance and
clear-cut patterns in W.
bosque
ciudad
Selección a favor del

recesivo (polillas claras)
6
Different kinds of Natural Selection Modes o kinds of selection:
1) Stabilizing or Balancing (one locus two alleles)
Natural Fecundity
Viability Eliminates both tails in the distribution
Selection Selection
Sexual Gametic t
selection Selection
2) Directional (Biston betularia) o puryfing (if it elliminates
the products of mutation /genetic load)
Eliminates one of the tails.
Frequency-dependant Denso-dependent
t
3) Disruptive selection Wright: Genetic drift

Eliminates the modal categories, the tails higher W
Random changes in the Allelic frequencies,
due the the finite sizes of populations...
Stronger in smaller populations!
latter we will see with more

care each Mode of selection...
7
1
Allelic frequency p
Ne =9 Genetic Drift
Large original population, N Time 0
Genetic Drift S. Wright basic

Frequency de A1 = p 0
0.5
The smaller the model
Ne, the changes Small Population
are more (Size n)
1
9 Time 1
0
0 10
20
violent and the 2
3 7
8
Generations 4 5 6
populations
Increases the variance in the allelic
1
diverge and
Ne =50 frequencies among populations (=
Allelic frequency p
1.0
genetic genetic differentiation)
variation is lost p0 Reduces the genetic diversity within

0.5 each population,
Frequency de A1
0.5
at a faster rate.
Increase inbreeding, due to the small
0.0 size of the populations
Time
0
0 10
TLEM09 Dr. Luis Eguiarte 20 29 TLEM09 Dr. Luis Eguiarte 30
Generations
Genetic Drift Genetic Drift:

H= expected heterocigosity, a measure of Differentiation among populations
genetic variation Vqt = poqo [1-(1-1/2 Ne ) t ]
t
Ht = ( 1- 1/2 Ne) Ho
if Ne infinite, Vqt =0, no divergence
if Ne =1, the genetic variation decreases by among the populations
1/2H in one generation if t is very large, Vqt = poqo.
if Ne = infinite, Ht=Ho; no changes
The differentiation is faster/ larger if the
with enough time and Ne is finite Ht= 0:
populations are small
there is always some decrease in genetic
(“less than 100 individuals”)
variation due to drift! (but low if Ne is large)
8
Genetic Flow:
Effective population size Ne:
In population genetics it is considered a synonym
The size of an ideal population that would of migration.
experience the same effects due to genetic
drift than the actual population studied. The incorporation of genes into the gene pool
of one population from one or more other
populations
Generally assumed to be similar to the number (Futuyma, 1986).
of reproductive adults,
adults but it is more complex....
m= migration rate,
probability that a randomly
chosen gene in any subpopulation comes from
a migrant.
migrant
Effective population size Ne is usually studied at How are the levels of Genetic
the same time that the gene flow: Variation in Natural Population?
Ne m = number of migrants per
generation. Models of the Genetic
If Ne m is large (larger than 1) the different
Structure of the Populations
populations behave as a single unit: no divergence due to T. Dobzhansky (1955): from his
drift. experiments and data on drosophila flies he
If Ne m is low (smaller than 1): each population proposed the “balance model”:
evolves independently by genetic drift. the population and even the
individual rich in genetic variation,
A single effective migrant per generation is heterozygous in most loci,
enough to inhibit any genetic divergence among maintained by balancing selection
population (advantage of the heterozygotes)
9
“ classic model” H.J.
“balanced model”
each individual heterozygous for most of
Muller
low genetic variation in
the loci... populations, almost “pure”...
high level of genetic variation in the the variation is due to deleterious
populations mutation, and is eliminated very
maintained by Natural Selection! fast and constantly by the
purifying selection
0.5
Levels of Genetic Variation in Natural Populations 0.45 Distribución regional
Lewontin y Hubby (1966): average H= 0.12 y P= 30% 0.4 Perennes de vida corta
Monocotiledóneas
in 18 loci in D. pseudoobscura... similar high levels in most 0.35

organisms!!!: 0.3
A. striata spp. striata
Fst 0.25 Perennes longevas

A. victoriae-reginae
Superficially seem to support the Balanced Model of T. 0.2 A. striata

Yucca filamentosa
Dobzhansky: neodarwinians happy!!! 0.15 A. deserti
A. celsii albicans
A. cupreata
0.1 A. subsimplex
A. difformis
A. cerulata A. striata ssp. falcata
A. potatorum A. lechuguilla
0.05
A. hidalguensis Manfreda brachstachya
A. xylonacantha
0
0.1 0.15 0.2 0.25 0.3 0.35 0.4 0.45 0.5
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 and
TLEM09 Dr. Luis Eguiarte 39 ecological
TLEM09adaptation (physiology, reproductive ecology)
Dr. Luis Eguiarte 40
10
Genetic Variation in A. cupreata y A. potarorum
But the data were not conclusive (could
support any of the models)! 12 years latter,
He, expected heterozygosity P, percentage of polymophic loci Kimura Genetic Club Meeting Fukuoka,
November 1967 (Nature, 1968):
* ** * Kimura two observations

*
*
**
*
* a) 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: Kimura (Nature, 1968):
The evolutionary rates of proteins are Kimura used Haldane (1957) concept
constant and too high to be of “cost of selection”: It is necessary
explained by selection (hemoglobin, to eliminate ca. 30 the size of the
cytochrome c, triosaphosfate population to change one allele for
dehydrogenase vertebrates) other by selection...
An Amino acid substitution every 28 x 106 years, if
every protein is formed by 100 aa, and the He suggested a maximum rate for
genome of a mammal is 4 x 109 pb: a rate of one natural population of one change
substitution per genome every 2 years: very every 300 generations (s= 0.1)
high to be explained
TLEM09 Dr. Luis by selection
Eguiarte 43 TLEM09 Dr. Luis Eguiarte 44
11
Cost of selection: eliminate ca. 30 the size of the KIMURA: Segregational Load.
population to change one allele for other by selection...
Maximum rate for natural population of one change every 300 If all the variation is maintained by Balancing
generations (s= 0.1) Selection:
If there are 2,000 polymorphic genes
The intensity of selection involve in the (reasonable, considering a total genome of 13,000
molecular change, if due to selection, would be genes and a polymorphism of 30%), and each gene
100 of times higher.... has only and advantage of s=0.01
The total fraction of eliminated individuals should be
0.9999546, each adult should leave a progeny of
If Ne ca. 500,000, it would have been necessary 22,000 to maintain the population (at constant size).
that each parent leaves 3.27 x 10 6
I.e., we should be several times dead to maintained
descendants to maintain the observed
the observed genetic variation (if all due to balancing
molecular
TLEM09
substitution rates...
Dr. Luis Eguiarte 45 selection).
KIMURA: Genetic Variation. Then what is happening?

Segregational Load. To account to the levels of genetic
If all the variation is maintained by Balancing Selection:
If there are 2000 polymorphic genes (reasonable, variation it is possible to suggest
considering a total genome of 13,000 genes and a
polymorphism of 30%), and each gene has only and
complex models of natural
advantage of s=0.01 selection, involving variable W,
The total fraction of eliminated individuals should be
0.9999546, each adult should leave a progeny of 22,000
frequency dependence, each physical
to maintain the population (at constant size). death involving the elimination of many
I.e., we should be several times dead to maintained the
genes, etc. Milkman, Maynard Smith
observed genetic variation (if all due to balancing and others...
selection).
12
Then what is happening? A simple solution: What if the molecular
evolution is controlled by a balance between
To account to the levels of genetic variation it is possible mutation and drift?
to suggest complex models of natural selection, involving I.e., extend Wright´s ideas to the Molecular
variable W, frequency dependence, each physical death
World (no only Mendel´s)
involving the elimination of many genes, etc.
Or a more simple solution: What if the

molecular evolution is controlled by a
balance between mutation and drift?
I.e., extend Wright´s ideas to the
Molecular World (no only Mendel´s)
W K
Kimura 1968, Evolutionary rate at the
molecular level: Balance mutation- drift
Genetic variation is the balance between
mutation, that produces the variation, and
genetic 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)
13
Infinite Alleles Model: IAM each mutation Kimura (1969, 1971): Infinite Sites
produces a new allele: Model (ISM)
Each mutation occurs in a different site
Heterozygosity = 4Nv / (4Nv +1) in the sequence, adequate for DNA.
H= 0.12 and v= 1.5 x 10 -5 (Drosophila)
k= substitution rate = 2Nvu
a Ne of 2,300 can maintain the
polymorphism without any selection
H=0.35 would need a Ne of 9,000. N= effective population size
v= mutation rate
H is higher if we have larger v or N u= probability that an allele is fixed
Kimura Infinite Sites Model (ISM) Kimura (1969, 1971): Infinite Sites Model (ISM)
Each mutation occurs in a different site in the sequence, adequate for k= susbtitution rate = 2Nvu
DNA. N= effective population size
v= mutation rate
k= substitution rate = 2Nvu u= probability that an allele is fixed
N= effective population size if there is no selection, the probability of fixation is the
v= mutation rate
same that the initial allelic frequency u = 1/2N
u= probability that an allele is fixed
(result of Wright 1931)
Selection: u = 2s (result of Fisher, 1930) k= 2Nv/2N = v
k= 4Nsv: thus, to be constant k, we need that the rate of evolution must be equal to the mutation
Ne , s and v always produce the same result! rate!
Not very likely... k=v!!!!
Higher rate of evolution if higher selection, Ne In completely neutral genes, the substitution rate should be the same (if
mutation rates are similar).
orTLEM09
mutation rate... Dr. Luis Eguiarte 55 TLEM09 Dr. Luis Eguiarte
All this directly generates molecular clock!
56
14
Kimura y Otha (1969): Kimura Neutral Theory: Similar to Muller´s Classic
Model:
How long take a neutral genes, the main role of selection is to eleminate the
mutation to fixate deleterious mutants, as PURIFYNG SELECTION....
Thus Lewontin(1974, The genetic basis of evolutionary change)
called the neutral theory the NEO- CLASSIC MODEL
t= 4Ne
(= total coalescent time...)
with a standard deviation of
ca. 2.5Ne
Ne smaller
but equal substitution

rates (k)
Ne larger
Kimura´s neutral theory But Kimura´s neutral theory does not work
for all molecular data.
It should be considered as the NULL MODEL, The really interesting thing happen when it is
that describe the evolutionary behavior in not followed by our data!
terms of population genetics when there is Heterogeneity in substitution rates among
no selection lineages, in time and among
Is the corner-stone of the study of Molecular In general we have less genetic
Evolution variation than expected by IAM
There are ample evidences and
But the really interesting thing signals in the sequence that indicates
happen when it is not followed different kinds of selection: purifying,
by our data! balancing and directional!
15
In species
/population
Fin Primera Parte
with a large
Ne we have Predicted
far less
genetic
Observed!!
variation than
the predicted
by Infinite
Alleles Model
16

1introduccion Genpoblaciones

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Taller Latinoamericano de Evolución Nueva Guía Mínima para

La evolución es el corazón de la biología En estas sesiones vamos a revisar

Debido a los métodos para obtener datos Genética de

Que alumnos con experiencia 11:50 3) Selección Natural Luis y Valeria

y entiendan la teoría básica y la 15:00 Programa TFPGA: frecuencias alélicas, H, P, estadísticos F

relación con la Evolución Jueves 2 de Julio

Primera Sesión : Construction of Molecular Evolution from

Classic Population Genetics:

TLEM09 Dr. Luis Eguiarte 13 TLEM09 Dr. Luis Eguiarte 14

The Evolutionary Forces violate the equilibrium of Hardy- A little bit of

The initial motivation of La Selección Natural según Darwin y

Natural Selection: d) Si se cumplen los puntos anteriores,

Fisher, Haldane & Wright show that Natural

TLEM09 Dr. Luis Eguiarte 21 TLEM09 Dr. Luis Eguiarte 22

Selección a favor del

3) Disruptive selection Wright: Genetic drift

latter we will see with more

Genetic Drift S. Wright basic

variation is lost p0 Reduces the genetic diversity within

Genetic Drift Genetic Drift:

TLEM09 Dr. Luis Eguiarte 37 TLEM09 Dr. Luis Eguiarte 38

in 18 loci in D. pseudoobscura... similar high levels in most 0.35

Fst 0.25 Perennes longevas

Superficially seem to support the Balanced Model of T. 0.2 A. striata

* ** * Kimura two observations

b) High levels of genetic variation in proteins

Constancias Tasas Kimura 1967: Kimura (Nature, 1968):

KIMURA: Genetic Variation. Then what is happening?

Or a more simple solution: What if the

Infinite Alleles Model: IAM (for isozymes,

TLEM09 Dr. Luis Eguiarte 51 TLEM09 Dr. Luis Eguiarte 52

but equal substitution

TLEM09 Dr. Luis Eguiarte 57 TLEM09 Dr. Luis Eguiarte 58

TLEM09 Dr. Luis Eguiarte 61 TLEM09 Dr. Luis Eguiarte 62

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