Quantitative Genetic Components As a Function
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The Unit of Selection: the level of genetic organization that allows the prediction of the genetic response to selection
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Transcript of Quantitative Genetic Components As a Function
The Unit of Selection: the level of genetic organization that allows the prediction of the
genetic response to selection
Fitnesses in population genetics are assigned to genotypic classes of individuals rather than
individuals themselves; the genotypic classes can be single locus genotypes, or two locus
genotypes, etc.The unit of selection is the level of genetic organization to which a fitness phenotype can be assigned that allows the response to
selection to be accurately predicted.This means that the unit of selection must have
genetic continuity across the generations.
Meiosis and Sexual Reproduction Break Up Multilocus Complexes in
Outbreeding Species (as a function of both physical recombination and
assortment, and system of mating), Which Reduces the Size of the Unit of
Selection.
Selection Upon Epistatic Complexes Builds Up Higher Level Units.
The Unit of Selection is a dynamic compromise between selection building
up complexes and effective recombination breaking them down.
The unit of selection can change as the population evolves or experiences altered demographic conditions.
Quantitative Genetic Components As a Function of Allele Frequencies: A. 4 allele at ApoE is
Rare, A2 at LDLR Common; B. Reversed
ApoE & LDLR ApoE LDLR0.00
10.00
20.00
30.00
40.00
50.00
60.00
A.Additive Variance
Dominance Variance
Epistatic Variance
Genetic Variance {
ApoE & LDLR ApoE LDLR0.00
5.00
10.00
15.00
20.00
25.00
30.00
35.00
B.
Epistasis Is Present, But Recombination Is High: The Unit of Selection Is A Single Locus.
Epistasis Strong, Recombination Weak; The Unit of Selection Is A Multilocus Complex
Persistence of Fetal Hemoglobin Ameliorates Impact of Sickle Cell Anemia
Epistasis Strong, Recombination Intermediate; The Unit of Selection Is A Multilocus Complex, But Only Selected
Haplotype Shows Extensive D: Must Be Constantly Built Up By Selection
Various Alleles At Loci in the MHC Complex Are Predictive of Multiple Sclerosis, an Autoimmune Disease
Extended Haplotype Homozygosity
Gregersen, J. W., K. R. Kranc, X. Ke, P. Svendsen, L. S. Madsen, A. R. Thomsen, L. R. Cardon, J. I. Bell, and L. Fugger. 2006. Functional epistasis on a common MHC haplotype associated with multiple sclerosis. Nat. 443:574-577.
(Templeton et al.,AMJHG 66: 69-83, 2000)
0
2
4
6
8
10
12
14
16
18
0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000
Number of Recombination Events
Region of Overlap of the Inferred Intervals Of All 26 Recombination and Gene Conversion Events Not Likely to Be Artifacts.
LD in the human LPL geneRecombination is notUniformly distributed in thehuman genome, but rather isConcentrated into “hotspots” thatSeparate regions of low to noRecombination.
Significant |D’|
Non-significant |D’|
Too Few Observationsfor any |D’| to be significant
Neutral Genetic Drift, Stable
Population Size
Neutral Genetic Drift, Expanding Population Size
Negative Selection
Positive (Directional) Selection or Bottleneck
Positive (Diversifying) Selection or Subdivision
Haplotype Network in 5’ Region of LPL
5'-1 5'-2 5'-823J
8J14J44N
3
17
13 7 84
5 16 9 10 2
14
36J12
6
15
188
49N
84R
175'-3
5'-4
17
5'-5
5'-6
5'-7
16
4
4
6
32J
9 10
Positive (Directional)
Selection
Haplotype Network in 3’ Region of LPL
3'-9
56N
53N
3'-4
64J 43J
59N
3'-12 19J
16J
30J
54N
41N 42N
40J
37J
59 44
50 38 54
50
64
42
65
4661
58
6566
6340
53 6724J34J
4136 69
T-136J
38 39 41 43 44 46 47 60 5764T-4
69
3'-10
3'-11
45J
53
59
75R
53
36
55
58
61
38J
51
55
40
45
3756
3'-8
8J 14J
T-3
48
52
29J44
55
35J
41
T-2
49
68
12J
3'-636
46
58 55
49
81R
39J
49N
50N
78R
46N
503'7
62
4450
26J
61
32J40
36
41 58 67
49 20J
77R
67N 48N
42
41
62
59
3'-161N
60N
56
59 45 63 3'-2
9N44N
38 3863
56 56
3'-351N 63
63 3'-5
53 53
28J
4259 45
5544
40 53
42
53
42
Positive (Diversifying)
Selection
Recombinantsand Post-
Recombinational
Evolutionin LPL 6NR
68R26
27
6
18
14
33J X Node l
15
11
17
21
31
5987R X T-2
82R29
2315J
8J
16
55844
u
14J
4
Node s X Node r X 62N X 45J X 83R
Node m X 73R
55N
23 53
69
1
19
29
35
36
5557 58 61
38J
T-2 X Node x
4
6
28
32J
Node m
61
26J
14
15
6
19402935
36
41
58
67
3
18
25
30
4920J
63N 71R62
Node i X Node k
Node j X 28J
Node v X T-3
Node h X T-4
Node f X Node e X T-2
13J
72R
23
3469
59
58N
75R
53
T-4 X Node w
Node g X T-2
2JNR X T-2
11J 17J X T-39 10
19 217
11(19-25)
57J
22J
35J
22
24
28
35
4155
25(17-25)
T-1 X
6(16-19)
14(16-31)
12(5-9)
13(58-63)
24(18-29)
1236J
GeneConversion
80R
18J
30
55
49
81R 39J
77R
67N48N44
26
42
4053
2741
Node a X 1JNR
4(13-29)
44N
3
1738
T-2 X Node t
23(19-33)
26(23-34)
Node a X 2JNR
2(13-29)
5NR X T-220
26
27
74R
3JNR7NR
85R54N 41N
42N
51N63
31
59
20
44 19
30 50
33
31
38
541(27-29)
24J 56
88R
9(29-35)
10(21-29)
8(29-34)
18(33-35)
49N
46N30 50
172642q
19(33-44)
79R X T-2
16(29-31)
84R 21J
86R
62
35
413
23
50N
X T-2
X 4JN
3(33-35)
69R
78R29 30 50
47N
27(27-33)
66N
53
59
28(19-33)
29(64-68)
Node b X Node c
76R
60
5(56-61)
T-2 X Node n
12J
25J30
35
36
4658
15(16-29)
T-2 X Node p
17(33-35)
65N
7(19-29)
20(33-44)
22(33-35)
21(5-9)
62
12 Recombination Events Occurred Between T-1
Haplotypes With T-2,3, or 4 Haplotypes
In All 12 Cases, the 5’ End Was Of The T-1 Type. Under Neutrality, This Has A
Probability of (1/2)12 = 0.002.
Therefore, the 5’ End Experienced A Selective Sweep Enhanced By Recombination
The Unit of Selection:
For LPL, the unit of selection is smaller than the gene because of the recombination hotspot in the
middle of this locus.
Target of Selection:the level of biological
organization that displays the phenotype under selection.
Targets Below The Level of The Individual:
Example: the t-complex in mice and meiotic drive.
The t-complex in mice
20 cM region of chromosome17 of the mouse genome that constitutes about 1% of the mouse genome. Inversions suppress most recombination in this region that contains genes for sperm
motility, capacitation, binding to the zona pellucida of the oocyte, binding to the oocyte membrane, and penetration of the oocyte –
and also notochord development. Because of strong epistasis and low recombination, it behaves as a unit of selection that can be
modeled as a single locus.
The t-complex in mice
p’=Gtt+ kGTt=Gtt+1/2GTt-1/2GTt+kGTt=p+GTt(k-1/2)
p=p’-p=GTt(k-1/2)
Adult Populationtt Tt TT
Gtt GTt GTT
Mechanisms ofProducing Gametes
(Violation of Mendel's First Law)
t T
1 k 1
p' = Gtt + kGTt q' = GTT + (1-k)GTt
Gene Pool(Populationof Gametes)
(1-k)
1/2
Need this 1/2 for t-alleles becausethe meiotic drive is expressedonly in males.
The t-complex in miceA single Unit of Selection can have more than one Target of Selection
At the individual level, the t-alleles affect viability:
TT
1
Tt
1-s
tt
0
The t-complex in miceA single Unit of Selection can have more than one Target of Selection
TT
1
Tt
1-s
tt
0
Assume random mating; then meiotic drive changesThe gamete frequencies to p’=p+pq(k-1/2):
€
at = ′ q (1− s− w )+ ′ p (−w )
Where
€
w = ′ q 2 + 2 ′ p ′ q (1− s)
After fertilization, selection at the individual level is governed by:
The t-complex in miceThe total change in allele frequency is:
€
p = ′ ′ p − p = ′ ′ p − ′ p + ′ p − p
= ′ p at
w + pq k − 1
2( )
Change due to selection at the level of the gamete; always positive.
Change due to selection at
the level of the individual;
always negative.
The t-complex in mice
Molecular Drive (Dover)
“The nuclear genomes of eukaryotes are subject to a continual turnover through unequal exchange, gene
conversion, and DNA transposition. … Both stochastic
and directional processes of turnover occur within nuclear
genomes.”
Gene Conversion
Holliday ModelDouble-Strand Break Model
Unequal gene conversion Equal gene conversion
Gene Conversion Can Be A Major Source of Genetic Variation in Multigene Families
Holliday ModelDouble-Strand Break Model
Unequal gene conversion Equal gene conversion
Takuno, S. et al. Genetics 2008;180:517-531
Gene conversion increases the number of haplotypes in multigene systems, particularly when the tract length is short. If there is diversifying selection (e.g., MHC, S alleles), selection often favors these new haplotypes, even if the source of the converted segment is a pseudogene.
Walsh (Genetics 105: 461-468, 1983)1 Locus, 2 Allele Model (A and a) Such That:
= the probability of an unequal gene conversion event
= the conditional probability that a converts to A given an unequal conversion occurs
1-=the probability of getting a 1:1 ratio of Mendelian Segregation
=probability of segregation yielding only A alleles
=probability of segregation yielding only a alleles
Then the segregation ratio A:a in Aa heterozygotes is:
1/2(1- )+ 1/2(1- )+ or k:1-k where k= 1/2(1- )+
A is fixed if k> 1/2, and a is fixed if k< 1/2, at a rate dependent upon the frequency of heterozygotes in the population
Extension of Walsh’s Model To Include Molecular Drive Drift (Nev), and System of
Mating/Population Subdivision (f)
Probability of Fixation of a Neutral Mutation = 1/(2N)
Probability of Fixation of a Mutation With Biased Gene Conversion =
Thus, the evolutionary impact of gene conversion interacts with and is modulated by traditional evolutionary forces. For example, as f goes down, the probability of fixation of a biased gene conversion allele goes up.
€
2(2k −1)Nev (1− f )
N when 4Nev (1− f )(2k −1) >>1
(2k −1)Nev (1− f )e4 Nev (2k−1)(1− f )
N when 4Nev (1− f )(2k −1) <<1
Molecular Factors Do Not Override Traditional Evolutionary Forces; Rather, They Strongly Interact With Them
Transposition
Transposition: Mutator
A flower of Petunia hybrida transposon genotype derived from the inbred line W138 showing a large number of white-pink sectors (see Ramulu et al., ANL10: 19-21, 1998).
Transposition: Evolutionary Co-option (or exaptation)
Piriyapongsa, J. et al. Genetics 2007;176:1323-1337
Percentage of TE-derived residues in miRNA genes.MICRORNAS (miRNAs) are small, 22-nt-long,
noncoding RNAs that regulate gene expression. In animals, miRNA genes are transcribed into primary miRNAs (pri-miRNAs) and processed by Drosha to yield 70- to 90-nt pre-miRNA transcripts that form hairpin structures. Mature miRNAs are liberated
from these longer hairpin structures by the RNase III enzyme Dicer. Drosha acts in the nucleus,
cleaving the pri-miRNA near the base of the hairpin stem to yield the pre-miRNA sequence. The pre-
miRNA is then exported to the cytoplasm where the stem is cleaved by Dicer to produce a miRNA
duplex. One strand of this duplex is rapidly degraded and only the mature 22-nt miRNA
sequence remains. The mature miRNA associates with the RNA-induced silencing complex (RISC),
and together the miRNA–RISC targets mRNAs for regulation. miRNAs have been implicated in a
variety of functions, including developmental timing, apoptosis, and hematopoetic differentiation
Human miRNA gene sequences
Human mature miRNA sequences
Transposition: Evolutionary Co-option (or exaptation)
TE’s (brown segments) have been co-opted for both transcriptional and post-transcriptional regulation. Can build up regulatory networks in evolution.
Feschotte. 2008. Nat Rev Genet 9:397-405.
Transposition: Direct Phenotypic Effects
Transposition: Horizontal & Vertical Transfer
Anxolabehere et al. Mol. Biol. Evol. 5: 252-269, 1988
Transposition: Horizontal Transfer
Comparison of a) species and b) P-element phylogenetic histories. Diagonal lines unite P-element clades with the species from which they were sampled. From Silva, J.C. and M.G. Kidwell. Horizontal Transfer and Selection in the Evolution of P Elements. Mol Biol Evol 17(10): 1542-1557, 2000.
Transposition: Horizontal Transfer
Transposition: Horizontal Transfer
Unequal Exchange
Unequal Exchange Can Also Create New Types of Genes
Unequal Exchange: Concerted Evolution
Gene Duplication WithoutConcerted Evolution
Gene Duplication WithConcerted Evolution
Unequal Exchange: Concerted Evolution
Gentile, K.L., W.D. Burke and T.H. Eickbush. Multiple Lineages of R1 Retrotransposable Elements Can Coexist in the rDNA Loci of Drosophila. Mol Biol Evol 18(2): 235-245, 2001.
Unequal Exchange: Concerted EvolutionModel of Weir et al. J. Theor. Biol. 116: 1-8, 1985
n=number of repeats in a multigene family
N=ideal population size
=neutral mutation rate per repeat per generation
1/(2N)=probability of fixation of new mutant at homologous sites
=probability of a repeat converting a paralogous repeat to its state (Molecular drive exists such that a neutral mutant will eventually go to fixation at all paralogous sites as well)
1/(2Nn)=probability of fixation of a new mutant at all homologous and paralogous sites
2Nn=expected number of new mutants per generation
Rate of neutral evolution in multigene family evolving in concert =
(2Nn1/(2Nn)== Same neutral rate as if it were a single locus!
Unequal Exchange: Concerted EvolutionRecall that the time to neutral coalescence of all homologous copies of a gene to a common ancestral form = 4N
The time to neutral coalescence of all homologous and paralogous copies in a multi-gene family to a common ancestral form = 2/(1-) where is the Maximum of one of two forms:
1. 1-1/(2N) or 2. 1-
In the first case [>1/(2N); that is molecular drive is more powerful than drift], then t= 2/{1-[1-1/(2N)]} = 2/[1/(2N)] = 4N = the same rate of coalescence as a single locus and no effect of !
In the second case (<1/(2N); that is molecular drive is weak compared to drift), dominates the coalescence process!
Therefore, molecular drive has its biggest evolutionary impact when it is Weak compared to drift. Under these conditions, the multigene family will have much diversity among paralogous copies within a chromosome.
Concerted Evolution With Selection
Simple co-dominant model:start with fixation of a allele, fitness aa is 1mutation creates A allele, with fitness of
Aa being 1+s, and AA 1+2s Under Neutrality, Probability of Fixation of A is:
1/(2N)
Kimura showed that fixation probability here is:
Where p is the initial frequency; that is, 1/(2N)
Concerted Evolution With Selection
Mano, S. et al. Genetics 2008;180:493-505 Considered a similar model, but now assume that we have a multigene family with n copies and that the mutant A allele can spread due to molecular mechanisms leading to concerted evolution. Then, the probability of fixation of A is given by:
Concerted evolution has the effect to increase the "effective" population size, so that weak selection works more efficiently in a multigene family – the opposite of Dover!
Molecular Drive Does NOT Negate The Importance of Other
Evolutionary Forces.Molecular Drive INTERACTS
With Other Evolutionary Forces In Determining the Path of
Evolution.
