1

Concerted EvolutionConcerted EvolutionDan Graur

2

Three evolutionary models for duplicated genes

3

4Concerted EvolutionConcerted Evolution

Divergent (classical) evolution vs. concerted evolution

Ganley AR, Kobayashi T. 2007. Genome Res. 17:184-191.

Expected Observed

6

Ribosomal RNA gene unit (in a cluster)Ribosomal RNA gene unit (in a cluster)

ITS = internally transcribed sequencesETS = externally transcribed sequencesNTS = nontranscribed sequences

7

Xenopus laevisXenopus borealis

8

18S and 28S in X. laevis and X. borealis are identical.

NTS regions differ between the two species.

NTS regions are identical within each species.

Conclusion: Conclusion: NTS regions in each species have evolved in concert, but have diverged rapidly between species.

9

(a) Stringent selection.(a) Stringent selection.(b) Recent multiplication.(b) Recent multiplication.(c) Concerted evolution.(c) Concerted evolution.

10

(a) Stringent selection.(a) Stringent selection.

Refuted by the fact that the NTS regions are as conserved as the functional rRNA sequences.

11

(b) Recent multiplication.(b) Recent multiplication.

Refuted by the fact that the intraspecific homogeneity does not decrease with evolutionary time.

12

(c) Concerted evolution.(c) Concerted evolution.

13

CONCERTED EVOLUTION

A member of a gene family does not evolve independently of the other members of the family.

It exchanges sequence information with other members reciprocally or nonreciprocally.

Through genetic interactions among its members, a multigene family evolves in concert as a unit.

14

CONCERTED EVOLUTION

Concerted evolution results in a homogenized set of nonallelic homologous sequences.

15

CONCERTED EVOLUTION REQUIRES:

(1) the horizontal transfer of mutations among the family members (homogenization).

(2) the spread of mutations in the population (fixation).

16

Mechanisms of concerted evolution

1. Gene conversion2. Unequal crossing-over3. Duplicative transposition.4. Gene birth and death.

17

gene conversiongene conversion

concerted evolutionconcerted evolution

18

19

20

Gene Conversion

Unbiased Gene Conversion: Sequence A has as much chance of converting sequence B as sequence B has of converting sequence A.

Biased Gene Conversion: The probabilities of gene conversion between two sequences in the two possible directions occur are unequal.

If the conversional advantage of one sequence over the other is absolute, then one sequence is said to the mastermaster and the other to be the slaveslave.

21

22

Gene conversion has been found in Gene conversion has been found in allall ssppeciesecies and at and at allall lociloci that were that were examined in detail. examined in detail.

BiasedBiased gene conversion is more gene conversion is more common than common than unbiasedunbiased gene gene conversion.conversion.

The rate of gene conversion varies The rate of gene conversion varies with genomic location.with genomic location.

23

unequal crossing-overunequal crossing-over

concerted evolutionconcerted evolution

24

UnequalUnequal crossing overcrossing over

Unequal crossing overUnequal crossing over

25

Tomoko OhtaTomoko Ohta

26

concerted evolution:Advantages of Gene Conversion over Unequal Crossing-Over

1. Unequal crossing-over changes the number of repeats, and may cause a dosage imbalance. Gene conversion does not change repeat number.

27

normal configuration

28mild -thalassemia

following unequal crossing-over

29

concerted evolution:Advantages of Gene Conversion over Unequal Crossing-Over

2. Gene conversion can act on dispersed repeats. Unequal crossing-over is severely restricted when repeats are dispersed.

30

deletiondeletion

duplicationduplication

31

concerted evolution:Advantages of Gene Conversion over Unequal Crossing-Over

3. Gene conversion can be biased. Even a small bias can have a large effect on the probability of fixation of repeated mutants.

32

concerted evolution:Advantages of Unequal Crossing-

Over over Gene Conversion

1. Unequal crossing-over is faster and more efficient in bringing about concerted evolution. At the mutation level, UCO occurs At the mutation level, UCO occurs

more frequently than GC.more frequently than GC.

33

concerted evolution:Advantages of Unequal

Crossing-Over over Gene Conversion

2. In a gene-conversion event, only a small region is involved.

34

In yeast, an unequal crossing-over event involves on average ~20,000 bp20,000 bp. A gene-conversion track cannot exceed 1,500 bp1,500 bp.

35

Factors affecting the rate of concerted evolution

1. the number of repeats. 2. the arrangement of the repeats. 3. relative sizes of slowly and rapidly

evolving regions within the repeat unit.

4. constraints on homogeneity.5. mechanisms of concerted evolution. 6. population size.7. dose requirements

36

1. the number of repeats.1. the number of repeats.

37

38

The number of unequal number of unequal crossing-overscrossing-overs required for the fixation of a variant fixation of a variant repeatrepeat increases roughly with nn22, where n is the number of repeats.

39

2. the arrangement of the repeats. 2. the arrangement of the repeats.

40

Types of arrangement of repeated units:

DispersedClustered

41

The dispersed arrangement causes unequal crossing-over to lead to disastrous genetic consequences.

The dispersed arrangement reduces the frequency of gene conversion.

42

3. relative sizes of slowly and rapidly 3. relative sizes of slowly and rapidly evolving regions within the repeat unit.evolving regions within the repeat unit.

43

Noncoding regionsNoncoding regions evolve rapidlyrapidly.

Coding regionsCoding regions evolve slowlyslowly.

Both unequal crossing-over and gene conversion depend on sequence sequence similaritysimilarity for the misalignment of repeats.

The more coding regions there are, the higher the rates concerted evolution will be.

44

4. constraints on homogeneity.4. constraints on homogeneity.

45

Two extreme possibilities:

1. The function requires large amounts of an invariable gene product.

rRNA and histone genes

2. The function requires a large amount of diversity.

immunoglobulin and histocompatibility genes

46

Two extreme possibilities:

1. The function requires large amounts of an invariable gene product.

rRNA and histone genes

2. The function requires a large amount of diversity.

immunoglobulin and histocompatibility genes

47

5. mechanisms of concerted evolution.5. mechanisms of concerted evolution.

48

Concerted evolution Concerted evolution under unequal under unequal crossing-over is crossing-over is quickerquicker than that than that under gene under gene conversion. conversion.

49

6. population size.6. population size.

50

The time required for The time required for a variant to become a variant to become fixed in a population fixed in a population depends on depends on population population sizesize..

51

7. dose requirements.7. dose requirements.

52

Centripetal selection against too many or too few repeats.

53

54

Decreases variat

ion

Decreases variation

Decreases variation

55

2 loci, 33 alleles

gene conversiongene conversion

2 loci, 44 alleles

56

DDeetteeccttiinngg CCoonncceerrtteedd EEvvoolluuttiioonn

57

When dealing with similar paralogous sequences, it is usually impossible to distinguish between two alternatives:

(1) the sequences have (1) the sequences have only recently diverged only recently diverged from one another by from one another by duplication.duplication. (2) the sequences have (2) the sequences have evolved in concert.evolved in concert.

58

The phylogenetic approach.

The two -globin genes in humans are almost identical. They were initially thought to have duplicated quite recently, so there was no sufficient time for them to diverge in sequence.

59

The phylogenetic approach.

However, duplicated -globin genes were also discovered in distantly related species, so most parsimonious solution to assume that the duplication is quite ancient, but its antiquity is obscured by concerted evolution.

60

G A

GAGA

duplication

speciation

55 million years ago

5 million years ago

The The orthologs orthologs should be should be closer to closer to one one another another than the than the paralogs.paralogs.

61

In humans, the 5’ parts of G and A differ from one another at only 7 out of 1,550 nucleotide positions (0.5%).

In contrast, the 3’ parts of G and A differ from one another at 145 out of 1,550 nucleotide positions (9.4%).

62

exon 3exon 3 exons 1 and 2 exons 1 and 2

63

exon 3exon 3 exons 1 and 2 exons 1 and 2

Expected phylogenetic tree for exons 1 and 2, if gene conversion had only occurred in the human lineage.

64

Death is not final: The resurrection of Death is not final: The resurrection of pancreatic ribonuclease as seminal pancreatic ribonuclease as seminal ribonuclease in Bovinae by gene ribonuclease in Bovinae by gene conversionconversion

65

The resurrection of pancreatic The resurrection of pancreatic ribonuclease as seminal ribonuclease in ribonuclease as seminal ribonuclease in Bovinae through gene-conversion of a Bovinae through gene-conversion of a small region at the 5' end of the gene. small region at the 5' end of the gene.

66

Pseudogenes may Pseudogenes may represent reservoirs of represent reservoirs of genetic information that genetic information that participate in the participate in the evolution of new genes, evolution of new genes, not only relics of not only relics of inactivated genes whose inactivated genes whose fate is genomic fate is genomic extinction.extinction.

67

68

21-hydroxylase 21-hydroxylase (cytochrome (cytochrome P21)P21) gene gene

In humans, the 10-exon gene is located on chromosome 6.

The gene has a paralogous pseudogene in the vicinity.

69

70

21-hydroxylase 21-hydroxylase (cytochrome (cytochrome P21)P21) gene gene

Hundreds of mutations in the 21-hydroxylase gene have been described.

75% of them are due to gene conversion.

71

72

gene ATGTCTCTGACCAAGGCTGAGAGGACCATGGTCGTGTCCATATGGGGCAApseudogene ATGTCTCTGACCAAGGCTGAGAGGACCATGGTCGTGTCCATATGGGGCAA **************************************************

gene GATCTCCATGCAGGCGGATGCCGTGGGCACCGAGGCCCTGCAGAGGTGAGpseudogene GATCTCCATGCAGGCGGATGCCGTGGGCACCGAGGCCCTGCAGAG----- *********************************************

gene TGCCAGACAGCCTGGGACAGGTGACAGTGTCCCAGGTGACACTGGTGTAGpseudogene --------------------------------------------------

Gene GTGACAGCGTGAGTTTAGTGAGGACAGGGGCCAGTGAAGAGGGGGCAATGpseudogene --------------------------------------------------

gene AGGAAGCGACAGTGTGGAGGGGTAATTGTGGTGGGGAACTGTGAGGACCC...pseudogene --------------------------------------------------

Were it not for the fact that the pseudogene is truncated, we would be hard pressed to say which is the gene and which is the pseudogene.

73

gene ATGTCTCTGACCAAGGCTGAGAGGACCATGGTCGTGTCCATATGGGGCAApseudogene ATGTCTCTGACCAAGGCTGAGAGGACCATGGTCGTGTCCATATGGGGCAA **************************************************

gene GATCTCCATGCAGGCGGATGCCGTGGGCACCGAGGCCCTGCAGAGGTGAGpseudogene GATCTCCATGCAGGCGGATGCCGTGGGCACCGAGGCCCTGCAGAG----- *********************************************

gene TGCCAGACAGCCTGGGACAGGTGACAGTGTCCCAGGTGACACTGGTGTAGpseudogene --------------------------------------------------

Gene GTGACAGCGTGAGTTTAGTGAGGACAGGGGCCAGTGAAGAGGGGGCAATGpseudogene --------------------------------------------------

gene AGGAAGCGACAGTGTGGAGGGGTAATTGTGGTGGGGAACTGTGAGGACCC...pseudogene --------------------------------------------------

Were it not for the fact that the pseudogene is truncated, we would be hard pressed to say which is the gene and which is the pseudogene.

74

The birth-and-death model for the evolution of gene families was proposed by Hughes and Nei (1989).

In this model, new copies are produced by gene duplication.

Some of the duplicate genes diverge functionally; others become pseudogenes owing to deleterious mutations or are deleted from the genome.

The end result of this mode of evolution is a multigene family with a mixture of functional genes exhibiting varying degrees of similarity to one another plus a substantial number of pseudogenes interspersed in the mixture.

75

The birth-and-death model for the evolution of gene families

An important prediction of the birth-and-death process is that gene-family size will vary among taxa as a result of differential birth and death of genes among different evolutionary lineages.

Thus, an understanding of the evolutionary forces governing the birth-and-death process is predicated upon an accurate accounting of the number of births (duplications) and deaths (nonfunctionalization events + deletions) in each lineage.

This “bookkeeping” turns out to be anything but a trivial undertaking.

76

Expansions/no change/contractions in the evolution of gene families in five Saccharomyces species. Estimates of divergence times (in millions of years) are shown in circles.

77

There were 3517 gene families shared by the five species. Of these, 1254 (~37%) have changed in size across the tree. On each branch in the tree, the vast majority of gene family sizes remain static. Expansions outnumbered contractions on four of the eight branches, and contractions outnumbered expansions on the other four.

78

Let us compare the number of expansions and contractions on the branches leading to S. mikatae and S. cerevisiae from their common ancestor, approximately 22 million years ago. On the lineage leading to S. mikatae there were 509 families that expanded and 86 families that contracted—a ratio of 6:1. On the lineage leading to S. cerevisae a smaller number of families changed their size, and the ratio of expanded families (54) to contracted ones (241) was inverted, 1:5.

Lineage specificity

79

Turnover Rates

Turnover = Gains + Losses

The gene turnover rate in primates is nearly twice that in non-primate mammals (0.0024 versus 0.0014 gains and losses per gene per million years).

A further acceleration must have occurred in the great-ape lineage, such that humans and chimps gain and lose genes almost three times faster (0.0039 gains and losses per gene per million years) than the other mammals.

80

BIRTH-AND-DEATH EVOLUTION: EXAMPLESThe evolution of olfactory receptor gene repertoires Olfactory receptors are G-coupled proteins that have seven α-helical transmembrane regions. Olfactory receptor genes are predominantly expressed in sensory neurons of the main olfactory epithelium in the nasal cavity. Animals use different olfactory receptors and different combinations of olfactory receptors to detect volatile or water-soluble chemicals.

81

BIRTH-AND-DEATH EVOLUTION: EXAMPLESThe evolution of olfactory receptor gene repertoiresTetrapods have 400-2,100 olfactory receptor sequences, but 20-60% are pseudogenes. These numbers are small in comparison to the number of odorants, but olfactory receptors function in a combinatorial manner, whereby a single receptor may detect multiple odorants, and a single odorant may be detected by multiple receptors.

Functional olfactory receptor genes (red) Pseudogenes (blue)

82

BIRTH-AND-DEATH EVOLUTION: EXAMPLESThe evolution of olfactory receptor gene repertoiresVertebrate olfactory receptors genes are classified into at least nine subfamiles (, and ), each of which originated from one or a few ancestral genes in the most recent common ancestor of vertebrates. There was an enormous expansion in the number of and genes in non-amphibian tetrapods. The remaining gene families are present primarily in fish and amphibian genomes. This observation suggests that and mostly detect airborne odorants, while the function of the other gene families is to detect water-soluble odorants.

83

BIRTH-AND-DEATH EVOLUTION: EXAMPLESThe evolution of olfactory receptor gene repertoiresPrimates generally have a smaller number of functional olfactory receptor genes than rodents and a higher proportion of pseudogenes.

388 genes, 414 pseudogenes (52%)

1063 genes, 328 pseudogenes (24%)

84

Color Vision

BIRTH-AND-DEATH EVOLUTION: EXAMPLES

85

86

Color vision in primates is mediated in the eye by up to three types of photoreceptor cells (cones), which transduce photic energy into electrical potentials.

87

Each type of color-sensitive cone expresses one type of color-sensitive pigment (photopigment). Each photopigment consists of two components: a transmembrane protein called opsin, and either of two lipid derivatives of vitamin A, 11-cis-retinal or 11-cis-3,4-dehydroretinal. Variation in spectral sensitivity, i.e., color specificity is determined by the sensitivity maximum of the opsins.

88

John Dalton. 1794. “Extraordinary Facts Relating to the Vision of Colours.” Memoirs of the Manchester Literary & Philosophical Society.

89Ishihara Plates

90

OpOpsinssins

Long wavelength (red)Medium wavelength (green)Short wavelength (blue)

Suggested flag for Mars

91

• Routine trichromacy = all individuals regardless of sex can achieve trichromacy. • Dichromacy (in humans, referred to as color blindness):

protanopia (L-deficiency), deuteranopia (M-deficiency), tritanopia (S-deficiency).

• Because of X-linkage, protanopia and deuteranopia are considerably more common in males than in females. •Monochromacy can occur if both L and M photopigments are faulty.

92

Most prosiminas (Strepsirrhini) and New World monkeys (Platyrhhini) carry only one X-linked pigment gene, and are, therefore, dichromatic. The ancestral X-linked opsin is thought to resemble the M-opsin, and indeed most prosimians and New World monkeys are protanopic.

93

However, because shifts in the maximal sensitivity of opsins can be achieved quite easily by missense mutations in as few as 3-5 codons, in a few diurnal taxa of prosimians, L-alleles have been produced. In some lineages, the L-allele became fixed in the population at the expense of the M-alleles. In consequence, these taxa are deuteranopic.

94

In other cases, a polymorphic state consisting of two or more alleles is maintained in the population. As an example, in white-faced capuchin monkeys (Cebus capucinus), there exist two alleles at the X-linked opsin locus, the maximal-sensitivity peaks of which being similar to those of human L and M opsins, respectively. For this reason, while males and homozygous females are dichromatic, heterozygous females are trichromatic (Figure 6a.8). This type of trichromacy is called allelic trichromacy.

95

Saimiri sciureusSquirrel monkey

New-World monkeys possess only two opsin loci, one autosomal and one X-linked. However, the X-linked opsin locus is highly polymorphic. Two of these alleles have maximal-sensitivity peaks similar to those of human red and green opsin, while the third allele has an intermediate peak. A heterozygous female will be trichromatic, while males and homozygous females are dichromatic.

96

97

98