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Home , Linkage disequilibrium

BIOL2007 - AT MORE THAN ONE GENE

SO FAR • Evolution at a single locus • No interactions between genes Evolution at more than one • One gene one trait gene REAL evolution: • 10,000 100,000 genes producing mRNA • linkage, a physical interaction • mechanistic interactions in gene action

How do AND PLEIOTROPY affect our view of GENE INTERACTIONS evolution?

Pleiotropy Gene interactions affect genotypic frequencies at many loci. • single gene affects multiple traits , selection, migration etc. cause a deviation from Epistasis HardyWeinberg equilibrium at a single locus. • multiple genes interact to affect a trait • multiple traits interact to produce Selection (also migration, drift ) can cause deviation from • therefore, for gene combinations multilocus equilibria, and lead to prevalence of particular 2 locus combinations.

1 If two genes are independently inherited and randomly combined:

A a frequencies in population Linkage disequilibrium

B b Locus A: A = pA When two genes deviate from the expected two locus equilibrium, the genes a = 1 – pA are said to be in linkage disequilibrium (or gametic disequilibrium ). Locus B: A A a a Gamete B b B b B = pB The strength of this deviation is measured by the genotypes b = 1 – pB linkage disequilibrium coefficient, D (max = 0.25, min = 0.25)

Observed random two ASSUMING RANDOM COMBINATION OF GENES gametic locus A a frequencies = expectation + deviation p = p p + D B AB aB AB A B Expected genotype pAb = pA(1pB) - D frequencies in paB = (1pA)p B - D gametes b Ab ab pab = (1pA)(1pB) + D

Also, D = pAB pab - pAb paB

Genotype frequencies with linkage disequ. What can cause linkage disequilibrium Maternal gametes

AB Ab aB ab • Selection p p + D p (1-p ) D (1-p )p D A B A B A B (1-pA)(1-pB) + D • Migration/ population mixing AB AB /AB AB /Ab AB /aB AB /ab • pApB + D Ab Ab /AB Ab /Ab Ab /aB Ab /ab

pA(1-pB) D aB aB /AB aB /Ab aB /aB aB /ab

(1-pA)p B D Paternal gametes ab ab /AB ab /Ab ab /aB ab /ab

(1-pA)(1-pB) + D

2 Papilio memnon , a Batesian mimic model Cowslip – Primula veris species mimics Thrum-morph Pin-morph polymorphic Batesian mimicry (palatable mimics): Characters

Mimicry controlled by several Genotype genes. Rarely get recombinant patterns. In a population, most individuals are either thrum or pin, i.e. either (Gg, Pp, Aa) or (gg, pp, aa)

Only occasionally get other combinations: e.g. (Gg, Pp, aa) or (gg, Pp, Aa)

Clearly genes are in linkage disequilibrium male is non Thrumthrum and pinpin matings are largely incompatible mimetic http://wwwbiol.paisley.ac.uk/bioref/Genetics/Primula_heterostyly.html

Migration causing linkage disequilibrium Migration causing linkage disequilibrium

migration migration N

AA/BB aa/bb AA/BB aa/bb aa/bb aa/bb AA/BB AA/BB AA/BB aa/bb Tarapoto emma AA/BB aa/bb AA/BB aa/bb AA/BB aa/bb aa/bb AA/BB aa/bb aa/bb AA/BB AA/BB aa/bb AA/BB AA/BB favorinus aa/bb aa/bb aa/bb AA/BB AA/BB aa/bb ZONE aa/bb aa/bb 75 km AA/BB AA/BB Races of Heliconius erato Three major genes controlling colour pattern differences Population 1Mixed Population 2 population Within the hybrid zone, linkage disequilibrium between genes

3 Disequilibrium declines by a fraction (given by the Recombination breaks down recombination rate) every generation. linkage disequilibrium If c = proportion of recombination, then: D = D (1 - c) is the creation of new combinations t t-1 of during sexual reproduction t D D c t after many generations ( ): t = 0(1 - ) 0.25 Recombination reduces linkage disequilibrium by a

maximum of 50% in each generation 0.2

0.15 Recombination frequency = 50% c = 0.5 0.1 Linkage disequilibrium 0.05

0 0 10 20 30 40 50 60 Generation

Linkage diseq. on human chromosome 22 Genes on the same chromosome?

A a Individual genotype: B b A a A a a A ABC/abc B b b B B b

C c c C c C c C

But can we form these by RECOMBINATION Possible genotype of gametes

ABC ABc Abc AbC abc abC aBc aBC

Physical distance (kB) Dawson et al. 2002. Nature 418: 544548

4 Disequilibrium declines by a fraction (given by the recombination rate) every generation Linkage If c = proportion of recombination, then: disequilibrium RAB D D c t = t-1 (1 - ) A a B b t D D c t after many generations ( ): t = 0(1 - ) 0.25 c = 0.001 0.2

0.15

0.1 c = 0.01 Linkage Linkage disequilibrium 0.05 c = 0.1 c = 0.5

A a 0 0 10 20 30 40 50 60 b B Generation

So why may linkage disequ. persist? So why may linkage disequ. persist?

Three genes in strong linkage disequilibrium: GPA or gpa Linkage disequilibrium “topped up” by constant migration into the mixed population Most individuals either (Gg, Pp, Aa) or (gg, pp, aa) migration migration Thrumthrum and pinpin matings are largely aA/BB incompatible AA/BB aa/bb AA/BB aa/bb aa/bb aa/bb AA/BB G, P and A loci are tightly linked, forming a AA/BB AA/BB aa/bb AA/BB aa/bb AA/BB aa/bb 0.25 AA/BB aa/bb aa/bb AA/BB aa/bb "Thrum" "Pin“ c = 0.001 aa/bb morph morph 0.2 AA/BB AA/BB aa/bb AA/BB AA/BB 0.15 aa/bb Selection countering aa/bb aa/bb c = 0.01 AA/BB AA/BB aa/bb low level of recombination 0.1 aa/bb aa/bb Linkage disequilibrium Linkage 0.05 c = 0.1 c = 0.5 AA/BB aa /B b

0 0 10 20 30 40 50 60 Population 1Mixed Population 2 Generation population

5 Genetic drift causing linkage disequilibrium International HapMap Project

a A a * a over 3 million SNPs mapped in the human genome A a A a A a A a A A a a A A a a * * * Increase in (A, *) = marker loci, eg. SNPs disease causing mutation arises due to genetic drift

new mutation Tight linkage with nearby marker alleles Linkage disequilibrium, as effect Association between disease mutation and nearby markers i.e. linkage disequilibrium a of recombination weaker than Close linkage means * recombinants very rare. that of genetic drift Therefore, linkage Allows identification of “candidate genes” which may contain the mutation disequilibrium persists

Take home points Questions to think about Gene interactions: pleiotropy, epistasis

In general, selection acts on combinations of genes , rather than single loci Thinking about the Primula veris example again:

Deviation from 2locus equilibrium is known as gametic Why are all thrum phenotypes dominant? disequilibrium or linkage disequilibrium , measured by D Why does each morph only have one allele at each gene (i.e. linkage disequilibrium complete, D≈1), and not recombinant D is destroyed by recombination , c, so D = D (1 -c)t t 0 phenotypes? D can increased by selection, migration, drift D is involved in maintaining ''. D can be used in linkage mapping, studies of migration in natural populations READINGS: Futuyma: Chapter 9: 205207, Chapter 13: 303304 Freeman & Herron: Chapter 7: 197213

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