Engineering local and reversible gene drive for population replacement. Bruce A. Hay.

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1 Engineering local and reversible gene drive for population replacement Bruce A. Hay

2 To prevent insect-borne disease Engineer insects to resist infection Replace the wild insect population with engineered counterparts that cannot transmit disease Less transmission = less disease. Insect Host

3 Two general kinds of replacement gene drive mechanisms: low threshold and high threshold Unlimited spread / Limited spread (Low threshold) (High threshold) Reversible? (Can transgenes be eliminated?)

4 With low threshold gene drive the spread of transgenes to high frequency is not (very) limited by migration rate

5 With low threshold gene drive the spread of transgenes to high frequency is not (very) limited by migration rate

11 Many social and regulatory environments will require that spread only occur locally, and that it be reversible High threshold-dependent gene drive mechanisms bring about reversible and local population replacement Transgenes spread to fixation Unstable equilibrium Transgenes are lost Frequency of transgenics 0 Generations

12 Gene flow from GM crops: examples of successful risk analysis and regulation

13 Medea, a low threshold drive: less confinable, reversible Double Medea and translocations, high threshold drive: confinable, reversible

14 Replace the wild population with individuals refractory to disease transmission The challenge How do we cause a trait to rapidly spread throughout a population

15 Problem: Genes that confer disease refractoriness are likely to result in a fitness cost to carriers Relative fitness Solution: Increase the fitness cost associated with NOT carrying the gene of interest A form of gene drive Relative fitness

16 Medea ( ), a novel selfish genetic element When Medea ( ) is present in females, only progeny that inherit Medea survive (1992)

17 Medea ( ), a novel selfish genetic element When Medea ( ) is present in females, only progeny that inherit Medea survive Medea gains a transmission advantage by causing the death of those that lack it

18 Medea can spread rapidly through a population when introduced at high frequency

19 Medea as a low threshold, two component, toxin-antidote gene drive system Maternal toxin Cargo Embryo antidote ~ ~ Toxin Germ cell Meiosis Chen et al., (2007) Science 316:

Medea elements can be generated by targeting at least three different developmental processes Fraction Medea individuals 1 0.9 0.8 0.7 0.

20 Medea elements can be generated by targeting at least three different developmental processes Fraction Medea individuals Generations Chen et al., (2007) Science 316: Akbari et al., (2013) ACS Synthetic Biology doi: /sb300079h

21 Medea is predicted to be an invasive drive mechanism, spreading even when migration rates are low Transgene-bearing Wildtype Population A µ µ µ Population B Frequency of transgenic individuals (%) Spread of Medea between populations (s=0.05, h=0.5, µ=0.01/gen) Release at 50% In population A Initially absent from population B Population A Population B Generations Marshall and Hay Journal of Theoretical Biol. 294, 153

22 Medea is predicted to be an invasive drive mechanism, spreading even when migration rates are low Transgene-bearing Wildtype µ Population A Population B µ µ Population A Population B Marshall and Hay Journal of Theoretical Biol. 294, 153

bring about reversible and local population replacement 100 75 50 25 Transgenes

23 Many social and regulatory environments will require that spread only occur locally, and that it be reversible High threshold-dependent gene drive mechanisms bring about reversible and local population replacement Transgenes spread to fixation Unstable equilibrium Transgenes are lost Frequency of transgenics 0 Generations

24 Underdominant systems show threshold-dependent, bi-stable behavior. Frequency-dependent selection

25 Underdominant systems show threshold-dependent, bi-stable behavior. Frequency-dependent selection Population %

26 Underdominant systems show threshold-dependent, bi-stable behavior. Frequency-dependent selection Population %

27 UD MEL (Double Medea): Threshold-dependent gene drive for local and reversible population modification Single locus Akbari et al., (2013). Current Biology, 23, 671

28 UD MEL (double Medea): Threshold-dependent gene drive for local and reversible population modification Single locus Transgenic frequency Transgenic frequency Generations Akbari et al., (2013). Current Biology, 23, 671

29 UD MEL (double Medea): Threshold-dependent gene drive for local and reversible population modification Two locus, Two Autosomes Transgenic frequency Transgenic frequency Generations Akbari et al., (2013). Current Biology, 23, 671

30 Reciprocal translocations can, in principal, bring about high threshold population replacement

31 Reciprocal translocations can, in principal, bring about high threshold population replacement

32 Transgenes located at the translocation breakpoint share the fate of the translocation Engineered 2:3 translocation Akbari and Hay labs, submitted

33 Medea, a low threshold drive: less confinable, less reversible Double Medea and translocations, high threshold drive: confinable, reversible

34 Safe, local and reversible gene drive can be achieved

Medea drives non-medea individuals from the

and introduction ratio Generations required for

shows number of generations required for frequency

36 Medea drives non-medea individuals from the population at a rate that depends on fitness cost and introduction ratio Generations required for frequency of Medea Individuals to be > 99% Heat map shows number of generations required for frequency of Medea to be >99% Medea is eliminated Ward et al., Evolution. 65, 1149

1. Drosophila models of human neurodegenerative

1. Drosophila models of human neurodegenerative Professor of Biology: Bruce A. Hay Research Fellows: Chun Hong Chen, Nikolai Kandul, Geoff Pittman, Arun Kumar, Omar Akbari Graduate Students: Kelly J. Dusinberre, Catherine M. Ward, Anna Buchman Undergraduate