Strong Selection is Necessary for Repeated Evolution of Blindness in Cavefish

Strong Selection is Necessary for Repeated Evolution of Blindness in Cavefish Alexandra L. Merry and Reed A. Cartwright School of Life Sciences and Center for Human and Comparative Genomics The Biodesign Institute Arizona State University SCalE 2014

Research Overview: Computational Evolutionary Genomics Evolutionary Bioinformatics Mutational Biology Pathogen Genomics Human Population Genetics Statistical Genetics

Dramatis personæ Alex Rachel Megan

Model Organisms for Evolution Thousands of cave-dwelling species Repeated across taxa Neotrogla curvata Yoshizawa et al. 2014

Why do Cave Populations go Blind? Mutation Pressure: Relaxation of purifying selection allows mutations to accumulate. Darwin: eyes would be lost by disuse. Lots of mutations observed in putative eye genes in A. mexicanus (Hinaux et al. 2013) Genetic Drift: Without selection blindness alleles can go to fixation. Adaptation: individuals without eyes have greater fitness, resulting in the eventual elimination of seeing fish.

Astyanax mexicanus: Mexican Tetra Multiple colonization events Phenotypic convergence / repeated evolution of cave phenotype Cave populations receive migrants Repeated loss of functional constraint Bradic et al. 2012 biodesign.asu.edu RA Cartwright cartwrig.ht/lab/

Astyanax mexicanus: Mexican Tetra For phenotypes to evolve repeatedly in the face of migration requires strong selection. Bradic et al. 2012

Modeling Cavefish Evolution Assumptions Small, but infinite, cave population of diploid fish. A single biallelic locus with recessive blindness allele. Discrete, overlapping generations. Random mating in the cave. Immigration occurs from the surface. Emigration does not influence the surface. Blindness favored in the cave via constant viability selection. Loss-of-function mutations occur the the seeing allele at a constant rate. Blindness allele maintained on the surface via mutationselection balance.

Modeling Cavefish Evolution Variables and Parameters q Frequency of blindness allele, b, in the cave s Strength of selection favoring blindness p Frequency of seeing allele, B, in the cave q Frequency of blindness allele on the surface m Fraction of immigrants in the adult population u Mutation rate of B b (per-generation) Genotype: bb bb BB Fitness: 1 + s 1 1

Modeling Cavefish Evolution Life Cycle Stage Allele Frequency Event Zygotes q Birth

Modeling Cavefish Evolution Life Cycle Stage Allele Frequency Event Zygotes q Birth Juveniles q u = (1+u )u 2 +1u (1 u ) u Selection

Modeling Cavefish Evolution Life Cycle Stage Allele Frequency Event Zygotes q Birth Juveniles q u = (1+u )u 2 +1u (1 u ) u Adults q u = q u (1 m) + qm Selection Immigration

Modeling Cavefish Evolution Life Cycle Stage Allele Frequency Event Zygotes q Birth Juveniles q u = (1+u )u 2 +1u (1 u ) u Adults q u = q u (1 m) + qm Selection Immigration Gametes q = q u + (1 q u )u Mutation

Modeling Cavefish Evolution Life Cycle Stage Allele Frequency Event Zygotes q Birth Juveniles q u = (1+u )u 2 +1u (1 u ) u Adults q u = q u (1 m) + qm Selection Immigration Gametes q = q u + (1 q u )u Mutation Offspring q Fertilization

Migration-Selection Balance Theory Wright (1969), Hedrick (1985), Nagalaki (1992), etc. 0.015 0.010 q 0.005 0.000 0.005 s m u 0.010 0.0 0.2 0.4 0.6 0.8 1.0 q

Migration-Selection Balance Theory Wright (1969), Hedrick (1985), Nagalaki (1992), etc. 0.015 0.010 0.005 q 0.000 0.005 0.11 0.0021 0.88 0.010 0.0 0.2 0.4 0.6 0.8 1.0 q

Migration-Selection Balance Theory Wright (1969), Hedrick (1985), Nagalaki (1992), etc. 0.015 0.010 0.005 q ~ = 0.001 q 0.000 0.005 0.11 0.0021 0.88 0.010 0.0 0.2 0.4 0.6 0.8 1.0 q

Equilibria Analysis Δq = 0 Aq 3 + Bq 2 + Cq + D = 0 A = s B = s ( qm(1 u) m(1 u) + 1) C = m(1 u) u D = qm(1 u) + u

Equilibria Analysis Setting q = 0 and u = 0 makes analysis tractable. Δq = 0 Aq 3 + Bq 2 + Cq + D = 0 A = s B = s(1 m) C = m D = 0

Equilibria Analysis: Approximating is Okay 0.015 0.010 0.005 q 0.000 0.005 0.010 0.0 0.2 0.4 0.6 0.8 1.0 q

Equilibria Analysis Three possible equilibria: u = 0 is stable. And if s > 4u (1 u ) 2 : u = 1 2 (1 u (1 u ) 2 u 4u ) is unstable. u u = 1 2 (1 u + (1 u ) 2 u 4u ) is stable. u

Increasing Immigration Lowers Δq 0.015 0.010 0.005 q 0.000 0.005 0.010 0.0 0.2 0.4 0.6 0.8 1.0 q

Increasing q Raises Δq 0.015 0.010 0.005 q 0.000 0.005 0.010 0.0 0.2 0.4 0.6 0.8 1.0 q

Increasing q Raises Δq We can approximate Δq near q = 0 as Δq s(1 m)q 2 (m + u)q + (mq + u) This quadratic has two roots if s < (u + m) 2 4(1 m)(mq + u) Otherwise Δq > 0 when q is near 0.

Dynamics and Equilibria Summary 0 < s < 4u : one stable equilibrium near q = q. (1 u ) 2

Dynamics and Equilibria Summary 0 < s < 4u : one stable equilibrium near q = q. (1 u ) 2 4u < s < (u +u ) 2 (1 u ) 2 4(1 u )(u u +u ) : two stable and one unstable near q = 1 1 m (1 m) 2 s 4m 2 s

Dynamics and Equilibria Summary 0 < s < 4u : one stable equilibrium near q = q. (1 u ) 2 4u < s < (u +u ) 2 (1 u ) 2 4(1 u )(u u +u ) : two stable and one unstable near q = 1 1 m (1 m) 2 s 4m 2 s s > (u +u ) 2 : one stable equilibrium near 4(1 u )(u u +u ) q = 1 1 m + (1 m) 2 s 4m 2 s

Dynamics with Three Equilibria 0.015 0.010 0.005 q ~ = 0.001 q 0.000 0.005 0.11 0.0021 0.88 0.010 0.0 0.2 0.4 0.6 0.8 1.0 q

Frequency of b at Equilibrium u = 0, u = 0.001, u 0 = u 1 0.1 0.01 0.001 s 1e 04 1e 05 1e 06 1e 07 1e 08 Fixation Extinction 1e 08 1e 07 1e 06 1e 05 1e 04 0.001 0.01 0.1 1 m

Frequency of b at Equilibrium u = 0, u = 0.001, u 0 = 0.5 1 0.1 0.01 0.001 s 1e 04 1e 05 1e 06 1e 07 1e 08 Fixation Extinction 1e 08 1e 07 1e 06 1e 05 1e 04 0.001 0.01 0.1 1 m

Frequency of b at Equilibrium u = 10 5, u = 0.001, u 0 = u 1 0.1 0.01 0.001 s 1e 04 1e 05 1e 06 1e 07 1e 08 Fixation Extinction 1e 08 1e 07 1e 06 1e 05 1e 04 0.001 0.01 0.1 1 m

Importance of Genetic Drift 0.015 0.010 0.005 q ~ = 0.001 q 0.000 0.005 0.11 0.0021 0.88 0.010 0.0 0.2 0.4 0.6 0.8 1.0 q

Unreasonably Strong Selection Clearly, really strong selection is needed for a cave population to evolve blindness. If u = 0.001, u = 0.001, and u = 10 5, then u > 0.02 for fixation. If u = 0.001, u = 0.001, and u = 10 6, then u > 0.12 for fixation. But is strong viability selection probable for the evolution of blindness in cave fish? Shouldn t sight be a nearly neutral phenotype in darkness?

Sir E. Ray Lankester (1847 1929) Director of the Natural History Museum biodesign.asu.edu RA Cartwright cartwrig.ht/lab/

Sir E. Ray Lankester (1847 1929) Director of the Natural History Museum biodesign.asu.edu RA Cartwright cartwrig.ht/lab/

Phototaxis Could Produce Enough Selection

Evolutionary Predictions If there is immigration, then blindness will only evolve if there is strong selection against sight. Emigration of seeing fish produces this selection pressure. Cave phenotypes can only evolve via neutral processes if cave populations are isolated from the surface. However, drift is probably important to get selection started. biodesign.asu.edu RA Cartwright cartwrig.ht/lab/

Acknowledgments SCalE Organizers Minions Alexandra Merry Rachel Schwartz Megan Howell Barrett Honors College at ASU Funding ASU Startup Funds NSF DBI-1356548 NIH R01-GM101352 NIH R01-HG007178