Darwin didn’t know the basic mechanisms of evolutionary change. Mechanism of inheritance was a black box. Darwin’s last publication before his death was “on the dispersal of bivalves”. Why are freshwater bivalves so homogeneous in morphology? Describes a beetle with a conch attached to its leg, which provided a mechanism of dispersal. Turns out the specimen was sent to Darwin by Crick’s grandfather.

How is variation generated and maintained in natural populations? What genes matter? What will finding the genes tell us?

We find genes underlying phenotypic diversity by comparison of highly divergent taxa (flies vs. mice, for instance), or the study of variation within species. Latter gives us the opportunity to use genetics, also allows us to know something about the environmental context that drives the differences.

Looks for phenotypic differences in the wild that contribute to fitness, then works out the genetics and development to see how it works. Hoekstra looks at color, the genetics of mammalian pigmentation in Peromyscus. These mice show lots of variation in color. The oldfield mouse of the American south lives in abandoned fields and on beaches. Beach sand is white, with low levels of vegetation, which means they are subject to high levels of predation. They wanted to document the selective advantage of light pigmentation on the beach environment, so made model mice out of clay with different colors,. and measured predation on the models. Color matters, and dark models were attacked preferentially on light sand, light models attacked in dark environments. 50% more likely to survive if your color matches your background.

Made crosses of dark and light genes and used QTL analysis to search for candidate genes. Found 3 genes correlated with the color patterns seen in Peromyscus, Mc1r, Agouti, and Corin. Mc1r is a g-coupled receptor with many mutations scattered throughout the gene. One difference is found between light and dark mice: changing one amino acid reduces the activity of the gene product.

Mc1r is the receptor; agouti is a repressor of mc1r; and Corin is an upstream regulator of agouti.

Looked at populations in the wild. Do populations on the gulf coast have the same mutation as atlantic coast mice? No — atlantic mice do not have the same mutation im mc1r, and no significant mutations were found in the atlantic mc1r.

Going even further afield, mc1r was sequenced in mammoths, and the same mutation found in light mice was found in mammoths; were mammoths polymorphic in coat color?

What do these genes tell us? 1) how many and and what are the effect sizes of genes that contribute to adaptive phenotypes? A few genes can have a large affect. 2) Do adaptive alleles tend to be dominant or recessive? Adaptive alleles are rarely completely recessive. 3) What is the relative role of epistasis versus additivity? Epistasis is very important. 4) Are the same genes responsible for convergent phenotypes? sometimes, but not the case within beach mice. 5)Are adaptive mutations in protein-coding or cis-regulatory regions? Both.