Qnas with Hopi Hoekstra

QNAS QNAS QnAs with Hopi Hoekstra Prashant Nair Science Writer Mexico desert and the sweeping prairie grasslands of the American Great Plains. For her molecular insights into adaptation, Hoekstra won the 2015 Richard Lounsberry [N]ature cares nothing for appearances, except found otherwise. Among those who have in so far as they may be useful to any being. She Award (www.nasonline.org/programs/awards/ attempted to chronicle the inexorable march richard-lounsbery-award.html)oftheNational can act on every internal organ, on every shade of natural selection with clockwork pre- of constitutional difference, on the whole ma- Academy of Sciences. PNAS spoke to Hoekstra chinery of life. cision is Harvard University evolutionary to commemorate the honor. geneticist Hopi Hoekstra, whose well- PNAS: What spurred your interest in the Since its publication more than 150 years ago, recognized work has revealed how incre- genetic basis of adaptation? Charles Darwin’s sly observation has earned mental genetic changes allow animals to Hoekstra: As a graduate student, I entered the status of demonstrable fact. Darwin also acquire new traits and adapt to changing the field at a time when molecular markers, held that the stepwise process of natural se- ’ environments. Hoekstra stidyexperimental like microsatellites and mitochondrial DNA lection, which sifts through variation and designs have been tested in wide-ranging sequences, were being used to ask organism- winnows disadvantages, is largely hidden settings, such as the gypsum sands that level questions, such as what is a species’ from human view. Yet his followers have ripple through the carnelian-colored New migration pattern or phylogeographic his- tory? By design, these markers were neu- tral, meaning they were used to trace traits of interest but did not directly influence the traits. The latter, to me, seemed more in- teresting, so as a postdoctoral fellow, I be- gan focusing on the genes that actually mattered for the traits. PNAS: Among several examples of such traits, you described in a PNAS article how three species of lizards inhabiting White Sands—an awesome terrain of snow-white gypsum dunes that appear to undulate across the Chihuahuan Desert in New Mexico— have each evolved blanched skin to blend into the dunes and avoid predators, whereas the brown-colored ancestral species has col- onized the dark soil of the adobe desert around the dunes (1). What did you find about the evolution of skin color in the Eastern fence lizard, the little striped whip- tail, and the lesser earless lizard? Hoekstra: We were interested in under- standing how similar traits evolve independently in different species that live in similar environments. In other words, we wanted to know how many genetic solutions there are to a common ecological problem. Among the three species of lizards we studied, we found that a candidate gene, called the melanocor- tin-1 receptor, which is a signaling receptor in the pigmentation pathway, was implicated in skin color in two species. In each of these species, we found a different mutation in this gene. Although both mutations result in light coloration, each acts through a different mechanism; one mutation reduces the strength of the receptor’s signal and the other affects the receptor’s integration into Hopi Hoekstra at Harvard’s Museum of Comparative Zoology. Image courtesy of Bear Cierci. the cell membrane, resulting in fewer active www.pnas.org/cgi/doi/10.1073/pnas.1508757112 PNAS Early Edition | 1of2 Downloaded by guest on September 24, 2021 receptors. So you could have a few strong Once we nail down the relevant mouse genes, trait you may not immediately expect to be receptors or lots of weak receptors, and the we will of course look for similar variations in favored by natural selection as defense against functional outcome is roughly the same. the corresponding human genes, if any. But predation (after all, the bellies of mice are PNAS: In the same vein, you reported in that’s beyond the scope of this article. normally hidden from predators’ view). But, PNAS: Nature in 2013 that deer mice build small, Your work has led you into the the analysis suggested that belly color may simple burrows, unlike oldfield mice, a sister molecular thickets of adaptation. In your also be independently selected, bringing species, which build complex burrows with 2013 Science article, for example, you dis- us full circle to a surprising organism-level elaborately realized entrance and escape tun- sected the gene implicated in camouflage in insight. It is a case of one gene evolving nels (2). Your genetic analysis of differences in deer mice that scurry across the Nebraska mutations independently to fine-tune the burrow building revealed surprising insights. Sandhills, a rolling landscape of sand dune- Hoekstra: phenotype. We became interested in the speckled prairies that seem to recede into PNAS: ’ complex burrow architecture of the oldfield the horizon (3). You zeroed in on the mu- Your findings support Darwin s ’ mice when we found that the burrow-build- tations that enabled the ancestral dark- notion of evolution sstep-likeprogression. Hoekstra: ing trait in this species represented a gain of brownmicetoslowlyevolvebeigecoats If we had stopped with our ini- functional complexity. First of all, we were and dodge predators that hunt by sight. tial finding on the Agouti gene, we might surprised that the genetic control of what Hoekstra: In previous work, we had impli- have concluded that evolution proceeds in appeared to be a complex trait was largely cated the Agouti gene in deer mice coat color. big steps. But, when we dissected the gene to simple, tied to four regions of the genome, In this work, we probed the molecular mech- the level of mutations, we found that there are three of which were associated with the anisms underlying the adaptation. Because multiple, small-step mutations that underlie length of the burrow’s entrance tunnel. More- the light- and dark-colored mice have a lot adaptation. A lot of population genetics theory over, each region contributes specifically to a of pigmentation differences across their bod- is based on these mutations and not on the three-centimeter increase in tunnel length. So ies, we thought a single mutation in a classic genes themselves, so identifying the mutations if you introduced one of these regions from pigmentation gene, namely Agouti,mayun- does in fact reinforce Darwin’sideaofevolu- the big burrowing species into the genetic derlie the observed differences in the face, tion through small steps. background of the small burrowing one, the belly, back, and tail of the mice. But, we PNAS: What was your reaction to the prize small burrowing species will dig a tunnel, on found something quite surprising: There were announcement? average, three centimeters longer; add an- multiple mutations in the Agouti gene that Hoekstra: I was very surprised and am other region, and you get a tunnel six cen- affected color, and each mutation targeted a delighted to see that evolutionary genetics is timeters longer, add two, and the tunnel is different region of the body. And when we being represented in this way. I am also nine centimeters longer. We also found a looked for evidence of selection acting on different region of the genome that was these mutations, eight of the nine mutations thankful for all of the creative, dedicated, associated with the presence or absence of showed strong signatures of selection, but and hard-working collaborators, postdocs, an escape tunnel in the burrow. These find- only on the allele associated with light color and students with whom I have had the ings suggest that complex behaviors might (dark-colored mice stand out against the pleasure to work, both in the laboratory be built by piecing together small, simple dunes’ sun-bleached hues, inviting predators). and in the field, and in the past and in genetic modules. PNAS: Why was this finding surprising? the present. I have been very lucky to be PNAS: To go out on a limb, do the find- Hoekstra: Many studies have reported on part of such a fantastic team. ings have any bearing on human behavior? the genetic basis of adaptations, but few have Hoekstra: To understand how genes can pinpointed the mutations involved, and that affect specific behaviors at a neurobiological is because it is hard work. We started with an 1 Rosenblum EB, Römpler H, Schöneberg T, Hoekstra HE (2010) Molecular and functional basis of phenotypic convergence in white level is an exciting challenge. Even though observation at the organism level, asking lizards at White Sands. Proc Natl Acad Sci USA 107(5):2113–2117. this trait does not have a direct homolog in what mutations might underlie the color 2 Weber JN, Peterson BK, Hoekstra HE (2013) Discrete genetic humans—we don’t build burrows—it is variations in different regions of the body modules are responsible for complex burrow evolution in Peromyscus possible that some of the candidate genes between the two mouse species. That led us mice. Nature 493(7432):402–405. 3 Linnen CR, et al. (2013) Adaptive evolution of multiple traits we have pinpointed may underlie motivational to these eight different regions in the genome, through multiple mutations at a single gene. Science 339(6125): differences between the two mouse species. one of which is implicated in belly color, a 1312–1316. 2of2 | www.pnas.org/cgi/doi/10.1073/pnas.1508757112 Nair Downloaded by guest on September 24, 2021.

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