Wild fish thrive despite “hopeless monster” mutations

A series of experiments led by Stanford Medicine researchers, including fish connections, CRISPR and sea hopping, have confirmed a longstanding but unproven assumption about natural evolution. It also debunks a topic of conversation favored by advocates of intelligent design, who have argued that naturally occurring mutations can only harm or destroy an animal and cannot lead to useful new traits and body structures.

The researchers identified repeated changes in the regulation of a key developmental gene that increase the number and determine the length of the main defensive spines of a fish called a stickleback. New spinal features improve fish’s survival in the face of various predators – contradicting a central claim of anti-evolutionists that major changes will always render animals unable to survive in the wild.

“Scientists already know that changes in the regulation of this gene called HOX control the development of key body structures during development,” said David Kingsley, PhD, professor of developmental biology. “What’s new is that we show conclusively that mutations in this gene produce major changes in wildlife – new traits that help fish to thrive in natural environments. Our results refute the common argument that these types of genes are so important, so fundamental, that animals with mutations in these regions would not survive in nature – that if you play with master regulators, you will only create a hopeless monster.”

Kingsley, an HHMI investigator and professor of Rudy J. and Daphne Donohue Munzer, is the senior author of the study, which was published online Sept. 1 natural ecology and evolution. The first author of the study is the diploma student Julia Wucherpfennig.

Although the concept of evolution is widely accepted, it can happen in different ways. Regressive evolution is the loss of existing traits that were once useful but are now disadvantageous or useless, resulting in an animal that is better adapted to its natural environment. These changes are almost always either neutral—think cavefish, which lost their eyesight after generations in the dark—or helpful, like early humans shedding the hairy suit of our ape relatives, allowing us to hunt prey great distances , without getting overheated .

A gamble

In contrast, progressive evolution occurs when organisms acquire new traits that allow them to outperform their peers. But such changes are essentially a leap of faith, tantamount to rolling the genetic dice and hoping they all come up as six. Smaller, more gradual changes are less risky. Big structural changes, sometimes called big-impact mutations, can be particularly tricky: Imagine strutting out of your apartment one day with a third leg or two heads. Would you have an advantage over your neighbors if you ran to the bus, or are you more likely to trip and fall headfirst into traffic?

Although there have been a few instances where animals in nature have acquired beneficial traits through changes in the HOX genes—fruit flies developed specific patterns of sensory bristles on their legs and some honey bees acquired distinctive coloration on their abdomens—most have been larger structural gains caused by mutations in these regions were detrimental.

“Laboratory-bred four-winged fruit flies are a famous example of how relatively simple genetic changes in regulatory regions of the HOX genes can dramatically alter an animal’s body shape,” Kingsley said. “But because these flies can’t survive in the wild, anti-evolution advocates have seized on them — not as a good example of how genes drive evolution, but as proof that genetic modification can only make animals less functional.”

Two to four inch long sticklebacks that carry varying numbers of sharp spines on their backs make great objects of study because they evolve rapidly and dramatically in response to changing environmental conditions. A lake full of fish-eating insects often harbors sticklebacks with fewer and shorter spines to grasp. But a pond with larger fish or birds that swallow their fish sticks whole is likely to have a population of sticklebacks with longer, more numerous, throat-scratching spines. Forests of watery weeds are great for flexible, slippery fish that can hide in vegetation, while in the open ocean, armored plates and formidable spikes are the way to go.

The Kingsley lab kicked off the study with a touch of watery matchmaking. Previous graduate students crossed a two-spined female stickleback from a freshwater lake in British Columbia with a three-spined male stickleback from the salty waters of Bodega Bay, California. They then crossed the offspring from this match and analyzed the number and shape of their spines. Most of the 590 large fish had three spines, but six had two spines and 21 had four spines – more than any of their ancestors. Extensive genetic studies of the differently spined fish revealed differences in the region around a gene called HOXDB, which is a member of the HOX gene family.

A link between genes and anatomy

Wucherpfennig continued to collect and cross-breed sticklebacks from countless North American lakes and streams, studying their genetic makeup and using CRISPR methods to confirm the effects of the HOXDB gene on dorsal spines. She found a number of changes in regions close to the HOXDB gene and showed that they are linked to major anatomical changes developing in the defensive armor of wild fish.

“In Nova Scotia, some stickleback populations have evolved to have five or even six spines,” Kingsley said. “Nature left the coding region of this gene intact, but altered how and when it is expressed during normal development to add rather than remove structure. And fish with these new structures thrive in a totally wild environment that’s exposed to a whole range of environmental stresses.”

Wucherpfennig and her colleagues showed that repeated changes in the regulatory regions of the HOXDB gene are responsible for the recent development of new spine patterns in two different stickleback species she studied across North America. They are now interested in whether similar changes account for differences in fish that are even more distantly related.

“Are there predictable rules governing evolutionary change?” said Kingsley. “Will natural species use the same trick over and over again, or will they have to invent a new trick each time? So far, even in these very different sticklebacks from different environments, it has been the same gene. Here we show that nature routinely adds important structures to create animals that are better adapted to the environment, and that it does so repeatedly by adding the same thing Master regulatory gene used. It is a crucial argument for ongoing evolution, which has been debated in academic and non-academic circles for decades.”

Relation: Wucherpfennig JI, Howes TR, Au JN, et al. Evolution of stickleback spines through independent cis-regulatory changes in HOXDB. Nat Ecol Evol. 2022. doi: 10.1038/s41559-022-01855-3

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