Dr. William Ratcliff. Credit: Courtesy of Dr. William Ratcliff.
“Being a researcher is special because there aren’t many jobs that allow you to spend the majority of your time thinking about the things you find the most interesting in the whole world,” says William Ratcliff, Ph.D., an associate professor of biological sciences and the director of the interdisciplinary graduate program in quantitative biosciences at Georgia Institute of Technology (Georgia Tech) in Atlanta. We talked with Dr. Ratcliff about his career path, research on yeast, and advice to budding scientists.
Q: How did you first become interested in science?
A: My family owns land in Northern California that has been passed down for more than 100 years. When I was a child, my brother and I would spend summers on that land getting lost in the woods. We would really see the forest for its parts: seeing how organisms interacted with one other, tracking stages of development, and listening to birdcalls. My grandmother would identify plants by their scientific names, and we’d discuss their reproduction strategies. We became amateur natural historians during those summers. Perhaps it’s no surprise my brother and I both got Ph.Ds. in biology.
Dr. Pedro Márquez-Zacarías. Credit: Courtesy of Dr. Pedro Márquez-Zacarías.
When he started high school in Mexico, Pedro Márquez-Zacarías, Ph.D., wanted to be a politician. However, as he became aware of issues like corruption, he began looking into other fields. Chemistry fascinated him, so he enrolled in a class at his school that was later canceled partway through the year. He then joined a biology class because it included a unit on biochemistry, and through that experience, found that he enjoyed other aspects of biology as well—so much so that he went on to compete in the International Biology Olympiad, a competition for high school biology students.
After graduating from high school, Dr. Márquez-Zacarías majored in biomedical sciences at Universidad Nacional Autónoma de México and discovered a passion for ecology and evolution. During a class activity where students had to present scientific papers, the work of evolutionary biologist William Croft Ratcliff, Ph.D. riveted him. Dr. Márquez-Zacarías began an email conversation with Dr. Ratcliff that led to visiting his NIGMS-supported lab at the Georgia Institute of Technology (Georgia Tech) in Atlanta.
Sohini Ramachandran, Brown University. Credit: Danish Saroee/Swedish Collegium for Advanced Study.
Recent advances in computing enable researchers to explore the life sciences in ways that would have been impossible a few decades ago. One new tool is the ability to sequence genomes, revealing people’s full DNA blueprints. The collection of more and more genetic data allows researchers to compare the DNA of many people and observe variations, including those shared by people with a common ancestry.
Sohini Ramachandran , Ph.D., is director of the Center for Computational Molecular Biology and associate professor of biology and computer science at Brown University in Providence, Rhode Island. She is also a recent recipient of the Presidential Early Career Award for Scientists and Engineers (PECASE). Dr. Ramachandran researches the causes and consequences of human genetic variations using computer models. Starting with genomic data from living people, her lab applies statistical methods, mathematical modeling, and computer simulations to discover how human populations moved and changed genetically over time.
Dr. Melissa Wilson.
Credit: Chia-Chi Charlie Chang.
The X and Y chromosomes, also known as sex chromosomes, differ greatly from each other. But in two regions, they are practically identical, said Melissa Wilson , assistant professor of genomics, evolution, and bioinformatics at Arizona State University.
“We’re interested in studying how the process of evolution shaped the X and the Y chromosome in gene content and expression and how that subsequently affects literally everything else that comes with being a human,” she said at the April 10 NIGMS Director’s Early-Career Investigator (ECI) Lecture at NIH.
What do you have in common with rodents, birds, and reptiles? A lot more than you might think. These creatures have organs and body systems very similar to our own: a skeleton, digestive tract, brain, nervous system, heart, network of blood vessels, and more. Even so-called “simple” organisms such as insects and worms use essentially the same genetic and molecular pathways we do. Studying these organisms provides a deeper understanding of human biology in health and disease, and makes possible new ways to prevent, diagnose, and treat a wide range of conditions.
Historically, scientists have relied on a few key organisms, including bacteria, fruit flies, rats, and mice, to study the basic life processes that run bodily functions. In recent years, scientists have begun to add other organisms to their toolkits. Many of these newer research organisms are particularly well suited for a specific type of investigation. For example, the small, freshwater zebrafish grows quickly and has transparent embryos and see-through eggs, making it ideal for examining how organs develop. Organisms such as flatworms, salamanders, and sea urchins can regrow whole limbs, suggesting they hold clues about how to improve wound healing and tissue regeneration in humans.
The human petrous bone in the skull protects the inner ear structures. Though it is one of the hardest, densest bones in the body, some portions (such as the area in orange, protecting the cochlea) are denser than others. Possibly because the petrous bone is so dense, DNA within the petrous bone is better preserved than in other bones. In some cases, scientists have extracted more than 100 times more DNA from the petrous bone than other bones, including teeth. Credit: Pinhasi et al., 2015, PLOS ONE.
For the past few decades, new evidence about ancient humans—in the form of skeletal remains, tools, and other artifacts—has trickled in, inching us closer to an understanding of how our species evolved and spread out across the planet. In just the past few years, however, knowledge of our deep past expanded significantly thanks to a series of technological breakthroughs in sequencing of ancient human genomes. This technology can be used to find genetic links among populations of human ancestors dating back hundreds of thousands of years.
In addition to advances in genomic technology, another factor is driving the explosion of new discoveries—an inch-long section of the human skull. Found near our ears, this pyramid-shaped portion of the temporal bone is nicknamed the petrous bone. The bone is very hard, possibly because it needs to protect fragile structures such as the cochlea, which translates sound into brain signals, and the semicircular canals, which help us maintain our balance. Perhaps because the petrous bone is so dense, it also is the bone in the body that best preserves DNA after a person dies. As a result, archaeologists are scrambling to study samples taken from this pyramid-shaped structure to unlock the mysteries of our species’ formative years.
Here’s a sampling of headlines declaring new findings about ancient peoples from around the globe that were based on genetic information obtained from the petrous bone (NIGMS-funded research indicated in black):
“How the introduction of farming changed the human genome” November 2015
“Fourth strand’ of European ancestry originated with hunter-gatherers isolated by Ice Age” November 2015
“Scientists sequence first ancient Irish human genomes” December 2015
“Genetic studies provide insight into ancient Britain’s diversity” January 2016
“The world’s first farmers were surprisingly diverse” June 2016
“Study reveals Asian ancestry of Pacific islanders” October 2016
“Ancient DNA solves mystery of the Canaanites, reveals the biblical people’s fate” July 2017
“Ancient DNA data fills in thousands of years of human prehistory in Africa” September 2017
“European Hunter-Gatherers Interbred With Farmers From the Near East” November 2017
“Surprise as DNA reveals new group of Native Americans: the ancient Beringians” January 2018
“Ancient DNA reveals genetic replacement despite language continuity in the South Pacific” February 2018
“Stone Age Moroccan Genomes Reveal Sub-Saharan African, Near Eastern Ancestry” March 2018
“Some early modern populations in Britain may have had dark skin” March 2018
These glowing images of yeast (Schizosaccharomyces kambucha) reproductive cells show an example of a selfish gene at work. Here, the selfish gene boosts its chances of being passed to the next generation by producing both a toxin (stained cyan) and an antitoxin (stained magenta). Cells with a copy of the selfish gene are protected by the antitoxin, left and bottom ovals. Those without the selfish gene are destroyed by the toxin. Scientists suspect that selfish genes could be operating throughout many organisms’ genomes, possibly having a major impact on how genetic material is inherited over generations. Credit: Image courtesy of María Angélica Bravo Núñez and Nicole Nuckolls.
There’s an old saying that rules are meant to be broken. In the 1860s, Gregor Mendel found that each copy of a gene in an organism has an equal chance of being passed to the next generation. According to this simple rule, each version of a gene gets passed to offspring with the same frequency. The natural selection process can then operate efficiently, favoring the genes that produce an advantage for an organism’s survival or reproductive success and, over successive generations, eliminating genes from the gene pool that bring a disadvantage.
Of course, the way organisms inherit genes is not as straightforward as Mendel’s work predicted. In natural systems, inheritance often fails to follow the rules. One culprit scientists are identifying again and again are what are called “selfish genes”: one or more genes that have evolved a method of skewing inheritance in their favor.
Scientists refer to these selfish genes—which are often complexes of multiple genes working together—as “selfish” because they enhance their own transmission to the next generation, sometimes by killing off any of the organism’s reproductive cells that lack copies of those genes. Using a variety of techniques, the genes are effective at passing themselves on to future generations. However, their methods set up a conflict within the organism by damaging its fertility; overall, fewer reproductive cells or offspring survive to produce a new generation.
Selfish genes are a challenge for scientists to identify, but researchers say that knowing more about these genes could help explain a range of genetic mysteries, from causes of infertility to details on how species evolve. The methods these genes use could also be harnessed to help control the reproduction of certain populations such as mosquitos that spread disease.
One recently described selfish gene system is found in the yeast cells pictured above. Sarah Zanders and her colleagues at the Stowers Institute for Medical Research in Kansas City, Missouri, and the Fred Hutchinson Cancer Research Center in Seattle, Washington, study selfish gene systems in yeast to understand how common they are and how they affect a species’ fertility and evolution. “Usually we think about infertility stemming from the good guys failing. For example, a gene that normally promotes fertility could be mutated so that it can no longer do its job,” says Zanders. “But selfish genes are another potential source of infertility. Learning general principles about selfish genes in simple models will guide future searches for selfish genes that could be contributing to human infertility.”
Recently, the scientists discovered a single selfish gene, wtf4, that encodes both a toxin and an antitoxin protein. When yeast produce their reproductive cells, called spores, the wtf4 toxin protein is released into the immediate vicinity, but the antitoxin remains inside spores that contain a copy of wtf4. The toxin destroys all the spores that don’t have the antitoxin protein. Although the yeast has fewer spores—and therefore reduced fertility—each spore carries wtf4, ensuring that the gene will be passed to the next generation of yeast.
Leafing through my favorite biology textbook from a handful of years ago, I was struck by the relative brevity of the chapter on human evolution. While other fields of biological research have enjoyed a steady gallop of productivity over the last few decades due in part to advances in computing power, imaging technology and experimental methods, the study of human evolution can be seen as having lagged behind until recently due to an almost complete dependence on fossil evidence.
Fortunately, contemporary biology textbook chapters on human evolution are being primed for a serious upgrade thanks to the recent availability of high-quality genome sequences from diverse modern human populations as well as from ancient humans and other non-human hominids, including the Neanderthals and Denisovans (but, for purposes of this story, not the Great Apes).
Modern human skull (left) and Neanderthal skull (right), shown to scale. There are not enough Denisovan bone fragments to reconstruct its skull. Credit: Wikimedia Commons, hairymuseummatt.
What are the new resources for studying human evolution?
The cost of DNA sequencing has dropped precipitously in the last decade. As a result, more complete human genome sequences become available for analysis with each passing year.
For example, the 1000 Genomes Project includes more than 1,000 full human genome sequences of individuals from European, Asian, American and Sub-Saharan African populations. Earlier this year, the Simons Genome Diversity Project further increased the number of available human genomes by adding 300 individuals representing 142 populations around the globe.
This Sunday, February 12, is Darwin Day—an occasion to recognize the scientific contributions of 19th-century naturalist Charles Darwin. In this video (originally posted on Darwin Day 2016), our own evolutionary geneticist, Dan Janes, answers questions about Darwin and the role of evolution in health and biomedicine.
Nearly 10 percent of the human genome is derived from the genes of viruses. Credit: Stock image.
When viruses infect us, they can embed small chunks of their genetic material in our DNA. Although infrequent, the incorporation of this material into the human genome has been occurring for millions of years. As a result of this ongoing process, viral genetic material comprises nearly 10 percent of the modern human genome. Over time, the vast majority of viral invaders populating our genome have mutated to the point that they no longer lead to active infections. But they are not entirely dormant.
Sometimes, these stowaway sequences of viral genes, called “endogenous retroviruses” (ERVs), can contribute to the onset of diseases such as cancer. They can also make their hosts susceptible to infections from other viruses. However, scientists have identified numerous cases of viral hitchhikers bestowing crucial benefits to their human hosts—from protection against disease to shaping important aspects of human evolution, such as the ability to digest starch.
For a virus to successfully make copies of itself inside a host cell, it needs molecular tools similar to the ones its host normally uses to translate genes into proteins. As a result, viruses have tools meticulously shaped by evolution to commandeer the protein-producing machinery of human cells.
Sohini Ramachandran, Brown University.
Dr. Melissa Wilson.
The human petrous bone in the skull protects the inner ear structures. Though it is one of the hardest, densest bones in the body, some portions (such as the area in orange, protecting the cochlea) are denser than others. Possibly because the petrous bone is so dense, DNA within the petrous bone is better preserved than in other bones. In some cases, scientists have extracted more than 100 times more DNA from the petrous bone than other bones, including teeth. Credit: 
includes more than 1,000 full human genome sequences of individuals from European, Asian, American and Sub-Saharan African populations. Earlier this year, the 