It's in the genes
Genome biologists seek answers to disease, biodiversity and what makes us human
Sequencing the genomes of human beings and a rapidly growing number of other organisms fueled a revolution in the life sciences—a revolution UT Arlington has embraced with a fervor reminiscent of the early days of the space program.
In just a couple of years, the University has assembled a team of dedicated researchers who are passionate about eradicating disease and answering fundamental questions about what makes us human.
In January 2005, biology Associate Professor Paul Chippindale received a $498,000 grant from The University of Texas System to buy genomics research equipment. Purchases included a state-of-the-art DNA sequencer that cuts sequencing time by about 75 percent and enables the scientists to sequence millions of bases (subunits) of DNA each month.
“Although the grant was officially to me, the whole young research group pitched in and helped choose the optimal combination of resources,” Dr. Chippindale said. “We’re attracting top-notch new faculty members, putting our genome biology group on par with others at leading research institutions throughout the world.”
The group is composed of 12 faculty members, five collaborators from areas such as engineering, computer science and mathematics, four research associates or assistants and a platoon of graduate students. They work as a team, although their individual research is varied.
Assistant Professor Cedric Feschotte, for example, spends his days studying junk.
When the human genome was sequenced, he explains, researchers found that 97 percent of the DNA did not code for proteins and, essentially, had no known function. At least half of this non-coding DNA and, thus, nearly half of the human genome is derived from transposons, mobile genetic elements that can move around in the genome and replicate themselves. Transposons were initially labeled “junk DNA,” a term that is proving short-sighted.
“Junk DNA is the dark matter of genomes,” Dr. Feschotte said, adding that researchers are discovering that the “junk” can assume various functions, including regulatory roles for neighboring genes.
In other words, the “non-coding DNA” influences the behavior of the genes that are the “coding DNA.” This research is in its infancy, but the implications are huge. Feschotte believes the answer to the questions of evolution lies in the junk.
“A chimpanzee’s DNA is over 98 percent identical to a human’s, and their genes are virtually identical,” he said. “Yet the differences between a chimpanzee and a human are enormous.”
Feschotte believes those transposable elements, with their ability to reshuffle within the genome, may hold the key to why humans differ from other primates.
“DNA is like an office phone book,” he said. “It is a big book that everyone uses, but everyone uses different pages and makes use of different information.”
Since all animal species share a common ancestor, Assistant Professor Andre Pires da Silva is trying to answer the question of how they become so different from one another. One aspect that seems to change quickly in evolution is the genetic mechanism that determines gender.
Dr. Pires da Silva is exploring how an egg becomes male or female. In humans, embryos with a Y chromosome develop as males. In many other species, this is not the case. In pill bugs, the arbiter is bacteria. Eggs infected by a specific bacterium become females. For turtles, temperature is the decisive factor. Eggs incubated at high temperatures develop as females. Countless questions remain about the hows and whys of the genetic mechanisms responsible for creating males and females.
For reasons both practical and ethical, humans are difficult to study. To a lesser extent, so are turtles. So Pires da Silva works with nematodes. This tiny animal measures about 1 millimeter and is easy to maintain, which makes it a good candidate for experiments and genetic manipulations.
Females in some species of nematodes produce both oocytes (unfertilized eggs) and sperm cells. Consequently, the females (technically hermaphrodites) can self-fertilize and be completely independent of the males. Other species have males and females, like humans. When the hermaphrodite worms become adults, they produce sperm. After the worm produces about 200 sperm, they are stored in the spermatheca, an organ that works like a container for sperm. Then the gonad switches and starts to produce oocytes. The newly formed oocytes migrate through the spermatheca and are fertilized. Almost all of the fertilized eggs will be hermaphrodites. Only about 0.1 percent develop as males.
When one of those scarce males mates with a hermaphrodite, however, the outcome is different. Male sperm is larger and faster than hermaphroditic sperm and, when it reaches the spermatheca, almost always fertilizes the egg. Genetically, there are two kinds of sperm in males, one with an X chromosome and one without. All oocytes have an X. When a sperm with an X fertilizes an oocyte, it will form an XX animal, which will become a hermaphrodite. If the sperm has no X, the embryo will be XO (worms don’t have Y chromosomes) and develop into males. So of the worms with “fathers,” 50 percent will be male and 50 percent hermaphrodite.
How a single cell develops into a fully developed adult animal is a fundamental biological question that is not well understood. Also, the function of many genes common to both humans and nematodes is unknown. By manipulating the genes of the nematodes, it is possible to discover their function in humans. Indeed, the function of many genes involved in human cancer was discovered in worms. Research of the last decade revealed that flies, worms and humans use the same genes for similar functions, reflecting the “common ancestor.” Pires da Silva is interested in how genes regulate an embryo to develop into an adult and how that activity changes during evolution to make different animals.
Battling illness through genetics
Another area of research, funded by a grant from UT Arlington and UT Dallas, is identifying genes involved in neuro- degeneration, the premature death of neurons. During his doctoral studies in Germany, Pires da Silva induced genetic alterations in mice that resulted in massive neuronal death in the hindbrain and the eye, and he was able to identify the genetic defect that causes the death of the neurons. Building on that work, he is now exploring the function of the genes involved in neurodegeneration. The goal is to understand common features in the different neurodegenerative diseases such as Parkinson’s, Alzheimer’s and Lou Gehrig’s disease and to perfect therapeutic strategies.
For another disease, prevention strategies lie in the genes of mosquitoes.
Malaria is an infectious parasitic disease that annually kills up to 3 million people and debilitates hundreds of millions, mainly in the poor countries of sub-Saharan Africa. Assistant Professor Jaroslaw Krzywinski notes that of all mosquito species, only a small subset belonging to the genus Anopheles is capable of transmitting malaria.
Large-scale control is increasingly ineffective, due to the emergence of drug-resistant parasites and insecticide resistance in mosquitoes. Consequently, the number of malaria cases is rising. Since mosquito eradication programs are doomed to fail, biologists need to learn more about the biology of mosquitoes. Dr. Krzywinski uses molecular biology and bioinformatics tools to understand aspects of the structure, function and evolution of the Anopheles genome. One project concerns mate recognition. Genetically engineering mosquitoes to be incapable of transmitting the parasite to humans has been proposed as one way to combat the disease.
“But once they are released, these genetically engineered mosquitoes have to compete with other mosquitoes in the wild to get mates,” Krzywinski said. “And we don’t know yet what mosquitoes do to attract mates.”
Another laboratory is working with a virus that might be used to treat cancer. Assistant Professor Michael Roner is investigating how a virus with a genome divided into 10 pieces guarantees that all new viruses contain the same 10 pieces. In addition, this virus (the reovirus) is capable of selectively destroying human tumor cells with little damage to normal cells. Dr. Roner is exploring the mechanisms involved.
Chippindale studies evolutionary relationships and biological diversity, using DNA sequencing to reconstruct the phylogenies (historical relationships) of organisms. A phylogenetic tree, much like a family tree, provides the framework for investigation of diverse evolutionary phenomena like the Barton Springs salamander. The 2.5-inch amphibian, which lives only in a popular swimming hole in downtown
Austin, was given endangered species protection in 1997 by the federal government.
“That species exists only in Zilcher Park, nowhere else in the world,” Chippindale said, noting that it is not only valuable to understand the molecular basis of biodiversity, but also, if a species becomes extinct, what that foreshadows for other species, including humans.
“Like millions of other species, the Barton Springs salamander is an indicator of environmental health,” Chippindale said. “If it disappears, what does that tell us about the quality of water that Texans are swimming in and drinking?”
Assistant Professor Elena de la Casa-Esperón works with mice to understand the genetic basis of several phenomena that affect the transmission of genes and chromosomes throughout generations. These phenomena challenge the traditional genetic views and have important implications in regard to human fertility problems, genetic diseases, speciation and evolution. Many genomes have been sequenced, so the researcher goes one step further to investigate how the inheritance of traits can be affected by epigenetic modifications, which constitute an additional layer of genetic information beyond the pure DNA sequence. She has recently been awarded a University Research Enhancement grant.
Lorraine van Waasbergen is investigating how light controls gene expression in cyanobacteria, commonly known as blue-green algae. Cyanobacteria are an ecologically important group, producing much of Earth’s oxygen. They function much like higher plants, so they also serve as a simple model for studies of plant processes. Dr. van Waasbergen, an assistant professor, focuses particularly on how the cyanobacteria respond to the stress of high-intensity light, such as they might receive at mid-day. Studies such as these may ultimately lead to increases in crop yield.
Assistant Professor Esther Betrán works mainly with Drosophila melanogaster, commonly known as the fruit fly. The little insects, about 3 mm long, have been a model organism for research for almost a century. The entire genome has recently been sequenced in 12 related Drosophila species. Fruit flies have been used in genetics to discover that genes encode for proteins and to study the rules of genetic inheritance.
Dr. Betrán, whose work in funded by the National Institutes of Health, focuses on the origin of new genes, new functions and their role in genome evolution, adaptation and species differences. The benefits of new gene acquisition for the organisms have been enumerated since the 1960s, and recent molecular evidence indicates that the newly acquired genes (gene duplications) become fixed in all the individuals of the species and evolve further under positive selection.
Betrán has gathered this information from flies where she does her genome analyses and experimental work and also by looking at the genomes of humans, mice and chickens.
“One of my main interests is understanding the patterns in the generation of new gene copies and functions with respect to sex chromosomes because this is of primary significance to explaining sexual dimorphism, sex chromosome evolution and adaptation,” she said.
Pawel Michalak uses the new findings of molecular biology and the latest genomic and transcriptomics tools, such as DNA micro arrays, to explore natural variation at the level of populations and species, and their evolution. In his research, the assistant professor uses Drosophila and Xenopus African clawed frogs to address: (1) What genes make species distinct entities? (2) Are there any “speciation genes” that underlie the origin of new species? (3) Are males and females evolving at the same rate? (4) Is there any genetic regularity of dysfunctions characterizing interspecies hybrids?
These are among the questions that impel UT Arlington genomicists to investigate the complexity of living organisms and seek answers to disease.
— Sue Stevens