New technologies and techniques continue to accelerate the pace of discovery in human genetics research, a fact made clear by scientists who spoke about their searches for important mutations, gene variants and answers to basic biological questions at the UCSF Institute for Human Genetics’ fifth-anniversary symposium on Oct. 28.
The cost of spelling out the sequence of nucleic acids in long-stranded DNA molecules and incorporating these sequences into databases that can be used to probe links between genetic variation and disease risk keeps dropping, while the speed at which it can be done keeps getting faster.
These discoveries are beginning to make their way into medical practice as well, but the translation of lab findings into diagnostics and treatments proven safe and effective for standard medical practice cannot be expected to proceed at the same pace.
Even so, sequencing the entire genomes of cancer patients, as well the abnormal genomes of the tumors that plague them, may already have come to a nationally renowned medical center near you.
And in the search for genes at the root of inborn developmental disorders caused by DNA alterations in a single gene, highly skilled research teams no longer need to study the genes of large numbers of affected individuals to track down the gene at fault. It may be sufficient to sequence the genomes or partial genomes of a handful of patients, or even of one set of parents and a single child with the disease. A renaissance may be on the horizon for the discovery of causes of rare genetic disorders with simple Mendelian patterns of inheritance and distinctive clinical characteristics.
These medical possibilities were described convincingly at the UCSF symposium by Elaine Mardis, PhD, of the Washington University School of Medicine in St. Louis, and by Deborah Nickerson, PhD, of the University of Washington.
Old Order Amish School Scientists on Heart Disease
Another speaker, Alan Shuldiner, MD, from the University of Maryland’s School of Medicine, graphically illustrated what Michelangelo’s David would look like today on a typical fast-food diet – very obese. That was a prelude to describing studies on heart-disease risk factors and longevity in the Old Order Amish of Lancaster County, Penn.
The Amish have a small gene pool and good records of ancestry, reducing the complexity of finding genetic variants that may be associated with particular traits or diseases. With the help of the Amish, Shuldiner’s lab team has identified regions of the genome that contain genes conferring risk for type 2 diabetes, hypertension, elevated blood fat levels, and obesity. Shuldiner’s group also determined that a variant in the APOC3 gene found in 5 percent of the Amish improved fat profiles, and reduced calcification or “hardening” of the arteries.
Speaker James Evans, MD, PhD, from the University of North Carolina, has a research interest in policy questions related to the benefits and costs of the growing use of genetic information in medicine. As sequencing the entire genome becomes easier and cheaper, it is likely to be done for more and more patients, Evans says. He sees its greatest medical value in studies such as those described by Mardis and Nickerson for identifying clinically relevant DNA mutations in cancer and for finding mutations associated with inherited disease. But Evans also suggests that complete gene mapping to identify gene mutations is merited for undiagnosed individuals from families affected by heritable cancer.
“Perhaps one percent of the population has mutations, that if we knew about them, might be medically actionable,” Evans said.
Evans also said that a “tremendous application of whole genome sequencing” could be prenatal screening or even the screening of an expectant woman and spouse to identify disease genes and to let the couple know about risks of devastating “recessive” disorders in children who inherit an abnormal copy of the same disease-associated gene from each parent.
Men, Women and Neanderthals
Anyone who has ever taken a biology course probably knows that women have two X chromosomes, and that men have one X chromosome coupled with one Y chromosome with relatively few genes. Four decades ago scientists figured out that one of the X chromosomes is inactivated in a woman’s cells. In the 1970s, UCSF medical geneticist Charles Epstein, MD, determined that one stage of inactivation occurs before the embryo implants in the womb.
At the symposium Epstein and his wife Lois Epstein, MD, another long-time UCSF researcher, introduced speaker Terry Magnuson, PhD, an X-chromosome expert from the University of North Carolina School of Medicine, who is the first Charles J. and Lois B. Epstein Visiting Professor in Human Genetics and Pediatrics.
There’s more to discover about the genetics and biochemistry of X-chromosome inactivation, but Magnusson described remarkable progress made by his lab group using today’s state-of-the-art research tools.
In another talk about fundamental genetic discoveries, a scientist ventured into a realm previously ruled by anthropologists.
Starting with studies of quaggas and mummies and moving on to Ice Age mega-fauna before settling on our closest extinct relative, the Neanderthals, Svante Paabo, PhD, from the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, has pioneered the study of ancient DNA.
Paabo, who estimates that despite degradation of samples it might be possible to sequence DNA that is as much as one million years old, recently succeeded in mapping 55 percent of the Neanderthal genome from three 38,000-year-old bones taken from a Croatian cave. Based on comparison with human DNA, Paabo reported that except for Africans, most people alive today possess Neanderthal DNA as a result of interbreeding between Neanderthals and our prehistoric ancestors 30,000 years ago or more, The Neanderthal DNA makes up about one to four percent of the modern human genome, according to Paabo.
Genes, Environment and Disease
Neil Risch, PhD, director of the UCSF Institute for Human Genetics, along with UCSF scientist Pui-Yan Kwok, MD, PhD, and Catherine Schaefer, PhD, director of the Kaiser Permanente Research Program on Genes Environment and Health, described their on-schedule progress in a two-year collaborative project to scan the genomes of more than 100,000 members of Kaiser Permanente Northern California, research made possible by a $25 million in stimulus funds from the National Institutes of Health.
The wealth of data obtained will be coupled with an already rich and continually expanding Kaiser research resource that includes long-term medical records, augmented by already-collected survey data and information on environmental exposures that may pose health risks.
The researchers have worked with Affymetrix of Santa Clara, Calif. to customize a lab on a chip with 675,000 markers for human genetic variability that cover the entire genome. The genetic data collected, along with the clinical and environmental exposure data contained in Kaiser’s massive research resource, will prove invaluable to scientists who want to conduct genome-wide association studies to search for genetic risks for disease.
Kwok, who develops new strategies and technologies for DNA analysis, said that 44,000 samples already have been successfully analyzed, and that his UCSF lab is adding to the number at a rate of 2,000 per week.
In a related project using a portion of the same samples, UCSF Nobel laureate Elizabeth Blackburn, PhD, and colleagues will be measuring the length of protective DNA caps called telomeres. Telomere length and changes in telomere length have been associated with health status and longevity in earlier research.
“We’re totally on track and we are very excited about being able to begin analyzing the results,” Kwok said.
UCSF Researchers Are Mapping DNA from 100,000 People for Unique Kaiser Database,
Science Café, January 12, 2010
Accolades Mount for Esteemed UCSF Human Geneticist Charles Epstein,
UCSF Today, August 16, 2010
Researchers Probe Links Between Modern Humans and Neanderthals
UCSF Science Café