Cataloging the Structural Variations in Human GeneticsMay 10, 2007
Past studies of human genetic differences usually have focused on the individual "letters" or bases of a DNA sequence. But the genetic differences between humans amount to more than simple spelling errors. "Structural changes — insertions, duplications, deletions, and inversions of DNA — are extremely common in the human population," says Eichler. "In fact, more bases are involved in structural changes in the genome than are involved in single-base-pair changes."
In some cases, individual genes appear in multiple copies because of duplications of DNA segments. In other cases, segments of DNA appear in some people but not others, which means that the "reference" human genome produced by the Human Genome Project is incomplete. "We're finding new sequence in the human genome that is not in the reference sequence," Eichler says.
These structural changes can influence both disease susceptibility and the normal functioning and appearance of the body. Color-blindness, increased risk of prostate cancer, and susceptibility to some forms of cardiovascular disease result from deletions of particular genes or parts of genes. Extra copies of a gene known as CC3L1 reduce a person's susceptibility to HIV infection and progression to AIDS. Lower than normal quantities of other genes can lead to intestinal or kidney diseases.
Variation in the number of genes or in gene regulation caused by structural rearrangements may also contribute to more common diseases. "The million dollar question is what is the genetic basis of diseases like diabetes, hypertension, and high cholesterol levels?" says Eichler. " We know there is a genetic factor, but what is the role of single base pair changes versus structural changes?"
The project Eichler and his colleagues describe in their paper will help answer this question. Using DNA from 62 people who were studied as part of the International HapMap Project, they are creating bacterial "libraries" of DNA segments for each person. The ends of the segments are then sequenced to uncover evidence of structural variation. Whenever such evidence is found, the entire DNA segment is sequenced to catalog all of the genetic differences between the segment and the reference sequence.
The result, says Eichler, will be a tool that geneticists can use to associate structural variation with particular diseases. "It might be that if I have an extra copy of gene A, my threshold for disease X may be higher or lower." Geneticists will then be able to test, or genotype, large numbers of individuals who have a particular disease to look for structural variants that they have in common. If a given variant is contributing to a disease, it will occur at a higher frequency in people with the disease.
Knowing about structural variation in the human genome will also allow geneticists to analyze single-base-pair changes more effectively, according to Aravinda Chakravarti, a geneticist at The Johns Hopkins University School of Medicine who was not a coauthor of the paper. "We have to look at structural variants from a different perspective, because they are adding or subtracting something from the genome," Chakravarti says. By understanding the patterns of both structural variants and single-base-pair changes in the population, "we'll learn a lot." To use both kinds of information in tandem, Eichler and his colleagues plan to incorporate the structural information they gather into existing databases on single-base-pair changes.
The project, which is being funded by the National Human Genome Research Institute at the National Institutes of Health, is difficult and expensive, Eichler admits. "It's a lot of work, because it's essentially doing 62 additional human genome projects," he says. "Having been involved in the first one, I swore I would never do it again. But in this case we're looking at the coolest parts of the genome."
Howard Hughes Medical Institute
Related Human Genetics Current Events and Human Genetics News Articles
Tiny mitochondria play outsized role in human evolution and disease
Mitochondria are not only the power plants of our cells, these tiny structures also play a central role in our physiology.
A mutated gene found in families with multiple tumors, including cardiac angiosarcoma
A few years ago, Javier Benítez, director of the Human Genetics Group at the CNIO, received a call from Pablo García Pavía, from the Cardiology Unit of the Puerta de Hierro University Hospital.
Overweight firefighters more likely to attempt weight loss if advised by doctor
Overweight firefighters are twice as likely to attempt to lose weight if their health care provider gives them weight loss advice, according to new research from The University of Texas Health Science Center at Houston (UTHealth) School of Public Health. The results were published in this month's print edition of the American Journal of Preventive Medicine.
Maternal protein deficiency during pregnancy 'memorized' by fetal muscle cells
A new study has uncovered the genetic processes that link insufficient protein consumption during pregnancy with the development of muscle problems in mothers and their male offspring.
Whole-body PET scan with new imaging agent can locate hidden blood clots
A novel radiopharmaceutical probe developed at Massachusetts General Hospital (MGH) has the potential of providing physicians with information that could save the lives of patients with ischemic stroke or pulmonary embolism - conditions caused when important blood vessels are blocked by a clot that has traveled from another part of the body.
Survey finds many physicians overestimate their ability to assess patients' risk of Ebola
While most primary care physicians responding to a survey taken in late 2014 and early 2015 expressed confidence in their ability to identify potential cases of Ebola and communicate Ebola risks to their patients, only 50 to 70 percent of them gave answers that fit with CDC guidelines when asked how they would care for hypothetical patients who might have been exposed to Ebola.
Researchers use brain scans to predict response to antipsychotic medications
Investigators at The Feinstein Institute for Medical Research have discovered that brain scans can be used to predict patients' response to antipsychotic drug treatment. The findings are published online in the latest issue of The American Journal of Psychiatry.
New strategy improves detection of genetic mutations in hereditary colorectal cancer
About 3% of colorectal cancers are due to Lynch syndrome, an inherited cancer susceptibility syndrome that predisposes individuals to various cancers.
Study reveals effects of chemoradiation in brains of glioblastoma patients
A study from Massachusetts General Hospital (MGH) Cancer Center researchers - the first to examine the effects of combined radiation and chemotherapy on the healthy brain tissue of glioblastoma patients - reveals not only specific structural changes within patients' brains but also that the effect of cancer therapy on the normal brain appears to be progressive and continues even after radiation therapy has ceased.
Studies reveal how anesthesia's brain effects differ in older adults and in children
Recent Massachusetts General Hospital (MGH) investigations into the neurobiology underlying the effects of general anesthesia have begun to reveal the ways different anesthetic agents alter specific aspects of the brain's electrical signals, reflected by EEG (electroencephalogram) signatures.
More Human Genetics Current Events and Human Genetics News Articles