Deletions or additions to the genome explain some nervous system disorders
By Ruth SoRelle, M.P.H.
Understanding many nervous system disorders means taking the large view of the human genome, looking beyond small changes in the sequence of DNA, and identifying structural variations such as deletions or additions of large chunks of genetic material, said Baylor College of Medicine researchers in a review that appears in a recent issue of the journal Neuron.
In fact, said James Lupski, M.D., Ph.D., professor of molecular and human genetics and pediatrics at BCM, many nervous system disorders are associated with extra copies of genes or deletions of large chunks of the genome that can affect the amount of protein produced associated with a particular gene.
In the paper, co-authored by graduate student Jennifer Lee, the two scientists describe neurodevelopmental, neurodegenerative, behavioral and psychiatric disorders known or believed to result from these large genomic changes. These large changes can result in extra copies of genes being present in the genome or deletions of genes, which can affect the amount of circulating protein associated with the disease.
One advance that makes it easier to study such changes is the development of DNA microarrays that enable researchers to scan an entire human genome at once at higher resolution than previously possible with a microscope. While DNA sequencing looks at each base pair, these microarrays, or gene chips, allow scientists to evaluate thousands of bases or megabases at once, identifying large differences in the structure of genetic material.
In fact, said Lupski, the first disease in which this was identified in his lab was Charcot-Marie Tooth in which variation in the number of copies of a gene called PMP22 can cause different forms and severity of the neurodegenerative disorder.
"We can now identify several instances wherein changes in the normal two copies of a gene – one from Mom and one from Dad – can result in a clinical disease phenotype (or symptoms)," said Lupski.
"These larger structural changes can even be associated with behavioral disorders or psychiatric traits," said Lee.
This copy number variation thesis could explain the question as to why people could inherit a gene but not show signs of the disease until they are 40 or 50 years old. Parkinson's disease is a case in point.
"There is a tremendous amount of structural variation in the human genome," said Lupski. In some cases, the structural changes or variations in the number of genes may not have an effect, but in others it could be involved in susceptibility to disease.
In other cases, he said, a woman may have one chunk of her genome missing and marry a man with another chunk gone. They themselves may not have a disease, but the child they produce might because he or she inherited both structural variants.
Understanding this may change the way scientists study diseases, he said. If a genomic disorder results from altered gene dosage, it may be possible to intervene therapeutically by correcting the gene dosage.
"When you study an 85-year-old with Alzheimer's disease, you don't just look at the base pair changes. You look at the structural changes in the genome," he said.
Lupski is also vice chair of the BCM department of molecular and human genetics.
Other disorders discussed in the paper include: Charcot-Marie-Tooth disease type 1A, Williams-Beuren Syndrome, Miller-Dieker Syndrome and Lissencephaly, Angelman and Prader-Willi syndromes, Smith-Magenis Syndrome, Neurofibromatosis Type 1, spinal muscular atrophy (SMA), and Alzheimer's disease.
