While we may think of our genome as being relatively stable and unchanging, but there are many opportunities for subtle alterations to get into the genetic code. Many of those changes happen spontaneously. But nature was ready for that event; there is a lot of redundancy built into how the genetic code is translated into proteins rendering many mutations harmless. However, some of those changes can have major consequences, especially if they happen very early on in development. Mutations don't only involve differences in one or two bees or nucleotides, the individual letters that create the genome, some involve the replication of whole genes or portions of genes. Those mutations are called copy number variants, animated in the following video. After analyzing a huge amount of data from individual people, researchers at Baylor have found higher than expected rates of mutations, suggesting they are not all arising from random events. Their work, completed with an international team, has been published in Cell.
"As a part of the clinical evaluation of young patients with a variety of developmental issues, we performed clinical genomic studies and analyzed the genetic material of more than 60,000 individuals. Most of the samples were analyzed at Baylor Genetics laboratories," said the lead author of the report, Dr. Pengfei Liu, an Assistant Professor of Molecular and Human Genetics Baylor College of Medicine. "Of these samples, five had extreme numbers of genetic changes that could not be explained by random events alone."
People should normally have two copies of each gene. The researchers saw something surprising, however. "Copy number variants in human DNA can be compared to repeated or missing paragraphs or pages of text in a book," explained senior author Dr. James R. Lupski, the Cullen Professor of Molecular and Human Genetics at Baylor. "For instance, if one or two pages are duplicated in a book it could be explained by random mistakes. On the other hand, if 10 different pages are duplicated, you have to suspect that it did not happen by chance. We want to understand the basic mechanism underlying these multiple new copy number variant mutations in the human genome."
This event is referred to as multiple de novo copy number variants, because the copies arise newly, seemingly out of nowhere as they were not inherited from parents. This phenomenon also refers primarily to gains of new copies (duplications and even triplications) rather than losses. The nature of these copy number additions suggest they'e added very early on in development, so either in the egg or sperm, in the germ cells of a parent, right around the time of fertilization.
"This burst of genetic changes happens only during the early stages of embryonic development and then it stops," explained Liu. "Interestingly, despite having a large number of mutations, the young patients present with relatively mild neurological problems."
The research team is continuing to look at new data to understand more about copy number variation; they would like to figure out what's driving this process. "We hope that as more researchers around the world learn about this and confirm it, the number of cases will increase," Liu said. "This will improve our understanding of the underlying mechanism and of why and how pathogenic copy number variants arise not only in developmental disorders but in cancers."
Baylor Genetics laboratory has amassed a tremendous amount of patient genetic data, giving them the power for such an extensive and comprehensive survey. The expert staff is able to process hundreds of new samples every day, creating a rich resource for investigators, who have been able to use the information to further human genetics.
"The diagnostics lab Baylor Genetics is one of the pioneers in this new era of clinical genomics-supported medical practice and disease gene discovery research, " said Lupski. "They are developing the clinical genomics necessary to foster and support the Precision Medicine Initiative of the National Institutes of Health, and generating the genomics data that further drives human genome research."
"There is so much that both clinicians and researchers can learn from the data generated in diagnostic labs," Liu said. "Clinicians receive genomic information that can aid in diagnosis and treatment of their patients, and researchers gather data that can help them unveil the mechanisms underlying the biological perturbations resulting in the patients' conditions."
Check out the following talk on genetic sequencing and testing techniques featuring one author of this work, Dr. Pengfei Liu.