Monthly Archives: February 2017

February 24, 2017 Dr. Pengfei Liu holding human DNA treated with fluorescent dyes prepared for copy number variant analysis. Credit: Baylor College of Medicine

The genetic material of an organism encodes the instructions that guide its development. These codes are not written in stone; they can change or mutate any time during the life of the organism. Single changes in the code can occur spontaneously, as a mutation, causing developmental problems. Others, as an international team of researchers has discovered, are too numerous to be explained by random mutation processes present in the general population. When such multiple genetic changes occur before or early after conception, they may inform scientists about fundamental knowledge underlying many diseases. The study appears 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 lead author Dr. Pengfei Liu, assistant professor of molecular and human genetics Baylor College of Medicine and assistant laboratory director of Baylor Genetics. "Of these samples, five had extreme numbers of genetic changes that could not be explained by random events alone."

The researchers looked at a type of genetic change called copy number variants, which refers to the number of copies of genes in human DNA. Normally we each have two copies of each gene located on a pair of homologous chromosomes.

"Copy number variants in human DNA can be compared to repeated or missing paragraphs or pages of text in a book," said senior author Dr. James R. Lupski, 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."

A rare, early and transitory phenomenon that can affect human development

The researchers call this phenomenon multiple de novo copy number variants. As the name indicates, the copy number variants are many and new (de novo). The latter means that the patients carrying the genetic changes did not inherit them from their parents because neither the mother nor the father carries the changes.

In this rare phenomenon, the copy number variants are predominantly gains duplications and triplications rather than losses of genetic material, and are present in all the cells of the child. The last piece of evidence together with the fact that the parents do not carry the alterations suggest that the extra copies of genes may have occurred either in the sperm or the egg, the parent's germ cells, and before or very early after fertilization.

"This burst of genetic changes happens only during the early stages of embryonic development and then it stops," Liu said. "Interestingly, despite having a large number of mutations, the young patients present with relatively mild neurological problems."

The researchers are analyzing more patient samples looking for additional cases of multiple copy number variants to continue their investigation of what may trigger this rare phenomenon.

"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."

A new era of clinical genomics-supported medicine and research

This discovery was made possible in great measure thanks to the breadth of genetic testing performed and genomic data available at Baylor Genetics laboratory.

"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," Lupski said. "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."

Using state-of-the art technologies and highly-trained personnel, Baylor Genetics analyzes hundreds of samples daily for genetic evaluation of patients with conditions suspected to have underlying genetic factors potentially contributing to their disease. Having this wealth of information and insight into the genetic mechanisms of disease offers now the possibility of advancing medicine and basic research in ways that were not available before.

"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."

Explore further: Largest study of its kind finds rare genetic variations linked to schizophrenia

More information: An Organismal CNV Mutator Phenotype Restricted to Early Human Development. Cell, DOI: dx.doi.org/10.1016/j.cell.2017.01.037

Journal reference: Cell

Provided by: Baylor College of Medicine

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Scientists find a striking number of genetic changes can occur early in human development - Medical Xpress

February 24, 2017 by Geri Clark Killer T cells surround a cancer cell. Credit: NIH

A newly discovered type of genetic mutation that occurs frequently in cancer cells may provide clues about the disease's origins and offer new therapeutic targets, according to research from Weill Cornell Medicine and the New York Genome Center.

Using next-generation sequencing technology, scientists have previously traced cancer's roots to mutations that disrupt the sequence of proteins. As a result, the cell either creates hyperactive or dysfunctional versions of proteins, or fails to produce them at all, leading to cancer. Now, a study published Jan. 12 in Cell illuminates a possible new type of driver of the disease: small (one- to 50-letter) insertions or deletions of DNA sequence, also called "indels," in regions of the genome that do not code for protein.

"Those noncoding regions are still important because they contain sequences that affect how genes are regulated, which is critical for normal cell development," said lead author Dr. Marcin Imielinski, an assistant professor of pathology and laboratory medicine at Weill Cornell Medicine and a core member at the New York Genome Center. "We already know they are biologically important. The question is whether they can impact cancer development."

In the study, Imielinski and his colleagues analyzed sequencing data from several publicly available databases of tumor samples, focusing on the 98 percent of the genome that does not code for protein. They initially looked at lung adenocarcinoma, the most common type of lung cancer, and found that the most frequent indel-mutated regions in their genomes landed in genes encoding surfactant proteins.

Though these genes are essential for healthy lung function, they had not previously been associated with lung cancer. However, they are highly and specifically expressed by the cell type that gives rise to lung adenocarcinoma.

The researchers then looked at the genomes of 12 other cancer types and found similar patterns in liver, stomach and thyroid tumors.

"In each cancer, noncoding indels clustered in genes that are critical to organ function, but had not been associated with the cancer," said Imielinski, who is also an assistant professor of computational genomics in the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

Most strikingly, these noncoding indels are very common, occurring in 20 to 50 percent of the associated cancers.

"They occur as frequently as the most famous cancer-causing mutations," said Imielinski, a paid consultant for the company 10X Genomics, which sells devices and technology to analyze genetic information. "Any gene or any sequence that mutated at this frequency has been shown to play a causal role in cancer. That would be an exciting outcome, if we can prove it."

Even if these mutations are not shown to cause cancer, they can be used in the future to improve cancer diagnosis and treatment.

"These mutations can be biomarkers that help us to diagnose a cancer early, or they could be used to pinpoint a primary cancer when there are metastases and we can't find the original cancer," Imielinski said. "There are a lot of potential clinical implications from these findings."

Explore further: Researchers pinpoint key regulatory role of noncoding genes in prostate cancer development

More information: Marcin Imielinski et al. Insertions and Deletions Target Lineage-Defining Genes in Human Cancers, Cell (2017). DOI: 10.1016/j.cell.2016.12.025

Journal reference: Cell

Provided by: Cornell University

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Discovery of genetic mutation may boost cancer therapies - Medical Xpress