Category Archives: Genome

Every recipe has both instructions and ingredients. So does the human genome. An error in the instructions can raise the risk for disease.

Every cell in your body reads the same genome, the DNA-encoded instruction set that builds proteins. But your cells couldnt be more different. Neurons send electrical messages, liver cells break down chemicals, muscle cells move the body. How do cells employ the same basic set of genetic instructions to carry out their own specialized tasks? The answer lies in a complex, multilayered system that controls how proteins are made.

Frey compares the genome to a recipe that a baker might use. All recipes include a list of ingredientsflour, eggs and butter, sayalong with instructions for what to do with those ingredients. Inside a cell, the ingredients are the parts of the genome that code for proteins; surrounding them are the genomes instructions for how to combine those ingredients.

Just as flour, eggs and butter can be transformed into hundreds of different baked goods, genetic components can be assembled into many different configurations. This process is called alternative splicing, and its how cells create such variety out of a single genetic code. Frey and his colleagues used a sophisticated form of machine learning to identify mutations in this instruction set and to predict what effects those mutations have.

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The researchers have already identified possible risk genes for autism and are working on a system to predict whether mutations in cancer-linked genes are harmful. I hope this paper will have a big impact on the field of human genetics by providing a tool that geneticists can use to identify variants of interest, said Chris Burge, a computational biologist at the Massachusetts Institute of Technology who was not involved in the study.

But the real significance of the research may come from the new tools it provides for exploring vast sections of DNA that have been very difficult to interpret until now. Many human genetics studies have sequenced only the small part of the genome that produces proteins. This makes an argument that the sequence of the whole genome is important too, said Tom Cooper, a biologist at Baylor College of Medicine in Houston, Texas.

The splicing code is just one part of the noncoding genome, the area that does not produce proteins. But its a very important one. Approximately 90 percent of genes undergo alternative splicing, and scientists estimate that variations in the splicing code make up anywhere between 10 and 50 percent of all disease-linked mutations. When you have mutations in the regulatory code, things can go very wrong, Frey said.

People have historically focused on mutations in the protein-coding regions, to some degree because they have a much better handle on what these mutations do, said Mark Gerstein, a bioinformatician at Yale University, who was not involved in the study. As we gain a better understanding of [the DNA sequences] outside of the protein-coding regions, well get a better sense of how important they are in terms of disease.

Scientists have made some headway into understanding how the cell chooses a particular protein configuration, but much of the code that governs this process has remained an enigma. Freys team was able to decipher some of these regulatory regions in a paper published in 2010, identifying a rough code within the mouse genome that regulates splicing. Over the past four years, the quality of genetics dataparticularly human datahas improved dramatically, and machine-learning techniques have become much more sophisticated, enabling Frey and his collaborators to predict how splicing is affected by specific mutations at many sites across the human genome. Genome-wide data sets are finally able to enable predictions like this, said Manolis Kellis, a computational biologist at MIT who was not involved in the study.

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DALLAS - Dec. 23, 2014 - UT Southwestern Medical Center cancer researchers have demonstrated that whole-genome sequencing can be used to identify patients' risk for hereditary cancer, which can potentially lead to improvements in cancer prevention, diagnosis, and care.

This is the first study that has used whole-genome sequencing to evaluate a series of 258 cancer patients' genomes to improve the ability to diagnose cancer-predisposing mutations. The study is published online in the journal EBioMedicine.

"Whole-genome sequencing is a new genetic tool that can determine more of a person's DNA sequence than ever before. Our results show that nearly 90 percent of clinically identified mutations were confidently detected and additional cancer gene mutations were discovered, which together with the decreasing costs associated with whole-genome sequencing means that this method will improve patient care, as well as lead to discovery of new cancer genes," said Dr. Theodora Ross, Professor of Internal Medicine and Director of UT Southwestern's Cancer Genetics Program.

The physicians and genetic counselors in UT Southwestern's Cancer Genetics Clinic help patients assess their risk for many types of cancer, including kidney, skin, lung, breast, ovarian, colon, endocrine and prostate cancers. If a known genetic predisposition to cancer is found, Dr. Ross and her team counsel the patient about the best ways to detect early cancers or, better yet, prevent cancers from ever forming.

About 5 to 10 percent of all cancers are caused by known inherited gene mutations. These mutations are passed down from generation to generation. Mutations in the BRCA1 and BRCA2 genes are the most common cause of hereditary breast cancer. BRCA gene mutations are best known for their breast cancer risk, but they also cause increased risk for ovarian, prostate, pancreatic, and other cancers. In addition, there are many different genes, including ATM, CDH1, CHEK2, PALB2, PTEN, and TP53, that are associated with an increased risk for breast cancer, and researchers are continually discovering additional genes that may affect cancer predisposition.

In this study, researchers developed new methods to analyze the large amount of data generated by whole-genome sequencing. Specifically, Dr. Ross' team devised a method to compare the group of patients with BRCA1 or BRCA2 mutations to a group of patients without BRCA mutations. All expected BRCA1 and BRCA2 mutations were detected in the BRCA group, with at least 88.6 percent of mutations confidently detected. In contrast, different cancer gene mutations were found in the cohort without BRCA mutations.

"The results demonstrate that whole-genome sequencing can detect new cancer gene mutations in non-BRCA 'mystery' patients, demonstrating the added value whole-genome sequencing brings to the future cancer clinic," Dr. Ross said, although further investigation is needed in order to be able to interpret the precise clinical implications of the mutations found.

"Mystery patients are those who have a strong family history for cancer but after standard genetic testing, no genetic diagnoses are made. In our study, sequencing allowed us to discover novel candidate cancer gene mutations in mystery patients," said Dr. Ross, who holds the Jeanne Ann Plitt Professorship in Breast Cancer Research and the H. Ben and Isabelle T. Decherd Chair in Internal Medicine, in Honor of Henry M. Winans, Sr., M.D.

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Researchers confirm whole-genome sequencing can successfully identify cancer-related mutations

UT Southwestern Medical Center cancer researchers have demonstrated that whole-genome sequencing can be used to identify patients' risk for hereditary cancer, which can potentially lead to improvements in cancer prevention, diagnosis, and care.

This is the first study that has used whole-genome sequencing to evaluate a series of 258 cancer patients' genomes to improve the ability to diagnose cancer-predisposing mutations. The study is published online in the journal EBioMedicine.

"Whole-genome sequencing is a new genetic tool that can determine more of a person's DNA sequence than ever before. Our results show that nearly 90 percent of clinically identified mutations were confidently detected and additional cancer gene mutations were discovered, which together with the decreasing costs associated with whole-genome sequencing means that this method will improve patient care, as well as lead to discovery of new cancer genes," said Dr. Theodora Ross, Professor of Internal Medicine and Director of UT Southwestern's Cancer Genetics Program.

The physicians and genetic counselors in UT Southwestern's Cancer Genetics Clinic help patients assess their risk for many types of cancer, including kidney, skin, lung, breast, ovarian, colon, endocrine and prostate cancers. If a known genetic predisposition to cancer is found, Dr. Ross and her team counsel the patient about the best ways to detect early cancers or, better yet, prevent cancers from ever forming.

About 5 to 10 percent of all cancers are caused by known inherited gene mutations. These mutations are passed down from generation to generation. Mutations in the BRCA1 and BRCA2 genes are the most common cause of hereditary breast cancer. BRCA gene mutations are best known for their breast cancer risk, but they also cause increased risk for ovarian, prostate, pancreatic, and other cancers. In addition, there are many different genes, including ATM, CDH1, CHEK2, PALB2, PTEN, and TP53, that are associated with an increased risk for breast cancer, and researchers are continually discovering additional genes that may affect cancer predisposition.

In this study, researchers developed new methods to analyze the large amount of data generated by whole-genome sequencing. Specifically, Dr. Ross' team devised a method to compare the group of patients with BRCA1 or BRCA2 mutations to a group of patients without BRCA mutations. All expected BRCA1 and BRCA2 mutations were detected in the BRCA group, with at least 88.6 percent of mutations confidently detected. In contrast, different cancer gene mutations were found in the cohort without BRCA mutations.

"The results demonstrate that whole-genome sequencing can detect new cancer gene mutations in non-BRCA 'mystery' patients, demonstrating the added value whole-genome sequencing brings to the future cancer clinic," Dr. Ross said, although further investigation is needed in order to be able to interpret the precise clinical implications of the mutations found.

"Mystery patients are those who have a strong family history for cancer but after standard genetic testing, no genetic diagnoses are made. In our study, sequencing allowed us to discover novel candidate cancer gene mutations in mystery patients," said Dr. Ross, who holds the Jeanne Ann Plitt Professorship in Breast Cancer Research and the H. Ben and Isabelle T. Decherd Chair in Internal Medicine, in Honor of Henry M. Winans, Sr., M.D.

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The above story is based on materials provided by UT Southwestern Medical Center. Note: Materials may be edited for content and length.

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Whole-genome sequencing can successfully identify cancer-related mutations

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Newswise LOUISVILLE, Ky. Morris Animal Foundation has awarded a three-year, $155,000 grant to a team of Kentucky and Danish researchers to build a new reference genome sequence for the domestic horse. The sequence will be a much needed tool for animal researchers worldwide and the equine industry in particular because it will significantly improve the ability to understand the role of genetics in animal health and well being.

Ted Kalbfleisch, Ph.D., of the University of Louisville Department of Biochemistry and Molecular Biology, is the principal investigator on the grant. He will be joined in the research with Ludovic Orlando, Ph.D., of the Centre for GeoGenetics at the National History Museum, University of Copenhagen; and James MacLeod, V.M.D., Ph.D., of the Gluck Equine Research Center at the University of Kentucky.

Genome sequencing allows researchers to read and decipher genetic information found in DNA and is especially important in mapping disease genes discovering the diseases a horse might be genetically predisposed to developing.

In 2009, Morris Animal Foundation helped fund the first genome reference sequence for the domestic horse, Kalbfleisch said. We intend to build on this earlier work. In the past five years, there have been dramatic improvements in sequencing technology as well as the computational hardware and algorithms required to analyze the data generated by the technology. Therefore, we now have the tools necessary to vastly improve the reference genome for the horse.

The current reference genome for the horse, known as EquCab2, has been beneficial in studying horses and their genetic predisposition to disease, but it is not without its shortcomings, Kalbfleisch said.

The horse research community is working to understand the relationship among genomic structure, variation found within it and complex diseases and traits in the domestic horse, he said. The EquCab2 reference genome was developed prior to the development of todays highly sophisticated technology.

With the application of new high-throughput technologies we have available today, we will map the genome with a focus on what is known as the GC-rich regulatory regions.

These GC-rich regulatory regions control how genes are expressed (turned on) in order to participate in normal cellular processes. This work will enable scientists to better catalog genetic variation in these regions and understand how it affects health and performance.

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University of Louisville Leads New Study to Map Disease Genes in Horses

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