Tag Archives: human genetics

Prepare NGS for clinical use

Molecular diagnostics (MDx) is to my opinion the most sensitive application for all kinds of molecular biology techniques like PCR, Sanger Sequencing or Next Generation Sequencing. Today, NGS is still a niche application and needs further improvement to be a common tool for MDx. One thing that is lacking is the standardisation of NGS for clinical use.

The NGS Working Group, established by the Friends of Cancer Research worked out a master plan (The ASCO Post), with critical points that need to be addressed to use NGS more commonly:

1. Define a regulatory pathway for cancer panels (a selection of multimarker gene assays) intended to identify actionable oncogenic alterations (those with supporting data to create risk-benefit assessment of treatment choice) that allow flexibility in the appropriate FDA medical device pathway—for instance, one based on risk classification of different panel components depending on the specific marker.

2. Approaches to validation studies should be based on the types of alterations measured by the assay rather than on every alteration individually.

3. Determine the contents of a cancer panel by classifying potential markers based on current utility in clinical care and clinical trials and peer-reviewed publications, as well as recognized clinical guidelines. Draw upon various sources to determine the recommended marker set for an actionable cancer panel.

4. Promote standardization of cancer panels through development and use of a common set of samples to ensure reproducibility on each platform.

5. Establish a framework for determining an appropriate reference method rather than relying on any single method for all studies.

Get more information to each proposal here.

Unexpected Heroes

Image courtesy of FreeDigitalPhotos.netThere are several mutations known which are linked to childhood diseases. This knowledge is already being used e.g. to analyze genomes of sick newborns for any known diseases, or for prenatal diagnostics. However: A person carrying such a mutation must not necessarily get ill.

Some individuals carry a mutation that should have caused a severe disease in their childhood. However, some yet unknown factors have protected them from getting ill. Even though they may be very rare, studying such persons may help to understand more about the diseases, or even find new treatments.

Researchers of the “Resilience Project” are now looking for such individuals who they call “unexpected heroes”: Adults who are “resilient to a certain rare disease despite carrying genetic mutations that would indicate onset of the disease in childhood.” In order to find those rare individuals, they are asking for volunteers to donate DNA samples for the project. Since they expect only 1 of 20,000 individuals to be such an “unexpected hero”, they need to analyze the genomes of more than 100,000 individuals. Participants can register online and will receive a test kit by mail. In return, the volunteers get a report indicating whether any of the analyzed mutations have been found in his or her genome.

The researchers hope to identify genes that can “buffer” the effects of the mutations, as well as environmental factors which help people carrying the mutations to stay healthy. The goal is to find new treatments, or even prevent people from getting ill at all.

Why is Illumina so successful? Watch an interview with Illuminas CEO

In the 2nd quarter of 2014 Illumina reported adjusted earnings of 57% per share – most probably the biggest increase in the companies history. Watch this interview with the CEO of Illumina, Jay Flateley, to learn more about the reasons of Illumina’s success.


100,000, 40,000, 25,000, 19,000 – the shrinking human genome…

DNAFor sure many of you remember old textbooks, in which the total number of genes in the human genome was estimated around 40,000 to 100,000. After the human genome was sequenced this number shrunk to 26,000 – 40,000 genes. The 19th GENCODE release further reduced this number to 20,318 protein-coding genes. But not enough a recent study suggested that the actual number of protein-coding genes in humans lies around 19,000.

This astonishing result could be obtained by analyzing the data derived from seven large MS-based proteomics studies from more than 50 human tissues.

But the shrinking number of genes is not the only remarkable results – find below the most important results from this study as described in a recent ScienceDaily blog post:

  • Close to 12 000 human genes could be unambiguously identified
  • Despite high coverage from seven analyses, 40% of the peptides from the human gene set could not be detected; Possible reasons:
    • Thousands of genes annotated in the human genome did not appear in the proteomics analysis.
    • Apparently 1,700 genes that were previously thought to produce proteins most certainly don’t
  • Another hypothesis is that more than 90% of human genes produce proteins originating in metazoans or multicellular organisms living hundreds of millions of years ago
  • The difference between humans and primates at the gene and protein level is very small
  • “The number of new genes that separate humans from mice may even be fewer than 10”
  • Physiological and developmental differences between primates are more likely caused by gene regulation than by differences in the basic functions of proteins in question

Alfonso Valencia, the main researcher behind this project states that “the human genome is best annotated, but we still believe that 1,700 genes may have to be re-annotated”.

According to Alfonso Valencia these results may redefine the entire mapping of the human genome.

Possibility of Ideal Intestinal Remedy

I’m not able to keep intestinal condition without remedy which is prepared by Lactobacillus, Bifidobacterium, Lactococcus, and others. Eating yogurt is also okay for this purpose, ad personam I prefer to take these bacterial tablets and believe more effects. However, many people know these effects of current intestinal remedies are mild not fast-acting properties.

Several reports mentioned that intestinal bacterial flora and its regulation were not simple. It is starting discussion that natural immunity may regulate intestinal flora; e.g. antibacterial peptide α-defensins which is secreted from paneth cells on small-intestinal epithelium could regulate flora distribution (Salzman et al., 2010; Matsuda et al., 2011). By contrary, very simple strategy is reported as following: Clostridium difficile brings bad diarrhea that was resistant to antibiotic. Van Nood and co-workers (2013) injected healthy person’s feces into patient’s guts, and its curative effect was so good surprisingly, but we cannot call it a remedy!

Two NGS platforms, GS FLX/Junior and MiSeq, can perform distributional analysis via deep sequencing of 16S-rRNA amplicons. But it is still difficult for both platforms to do metagenome assembling for getting whole gene information in flora, because their read length is not long enough to make reliable contigs without chimeras between different bacteria one another. Therefore I strongly expect that super long read platforms including PacBio RS series and coming nano-pore technologies will break current limitations and will contribute to develop ideal intestinal remedy for my instable stomach.

Tumor Heterogeneity And The Underlying Genetics

Although this recorded seminar is promoted by Illumina, I still can recommend it as a very good talk about basic concepts on tumor heterogeneity and the underlying genetics. Kenneth Bloom, Chief Medical Officer at Clarient (GE Healthcare) and a pathologist, explains the needs for the application of NGS in clinical lab in a simple and very vivid manner. While watching this video I gained a better idea of the needs of a diagnostics lab and the challenges in developing a diagnostic NGS panel.

Genomics – A Curse Or A Blessing?

Is sequencing your personal genome a curse or a blessing? A recent radio broadcast from NPR news summarises two scientist’s opinions and their practical experiences with genome sequencing  (listen to the radio broadcast below).

World renowned scientist James Watson, from the famous Watson & Crick team that discovered the DNA structure, recently sequenced his own genome. His discovery didn’t earn him the next Nobel prize for science, but he found out that he belongs to the elite few people whose body is more sensitive to ß-blockers. Now James Watson finally realized why it was so difficult for him to balance his blood pressure. It definitely paid off for Watson to sequence his own genome since he could significantly reduce his weekly ß -blocker intake. But despite this “health-changing” experience, he forbid his colleagues to reveal any information about his likelihood to develop Alzheimer. He said, “since you cannot cure it why would you like to know about it?”

The second candidate to share his experience after he personally sequenced his genome is Stanford geneticist Michale Snyder. His genome sequencing revealed that he was at high risk to develop Type 2 diabetes. A few months after his discovery, Synder got the disease that his genome anticipated. Was this a coincidence or fate? For Snyder, knowledge about his genome gave him a head start against the disease.  By completely transforming his diet and participating in various sport activities,  he overcame his Type 2 diabetes.

From my perspective, both examples show that knowledge about our genetic information can be useful in preventing and treating diseases. It boils down to how much experience exist to reliably interpret the data.

How dirty is your office?

16S rRNA sequencing of samples from 54 office-common surfaces in 3 different cities (New York, San Franscisco, Tuscon) revealed that offices of men are dirtier than these of women and the offices in San Francisco are the cleanest among the three cities. This is part of the results from Hewitt et al. published in PLoS ONE just recently. Overall they found “more than 500 bacterial genera from 20 different divisions” (Hewitt et al.) whereas most could be found on chairs and phones (see graph). But interestingly the bacterial population from Tuscon was significant different to the one from San Francisco and NewYork although the distance between Tuscon and San Francisco is smaller. From my point of view this is a great study showing that distribution is not as obvious as we think and that we haven’t revealed every secret on earth yet.

The first human genome exhibit at The Smithsonian Institution

Last week The Smithsonian Institution’s National Museum of Natural History at Washington DC announced a new exhibit to celebrate the 10th anniversary of the completion of the human genome. The project is a collaboration between the museum and the National Human Genome Research Institute, with major funding coming from the Life Technologies Foundation. It will open in 2013 to the 7 million annual visitors of the museum.


“The goal of the exhibition is not just to celebrate but to look ahead and acknowledge that we are in the early stages of a very exciting genomic era, that we have learned a remarkable amount about how the genome works and how it contributes to health and disease, and that the pace of research is only accelerating and becoming increasingly relevant to people,” said NHGRI Director Eric Green.
Also announced last week was a new grant program by the NHGRI to study newborn genome sequencing. It will provide $25 million to study how whole genome or whole exome sequencing will benefit newborn care as well as its social implications.
“Genome”, “genomics” etc used to be terms understood by few outside of biology and bioinformatics. This is changing rapidly. It is exciting time ahead of us to witness the genomics revolution.

A Documentary on the Use of Sequencing Technologies in Medicine

A documentary titled “Cracking Your Genetic Code” was recently released, and it offers a glimpse on how genomics is transforming medicine. Prominent scientists are featured, including Francis Collins from the National Institute of Health and Eric Lander from the Massachusetts Institute of Technology. In the documentary we are introduced to technologies for sequencing the entire genome; Illumina is being mentioned as one of the companies with such technology. We hear real-life stories where genome sequencing and genotyping led to diagnoses and successful treatments that would not happen otherwise.

The documentary does not only present the promises that personalized medicine is bringing, it also raises important questions concerning the readiness of the society in adopting this new form of medicine. There are always pros and cons with introducing new technologies to our daily lives. It is a matter of engaging and educating the public so the society as a whole can make some informed decisions during this healthcare revolution. Cracking your Genetic Code is a great introduction to the new role of sequencing in medicine, and I hope you will share it with your colleagues and friends!