Eliminating Highly Polymorphic Genes from Whole Exome Sequencing

Whole exome sequencing yields thousands of variants for each individual sequenced.  Many of these variants are in genes that are highly polymorphic or in regions that do not sequence well and therefore would not be of interest when searching for a disease-causing variant.  This is because any frequently mutated gene containing many deleterious variants will have a low probability of containing the disease-causing mutation.  Also, if the gene is in a region that does not sequence well then a high number of variants will be often reported.  When you find such variants, this would be considered a false positive.   There is a big interest in detecting these false positive signals and eliminating these variants from the list reported back from whole exome sequencing.  

A paper was just published this month in Human Mutation describing a way to do this.  They published several lists of genes for researchers to use in their own projects.  The researchers hypothesize these genes will not contain the disease-causing mutation.   This list of genes could be an incredibly useful tool to filter out highly polymorphic genes or genes that simply do not sequence well.

Policy on 'Secondary findings' from Whole Genome Sequencing in Clinical Tests

The American College of Medical Genetics and Genomics (ACMG) is having their annual meeting this week in North Carolina.  One of the major discussion points is: when a patient has their genome sequenced to look for disease-causing mutations for a specific disease in a clinical setting, what do you do with the 'secondary-findings' or other mutations unrelated to the disease in question that have been found?  This is an incredibly difficult and convoluted question to answer.

For example in the clinical setting, say a patient's genome is being sequenced to test if their genome contains mutations related to high cholesterol, but in the process other mutations come back positive for Alzhimer's.  Should a patient be informed of the 'secondary-finding' information?  What if it were a child?  Should the child know at a young age that they have a high predisposition to Alzhimer's?

In a research setting, there currently exist hundreds of large sequencing studies which sequence the genomes of many individuals suffering from a particular disease in an effort to study the etiology of that disease.  When patients participate in these sequencing projects, thousands of mutations are often found which may or may not be related to a wide spectrum of diseases.  When researchers find mutations related to other diseases, should the researchers be responsible of reporting the information to the patient?  If the individual's genome is sequenced a second time at a later point in the future and mutations related to diseases that were not known before, but are now known are found, should the researcher be responsible of tracking down the individual to inform them?  If a patient was informed at one point in time to have a deleterious mutation, but in the future that mutation is no longer considered to be deleterious, what should happen?  At the American Society of Human Genetics (ASHG) annual meeting this fall in Montreal, I attended a similar forum that discussed many of these questions. The conversation can only be described as "intense and very heated".  There were individuals who were adamantly in support of informing patients of secondary-findings and individuals who were adamantly against it in both the research and clinical-based setting.

The ACMG is releasing a policy statement which will be finalized this summer in support of reporting secondary findings to patients in the clinical setting.   The policy says only disease-causing mutations with a high-prevelance for a treatable condition will be included for this clinical-based testing.  Mutations for diseases with no known treatments will not be included in the list.  I will be interested to see how we as a society decide to deal with all the other issues that will come out of this policy.  A few of the issues include: How we will relay the information to the patients?  Who is responsible to relay the information?  Who will help the patients interpret these variants? Who is responsible for updating the patient on new information in the future? Of course there are also the legal issues related to the patient's privacy?

Loss-of-function mutations

A study by the Welcome Trust Sanger Institute and Yale University released in Science this month set out to determine on average how many genuine loss-of-function mutations do humans carry and how many genes are inactivated because of the mutations.  Depending on what definition you use, humans carry ~20,000 genes.  These loss-of-function mutations cause the protein to lose its structure or function.   For example, one of the most common cancer genes, TP53, is called a tumor-suppressing gene because it controls the cell cycle.  When TP53 is mutated, tumor cells can replicate uncontrollably because TP53 has lost its ability to control (or suppress) the cell cycle properly.

Using the three pilot phases of the 1000 Genomes Project, the researchers suggest humans carry ~100 loss-of-function (or deleterious) mutations and ~20 genes that have been inactivated (that's ~.1% of your genes)!  This is such an interesting topic because up till now whenever researchers have found these loss-of-function mutations, they normally assumed it is somehow disease-causing.  This is no longer the case.  This news article from GenomeWeb states "as more and more apparently healthy individuals have their genomes and exomes sequenced, he added, investigators have unearthed a raft of apparent loss-of-function variants that are both intriguing and puzzling. "  The article in Science is suggesting that we should expect humans to have a given number loss-of-function mutations (~100).   What is still unclear is how to differentiate between the loss-of-function mutations that are disease-causing and the ones that are more benign.  As personalized medicine is becoming an increasingly important topic, this type of research will be critical when whole-genome sequencing becomes cost effective.