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Gene Mapping Dr Melody Caramins BMed PhD FRCPA FFSc (RCPA) Genetic Pathologist Gene mapping is a general term for discovering the genetic basis for a disease. The human genome (all the genetic code for an individual) consists of approximately 2 ‘sets’ of 3 billion letters, A, C, G, and T; one set from each parent. One of the aims of the Human Genome Project was to develop the techniques and technologies used for gene mapping, and indeed these have changed considerably over the years. When the project started, their ambitious aim was to sequence, or read, the entire genetic material from a human individual. This cost approximately USD 3 billion, and took about 15 years. Now, the entire human genome can be sequenced for approximately USD 5,000 and would take days to weeks, rather than years. For the same cost as the original human genome, you can now sequence the entire genome of over 20,000 individuals. Chromosome studies (karyotype) Exome sequencing Sequencing a panel of genes Chromosome microarray Simple gene test There are many ways of discovering the genetic basis of a disease, ranging from simple to complex. Imagine taking a landscape picture with a digital camera; you could use all the pixels to take a very clear picture of a tree, or a low resolution picture of the whole landscape, or you can buy a better camera and take a high resolution picture of the entire view. techniques. To use the picture analogy, you might just see a smear of green and blue in a landscape. These days, your doctor may choose to undertake a chromosome microarray, which looks for small bits of extra (duplicated) or missing (deleted) genetic material over the entire genome and provides more information than previously. This would be like taking a lower resolution picture of the whole landscape. You would see the main features of the landscape, such as trees, some hills, the sky and some clouds; but you might miss some of very fine details of the birds and the grass. At the simple end, if you saw your doctor, and there was a concern about a specific disease, then they could order a genetic test to determine whether you do in fact have a genetic variant in a gene that might cause the disease, or predispose to the disease. This would be like taking a very clear picture of a tree in the landscape. Finally, at the most complex end of genetic testing, is sequencing all of the known genes, or alternatively, sequencing the entirety of the genome. A slightly more complicated scenario is where you might have a condition, like hereditary deafness, where many genes could be involved. There are literally hundreds of genes (~400) that can cause hereditary deafness. Until recently, you would have to test these by sequencing them one by one; a daunting task. With the newer sequencing technologies, this could be achieved in a matter of weeks. Sequencing all of the known genes is also known as exome sequencing, which consists of sequencing ~2% of our entire genetic material. Exome sequencing is transitioning from a research test to a diagnostic test. Although no labs in Australia currently offer it routinely for diagnosis, it is anticipated it will be available more routinely in the next year. The exact cost is difficult to anticipate accurately, but would be expected to be $1000 - $2000, with no Medicare rebate currently available for this test. This would be like taking a pretty clear picture of the whole landscape. But you might end up seeing some things that you might not For something even more complicated, you might have a scenario where you have a child with developmental delay, where a genetic cause might be suspected. Some years ago, this test was done by examining all the chromosomes under a microscope, at 50 times less resolution and thus with much less information than current recognise if you had never been used to seeing this level of detail. About 1-3% of exome sequencing tests identify variants which were unexpected, and more whose effects cannot be completely predicted. Only about 4,000 of the 23,000 genes in the genome have been connected to a particular disease or diseases, and the genetic basis for some common illnesses such as heart disease and diabetes remain largely unknown, although much progress has been made with various cancers. Sequencing all of the genetic material, or whole genome sequencing, is the most complex genetic test and is currently only undertaken in a research setting due to the cost and difficulty of interpretation. Given that our knowledge of genetics is evolving very rapidly, if you could have your genome sequenced, the interpretation of the report you would receive now would more than likely change over time. As new information becomes available, that report might need to be updated, based on information that becomes available in the years to come. Gene mapping is a colloquial term; these days it is generally understood to refer to a test which looks at many genes at the same time – usually by exome or genome sequencing, or by chromosomal microarray testing. These tests all look at your genome at different levels of resolution. Which kind of picture is necessary will depend on what you need to see. Dr Melody Caramins BMed PhD FRCPA FFSc (RCPA), Genetic Pathologist Dr Melody Caramins is a genetic pathologist and a conjoint senior lecturer at the University of New South Wales. She is head genetic pathologist at QML Pathology and national head of genetics at Specialist Diagnostic Services. She has extensive experience with complex and simple genetic testing and has undertaken gene mapping research. Her research on gene mapping has been published in some of the leading genetics scientific journals. Specialist Diagnostic Services Pty Ltd (ACN 007 190 043) t/a QML Pathology PUB/MR/1195, version 1 (May-14)