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Germline, Somatic Distinction

Vol. 17 •Issue 3 • Page 22
The Molecular Edge

Germline, Somatic Distinction

The 19th century biologist August Weismann in his book, "The Germ-plasm: A Theory of Heredity,"1 proposed that the germ-plasm is responsible for inheritance, while the other cells do not contribute to the next generation. This means that a change in the DNA (mutation) in the germ-plasm, or the germline in modern parlance, can be inherited while a mutation that takes place in a non-germline cell is not inherited but can have health consequences nonetheless. This distinction remains important in the 21st century for an understanding of the function and evolution of multicellular organisms, but is also an important concept in the field of molecular pathology.

Germline Analysis

Testing for inherited disease means the analysis of the germline, while molecular oncology and molecular microbiology involve testing for things that are not in the germline. We refer to these non-germline tissues as somatic and the alterations in their DNA as acquired. Strictly speaking, a change in the DNA sequence in a somatic tissue can be called a genetic mutation, but it is still very different from a mutation that can be inherited. Although most acquired diseases have some facets of a genetic etiology, we prefer the terms germline vs. somatic, rather than genetic vs. non-genetic to describe these testing paradigms.

When we say "genetic testing" we usually mean testing for inherited characteristics. If this involves testing the germline, then why do we often use a somatic tissue, blood for example, to test for an inherited disease? Although we do not test the germline directly, the DNA sequence of all the cells in the body are, with a few known exceptions, identical to the germline since they are all descendents of the original fertilized egg. Thus, a mutation that causes an inherited disease (e.g., sickle cell anemia) can be detected not only in blood, the affected tissue, but also in amniotic fluid or even in DNA from a hair follicle.

Beyond the Germline

When we do molecular testing for a cancer, we are testing mostly for DNA alterations found in the tumor cells themselves, not in the germline. For example, detection of a mutation in the NPM1 gene helps predict prognosis for patients with acute myeloid leukemia and also may help in selecting a therapy.2,3 In this example, the relevant affected tissue needs to be examined. You could not use a hair follicle as a source of material. Similarly, for infectious disease testing you need a specimen with the organism of interest. The specimen requirements for a particular test depend on the clinical question that needs to be answered.

Ethical Issues

The germline vs. somatic distinction has an important ethical dimension. As in most aspects of clinical medicine, genetic testing embraces many of the central tenets of medical ethics, including privacy, informed consent and confidentiality. In many cases, testing of germline DNA is done to find a predisposition for a disease, rather than the disease itself.

For example, a person who has an inactivating mutation in the BRCA1 gene has an increased probability of eventually getting breast or ovarian cancer, but may be perfectly healthy at the time of the test. Knowledge of such a predisposition can result in difficulty in obtaining health or life insurance, in addition to the potentially powerful impact of such knowledge on self-image and social interactions.4 For this reason many providers require that that an individual give informed consent prior to a genetic test on the germline.

In New York State, this is the law.5 Detailed counseling prior to genetic testing is mandatory to ensure that patients make informed decisions about the use of tests with complex personal implications. This approach is the standard of care for genetic tests that involve reproductive decisions and incurable conditions, such as Duchenne muscular dystrophy.

Many tests for inherited germline variation are used as part of routine clinical practice, for example factor V Leiden testing in hypercoagulability syndromes, ordered by the internist or hematologist. Detailed counseling prior to testing may not be available, usually without serious ethical consequences. However, potential social and family implications should be considered by the ordering physician.

Direct-to-consumer marketing strategies offer genetic tests touted to predict lifetime risks for a plethora of conditions and offer to provide "personalized" genetic profiling. These tests are of dubious value, ethically shady and taint the genuine predictive value of genetic testing.6

Technical Issues

The molecular diagnostician must keep the germline vs. somatic distinction in mind. When studying an inherited disease, if a mutation is present it is either present in two copies, one on the chromosome inherited from each parent (called homozygous), or in one copy (heterozygous) with the other chromosome normal at this position. Although there are violations to this principle (e.g., mosaicism due to a de novo mutation), it holds true for the most part.

When studying a neoplasm or an infectious organism, the neat distinction of normal, heterozygous, homozygous (0, 1 or 2 copies) disappears. For a cancer, the number of copies of a mutation is influenced not only by the number of copies per cell, but by the fraction of the tissue analyzed that has a mutation. For example, the recently discovered JAK2 V617F mutation that contributes to several myeloproliferative diseases may be present in only a very small fraction or in a larger fraction of the blood cells with possible ramifications for its impact on health.7 It gets even more complicated with an infectious organism where the number of targets to be detected might range between zero and billions, and the numbers often are important.

Blurred Lines

Aspects of molecular pathology blur these distinctions. A laboratory might test the germline for particular DNA variants to predict the optimal dose of the anticoagulant warfarin.8 The testing is for germline DNA variation not linked to disease or risk of disease, but to aid in the selection of a drug and its proper dose. This type of "pharmacogenetic" testing is becoming increasingly common and was recently reviewed in "The Molecular Edge."9

While August Weismann never heard of molecular pathology, the dichotomy he proposed more than a century ago is relevant to the principles and practice of this field today.

Dr. Rothberg is a professor and director of the Section of Molecular Diagnosis in the Department of Pathology and Laboratory Medicine at the University of Rochester School of Medicine and Strong Memorial Hospital.

Dr. Nordberg is an associate professor and director of Molecular Pathology and Cancer Cytogenetics in the Departments of Pathology and Pediatrics, and The Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center. Drs. Rothberg and Nordberg are the chairs of the Genetics Subdivision of the Association for Molecular Pathology, 2007 and 2008, respectively.

For a list of references, go to


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