Environment Controls Gene Expression: Sex Determination and the Onset of Genetic Disorders

In this day and age, it seems that genes are "everything" when it comes to determining the characteristics of an organism. However, the importance of the environment in biology cannot be denied. For example, nearly everyone knows that a dry season can ruin crop yields. However, digging a little deeper reveals even more intriguing examples of environmental influence on organisms. For instance, research has shown that the sex of some species of reptiles is influenced by the temperature at which the reptiles' eggs are incubated during development. This kind of observation presents an apparent paradox, because sex is usually regarded as being genetically—not environmentally—determined.

Thus, there appear to be certain situations in which the environment affects not only the growth and health of an organism, but also the use or deployment of the organism's genes. Does this mean that genes aren't, in fact, everything? The observation that genetically identical organisms often vary greatly in phenotype clearly shows that gene-environment interaction is indeed an important regulator of phenotypic variation, including variation related to a number of diseases. In fact, the impact of environmental factors on disease etiology (or causation) has gained greater recognition in recent years. This has led to the conclusion that both genes and environment can affect disease—not just separately, but through direct interaction with each other. This relatively new attitude presents considerable challenges, as well as surprising benefits, for the study of human disease.

Scientists have long appreciated the role that environmental factors play in the production of traits in animals. Environmental factors such as diet, temperature, oxygen levels, humidity, light cycles, and the presence of mutagens can all impact which of an animal's genes are expressed, which ultimately affects the animal's phenotype. For this reason, scientists who study the genetics of model organisms usually seek to minimize environmental influence by maintaining constant environmental conditions for the organisms under study. Nevertheless, even genetically identical organisms exposed to controlled experimental conditions can have different phenotypes, pointing to the power of subtle environmental differences on gene expression.

Of course, most organisms are exposed to changing conditions, and in these cases, it is often difficult to imagine how the organisms' genes "sense" alterations in the environment. Consider the case of the crocodile. Scientists know that the temperature at which a crocodile egg is incubated influences the sex of the resulting baby crocodile, but how does the DNA in the egg "learn" about changes in temperature? Moreover, upon sensing such changes, how does the egg "know" to change the expression of genes to alter the sex of the developing crocodile?

Studies have shown that there is a specific point in the development of certain organisms, known as the thermosensitive period (TSP), during which the gonadal tissue is responsive to temperature. When exposed to one range of temperatures, this tissue develops into ovaries; when exposed to a different range, it develops into testes. Such is the case in the turtle Emys obicularis: at incubation temperatures of 25°C, all such turtles are born male, but at temperatures of 30°C, all are born female (Figure 1). Prior to the TSP, all of the embryonic gonads appear the same; however, during the TSP, something happens to tell the tissues to become either ovaries or testes. That "something" is a change in gene expression that results in differentiation of the tissue to its new identity. In particular, expression of the Sox9 gene has been shown to change in response to temperature, with high expression levels at lower temperatures and repressed levels at higher temperatures. Because the transcription factor produced by Sox9 affects a gene that plays a major role in sex determination, the expression of this gene changes when temperature (and therefore Sox9 expression) changes, thus resulting in a specific phenotype of maleness or femaleness.

In some cases, an organism's own genotype can alter the cellular environment. Take the example of differential enzyme activity. Scientists have found polymorphisms in many enzymes in humans, including those that alter individual responses to different chemicals. One of the earliest studies that connected enzymatic activity to different phenotypes was conducted by Lower et al. (1979). This study looked specifically at the activity of an enzyme called N-acetyltransferase. Here, the researchers noted that certain individuals who had lower N-acetyltransferase activity (called the slow-acetylator phenotype) also had a higher incidence of bladder cancer. But what was the connection between these two findings? It turns out that N-acetyltransferase activity is often high in the liver, an organ that plays a major role in breaking down potentially toxic chemicals. Such chemicals include acrylamine, a known carcinogen to which smokers and certain factory workers have increased exposure. N-acetyltransferase is involved in acrylamine detoxification; therefore, those individuals in the study who were slower to detoxify (i.e., the slow acetylators) were exposed to the carcinogen longer and potentially at higher concentrations than those individuals with the fast-acetylator phenotype. Thus, slow acetylation resulted in a change in environment (increase in acrylamine exposure) that led to increased incidence of a particular disease phenotype (bladder cancer).

More recently, scientists have examined how different polymorphisms in humans may impact the effectiveness of chemoprevention, or the use of medicines to prevent cancer. For example, data suggest that taking a daily low-dose aspirin, long known to be important in heart health, may also have an impact on colorectal cancer risk in some patients. In particular, two studies connected aspirin usage to cancer prevention, but only in one subset of users — those with a specific allele of a gene called UGT1A6, which is involved in aspirin metabolism. Protection from cancer was only found in the group of patients who were slow aspirin metabolizers (Figure 2). The actual mechanism by which aspirin mediates this protective effect remains unknown.

The number of combinations of different genotypic variants, environmental conditions, and possible phenotypes is not something researchers can predict. However, the complex interactions of multiple genetic loci with diverse environmental signals suggest that scientists must continue to develop novel methods of studying these situations, such as by simultaneously examining thousands of genes using techniques like microarray technology under different environmental conditions. While we may never be able to predict an exact phenotype, it is clear that when trying to understand biology and human disease, we must consider interactions of genes and environment in our analysis.