**4. Hypoxia and natural selection**

It is known that hypoxic microenvironment acts as a stress-induced mutagenesis by increasing genetic instability in human cell through highly regulated genetic mechanisms. The stabilization of HIF, the master transcriptional factor in hypoxia, down-regulates the major DNA repair mechanisms; mismatch repair and homologous recombination. This leads to a switch from the high-fidelity repair mechanisms to the error-prone mutagenic non-homologous end joining mechanisms, which result in a high degree of genetic variability. In earlier study, our findings revealed that genetic variability in periods of high hypoxic pressure in preeclamptic samples was more confined to certain genomic loci, in particular the HIF master regulators of hypoxia, compared to normal pregnancy [3, 13].

Different scenarios of genetic variability under stressful condition of hypoxia are proposed, and represent the basis for natural selection and adaptation. **Figure 1** shows

#### **Figure 1.**

*The degree to which the genes can be reprogrammed by mutations can be termed genetic flexibility [14]. Genetic variability permits flexibility and survival of a population in the changing environments. Here, the genetic variability is represented by circles. The dots in the circles are the number of genetic variants in a particular gene. The more the variants are, the highest is the genetic flexibility. (a) Different genes in the same individual with the same degree of stressful condition. Gene x shows a larger circle with more variants, and this may indicates that gene x is more influential at a particular stressful condition, and probably is more affected by the signals of that particular condition. (b) The same gene in different individuals under the same extreme condition. Individual 1 with a larger circle of genetic variability is more flexible and have higher chance to adapt under the certain condition than 2 and 3. Individuals 2 and 3 are either less flexible due to different reasons, or (c) may undergo a previous acclimatization experience that renders them to show a less degree of variability. In (c), gene x is in the same individual, but the larger circle is showing genetic variants in the first exposure to stressful microenvironment (hypoxia), followed by the second, and the third exposure. The decrease in the number of genetic variants in subsequent exposures reflects the stress relief, and probably acclimatization.*

**43**

*Placental Adaptation to Hypoxia as a Predictive Marker for Preeclampsia*

dotted circles that represent the flexibility of hypoxia pathway genes under stressful conditions. The dots represent the genetic variants or mutations. The more flexible the gene is, the larger the circle of genetic variability, and thus the higher chances for natural selection to the fittest variants. This can predict the possible path of evolutionary events, and the possible roles of the genes with larger circles under stressful conditions. In a previous report, we showed that preeclamptic samples had higher genetic variability in the key regulators of hypoxia pathway genes like EPAS1 and EGLN1 compared to normal pregnancy, which indicates that they were under a high level of stress. We also hypothesized that the high genetic variability that are reflected by the high number of mutations in preeclamptic samples can be considered as a "positive response" toward adaptation by increasing the chance of having adaptive mutations, yet they are still evolutionary late compared to controls. In other words, normal pregnancy has higher rate of fixation to the adaptive variants compared to preeclampsia, and this can be the reason for the delay in the process

**Genome-wide linkage studies** of preeclampsia and pregnancy-induced hypertension have identified different loci associated with preeclampsia that segregate with different populations: on 4q (between D4S450-D4S610 markers, found in Australia), 2q23 (between D2S112-D2S151 markers, Australia, NZ), 2p13 (D2S286, Iceland), 2p25 (D2S168, Finland), 9p13 (D9S169, Finland), and 10q22 (Netherlands). Additional loci are expected to exist in preeclamptic patients with certain complications, such as the locus 12q in patients with hemolysis, elevated

Candidate genes studies have provided evidence for an association with preeclampsia, frequently with inconsistent results. One of the common candidate genes is endothelial nitric oxide synthase gene (eNOS) on 7q36, which is responsible for nitric oxide production in endothelial cells. The endothelial dysfunction in preeclampsia reveals a strong association with eNOS polymorphisms. However, several other genome scans could not confirm this association. Another study found an evidence of moderate association with an increased risk for preeclampsia in women having mutations in coagulation factor genes; F5 Leiden (rs6025, G1691A), and the prothrombin (F2) gene (rs1799963, G20210A). This evidence may explain the association of the disease with coagulation disorders. Several studies found associations between renin-angiotensin-aldosterone system with gestational hypertension and preeclampsia. Earlier linkage studies found an association with angiotensinogen (AGT) locus, on 1q42-43 and the risk for hypertensive disease in different sets of population. They also found an association between specific allele AGT (T235, rs699) with essential hypertension and preeclampsia. Angiotensin converting enzyme (ACE) along with AGT receptor 1 (AGTR1) were also found to have a role in the pathogenesis of the preeclampsia. Another candidate gene that link preeclampsia to the risk of hypertension is the T allele (C677T) of the methy-

To conclude, no single gene or chromosomal locus currently known can explain the pathogenesis of preeclampsia. This indicates that preeclampsia is a polygenic disorder, and it reflects an integrated pathophysiological process of insufficient adaptation, not only in the placenta, but also in other tissues and organs. On the other hand, the geographical distribution of candidate genes and loci in association with the pathogenesis of preeclampsia may reflect the interaction between the

*DOI: http://dx.doi.org/10.5772/intechopen.86612*

of adaptation in some types of preeclampsia [3].

**5. Genetic association studies and preeclampsia**

liver enzymes, and low platelets (HELLP) syndrome [15–18].

lenetetrahydrofolate reductase (MTHFR) gene [19–23].

different environments and the gene pool of populations.

#### *Placental Adaptation to Hypoxia as a Predictive Marker for Preeclampsia DOI: http://dx.doi.org/10.5772/intechopen.86612*

*Prediction of Maternal and Fetal Syndrome of Preeclampsia*

of hypoxia, compared to normal pregnancy [3, 13].

survives the oxidative stress?

**4. Hypoxia and natural selection**

on what are the hidden mechanisms that enable the placenta to survive the oxidative stress and overcome the disease? What could happen in a subsequent pregnancy that renders them to be protected? Why the placenta from normal pregnancies

It is known that hypoxic microenvironment acts as a stress-induced mutagenesis

Different scenarios of genetic variability under stressful condition of hypoxia are proposed, and represent the basis for natural selection and adaptation. **Figure 1** shows

*The degree to which the genes can be reprogrammed by mutations can be termed genetic flexibility [14]. Genetic variability permits flexibility and survival of a population in the changing environments. Here, the genetic variability is represented by circles. The dots in the circles are the number of genetic variants in a particular gene. The more the variants are, the highest is the genetic flexibility. (a) Different genes in the same individual with the same degree of stressful condition. Gene x shows a larger circle with more variants, and this may indicates that gene x is more influential at a particular stressful condition, and probably is more affected by the signals of that particular condition. (b) The same gene in different individuals under the same extreme condition. Individual 1 with a larger circle of genetic variability is more flexible and have higher chance to adapt under the certain condition than 2 and 3. Individuals 2 and 3 are either less flexible due to different reasons, or (c) may undergo a previous acclimatization experience that renders them to show a less degree of variability. In (c), gene x is in the same individual, but the larger circle is showing genetic variants in the first exposure to stressful microenvironment (hypoxia), followed by the second, and the third exposure. The decrease in the number of genetic variants in subsequent exposures reflects the stress relief, and probably acclimatization.*

by increasing genetic instability in human cell through highly regulated genetic mechanisms. The stabilization of HIF, the master transcriptional factor in hypoxia, down-regulates the major DNA repair mechanisms; mismatch repair and homologous recombination. This leads to a switch from the high-fidelity repair mechanisms to the error-prone mutagenic non-homologous end joining mechanisms, which result in a high degree of genetic variability. In earlier study, our findings revealed that genetic variability in periods of high hypoxic pressure in preeclamptic samples was more confined to certain genomic loci, in particular the HIF master regulators

**42**

**Figure 1.**

dotted circles that represent the flexibility of hypoxia pathway genes under stressful conditions. The dots represent the genetic variants or mutations. The more flexible the gene is, the larger the circle of genetic variability, and thus the higher chances for natural selection to the fittest variants. This can predict the possible path of evolutionary events, and the possible roles of the genes with larger circles under stressful conditions.

In a previous report, we showed that preeclamptic samples had higher genetic variability in the key regulators of hypoxia pathway genes like EPAS1 and EGLN1 compared to normal pregnancy, which indicates that they were under a high level of stress. We also hypothesized that the high genetic variability that are reflected by the high number of mutations in preeclamptic samples can be considered as a "positive response" toward adaptation by increasing the chance of having adaptive mutations, yet they are still evolutionary late compared to controls. In other words, normal pregnancy has higher rate of fixation to the adaptive variants compared to preeclampsia, and this can be the reason for the delay in the process of adaptation in some types of preeclampsia [3].
