Developmental Genetics

 Development results from the action of genes interacting with environmental cues. The gene products involved include transcriptional regulators, growth factors (diffusible signals that interact with cells and direct them toward specific developmental pathways), the receptors for such factors, structural proteins, intracellular signaling molecules, and many others. It is therefore not surprising that most of the numerous developmental disorders that occur in humans are caused by chromosomal, subchromosomal, or gene variants.

Even though the genome is clearly the primary source of information that controls and specifies human development, the role of genes in development is often mistakenly described as a “master blueprint.” In reality, however, the genome does not resemble an architect’s blueprint that specifies precisely how the materials are to be used, how they are to be assembled, and their final dimensions; it is not a literal description of the final form that all embryologic and fetal structures will take. Rather, the genome specifies a set of interacting proteins and noncoding RNAs that set in motion the processes of growth, migration, differentiation, and apoptosis that ultimately result, with a high degree of probability, in the correct mature structures. Thus, for example, there are no genetic instructions directing that the phalanx of a digit adopt an hourglass shape or that the eye be spherical. These shapes arise as an implicit consequence of developmental processes, thereby generating correctly structured cells, tissues, and organs.

Probability

Although genes are the primary regulators of development, other processes must also play a role. That development is regulated but not determined by the genome is underscored by the important role that prob ability plays in normal development. For example, in the mouse, a pathogenic variant in the Dishevelled-2 gene produces congenital heart defects in only ~50% of mice who carry the variant, even when such carriers are from inbred strains of mice that are genetically identical. Thus the 50% penetrance of the Dishevelled-2 variant cannot be explained by different modifying gene variants in the mice affected with heart defects versus the mice who are unaffected. Instead, it appears likely that the Dishevelled-2 variant shifts the balance of some developmental process by increasing the probability that a threshold for causing congenital heart defects is exceeded, much as we explored in Chapter 9 when discussing complex patterns of inheritance in humans. Thus carrying a Dishevelled-2 pathogenic variant will not always lead to heart defects, but it sometimes will, and neither the rest of the genome nor nongenetic fac tors are responsible for development of the defect in only a minority of animals. Probabilistic processes provide a rich source of interindividual variation that can lead to a range of developmental outcomes, some normal and some not.

Environmental Factors

As indicated earlier, the local environment in which a cell or tissue finds itself plays a central role in pro viding a normal developmental context. It is therefore not unexpected that drugs or other agents introduced from the environment can be teratogens, often because they interfere with intrinsic molecules that mediate the actions of genes. Identification of the mechanism of teratogenesis has obvious implications not only for clinical medicine and public health but also for basic science; understanding how teratogens cause birth defects can provide insight into the underlying developmental path ways that have been disturbed and result in a defect.

Because the molecular and cellular pathways used during development are often not employed in similar developmental processes after adulthood, teratogens that cause serious birth defects may have few or no side effects in adult patients. One important example of this concept is fetal retinoid syndrome, seen in fetuses of pregnant women who took the drug isotretinoin during pregnancy. Isotretinoin is an oral retinoid that is used systemically for the treatment of severe acne. It causes major birth defects when taken by a pregnant woman because it mimics the action of endogenous retinoic acid, a substance that in the developing embryo and fetus diffuses through tissues and interacts with cells, causing them to follow particular developmental pathways.

Different teratogens often cause very specific patterns of birth defects, the risk for which depends critically on the gestational age at the time of exposure, the vulnerability of different tissues to the teratogen, and the level of exposure during pregnancy. One of the best examples is thalidomide syndrome. Thalidomide, a sedative widely used in the 1950s, was later found to cause a high incidence of malformed limbs in fetuses exposed between 4 and 8 weeks of gestation because of its effect on the vasculature of the developing limb. Another example is the fetal alcohol syndrome. Alcohol causes a particular pattern of birth defects involving primarily the central nervous system because it is relatively more toxic to the developing brain and related craniofacial structures than to other tissues.

Some teratogens, such as x-rays, are also mutagens. A fundamental distinction between teratogens and mutagens is that mutagens cause damage by creating heritable alterations in genetic material, whereas teratogens act directly and transiently on developing embryonic tissue. Thus fetal exposure to a mutagen can cause an increased risk for birth defects or other diseases (e.g., cancer) throughout the life of the exposed individual and even in his or her offspring, whereas exposure to a teratogen increases the risk for birth defects for current but not for subsequent pregnancies.

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اخبار العتبة العباسية المقدسة

قسم صناعة الشبابيك يباشر أعمال تركيب أجزاء شباك مرقد العلامة ابن فهد الحلي (قدس سره)

برعاية العتبة العباسية المقدسة.. جمعية العميد تفتح باب المشاركة في مؤتمر فتاوى الدفاع المقدسة العلمي السابع

قسم التطوير يواصل تقديم دورة أخلاقيات المهنة ضمن البرنامج التأهيلي لمنتسبي العتبة العباسية المقدسة

قسم الشؤون الفكرية يُهدي عددًا من إصداراته الثقافية لمكتبة السيدة زينب (عليها السلام) في النجف

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"أوميغا 3" صديق القلب.. هل يربك سكر الدم؟

بدائل لليمون.. 8 إضافات للماء تعزز فوائده الصحية

دراسة: محاولة متعمدة لنشر الإنفلونزا تنتهي بـ"مفاجأة"

المزيد

الآخبار التكنلوجية

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توقع خطير لماسك: الروبوتات ستتفوق على البشر من حيث العدد

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"ميتا" توقف وصول المراهقين إلى شخصيات الذكاء الاصطناعي ؟

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مواضيع ذات صلة

Gene Therapy

The Genetics of mtDNA Disease

The APOE Gene Is an Alzheimer Disease Susceptibility Locus

The Genetics of Alzheimer Disease

Molecular Testing for Spinal Muscular Atrophy

Genetics of Spinal Muscular Atrophy

The Phenotypes of Spinal Muscular Atrophy

Chondrodysplasias are Caused by Mutations in Genes Encoding Type II Collagen & Fibroblast Growth Factor Receptors

The Genetics of Osteogenesis Imperfecta

Molecular Abnormalities of Collagen in Osteogenesis Imperfecta

Prenatal Diagnosis of Hereditary Genetic Diseases

Prenatal Diagnosis of Non-hereditary Genetic Diseases