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DEVELOPMENTAL GENETICS. The spectrum of human developmental abnormalities is quietly wide. Most of the developmental abnormalities are realized at birth or in the first few months. But some of them can not be realized until adolescent or adulthood.
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The spectrum of human developmental abnormalities is quietly wide. • Most of the developmental abnormalities are realized at birth or in the first few months. But some of them can not be realized until adolescent or adulthood. • Some developmental abnormalities occur by some morphogenetic events in the result of single gene defects. The inheritance is like Mendelian inheritance. Sometimes the reason is chromosomal and sporadic. • Morphogenesis: The process of creatingthree dimensional structure of cell related to the changes of the cell shape, adhesion, movement.
Human developmental abnormalities occur by genetic factors, enviromental factors or both of them.
Developmental Genes • Fruit flies, fishes and worms are used as model organisms for a long time. One of the approaches is to screen mutagenesis by searching embryological developmental abnormalities of mating products after the exposure tomutagens.
Developmental genetic studies show that there are some preserved genes that control the development, especially in drosophila, and these genes take part in body planning during embryogenesis. • All these developmental control genes are assigned during human development. When they are mutated, they cause congenital malformations.
The Beginning of Development • After fertilisation, the firstly differentiated cells form the extraembryonic cells that are necessary for the formation of placenta. • Embryo originates from a small group of cells in blastocyst. This region is described firstly as inner cell mass (ICM), then primitive ectoderm. (inner cell mass developes in blastocyst and amniotic gap occurs). • Germ cells are the first tissues that are formed by embryo.
In mammalian blastocyst, removal of a part of blastocyst does not affect the development, conceptus develops normally. For example, to divide to two equal parts for blastocyst cause the formation of monozygotic twins. Another example is even a normal embryo can originate from only one cell of ICM. • The compansation of removed region is defined as regulator development. • The exposure to potential teratogens during the two weeks after conception creates minimal risk for congenital malformations because of the regulator development of early embryo.
Mosaic development means that a particular cell is independent from the enviroment. Mosaic development in mammalian embryos can be seen in developing organs before the differentiation occurs completely.
Gastrulation and Developmental Abnormalities • The cells that are going to form embryo are localised in a single tissue. This occurs after a short time from the implantation of conceptus (6th day of conception). This single tissue is called as primitive ectoderm or epiblast. • The three primer germ layers –ectoderm, endoderm and mesoderm- are originated from epiblast. This process is called as gastrulation and it consists of specialised signal transduction and cell movements. Precursor states of heart, brain and spinal cord, skeletal system and gastrointestinal systems become apparent after gastrulation.
Gastrulation is the beginning period of organogenesis, it is also the end of regulator period and in regulator period the damage or the loss of the embryo cell groups are easily compansated. So, developmental abnormalities mostly occur in organogenesis period.
Gene Expression During Development • Expression of different gene groups occur at different cells in embryo, in different times. • There are a few master (director) genes that create differences between a neuron, a keratinocyte and an osteoblast. These genes both regulate the development and preserve the differentiation. • The genes that are expressed in these cells are also expressed in other cells mostly. This common gene group is necessary for nucleic acid and protein synthesis, transport of nutrients, biosynthesis of organelles and cytoskeleton. These genes that regulate the basic functions of the cell are called as “housekeeping genes”.
Housekeeping genes express continuously, they can be responsible from 80-90% of gene expression in a cell. The rest of the genes are different and they create speciality for different genes. • The inheritance of gene expression to the other generations without any changes in the DNA sequence, is a type of epigenetic regulation and in this regulation phenotypic changes are inherited without genotypic changes. DNA modification, changes in chromatin structure or both of them can be responsible from this.
HOX Genes: Transcription Factors Determine the Developmental Identity • Problems in tissue specific transcription factors (TF) can disrupt the gene expression. • HOX genes are shortened name of “Homeotic Selective” term. They encode a specific TF group that firstly described in drosophila. • They have ability to convert a portion of the body to another part of the body, so their names in drosophila are homeotic genes (HOM). HOM genes share protein motifs named as homeodomain which can bind to DNA.
Drosophila has one cluster that consist of 8 HOM genes. There are 4 clusters in humans and mammalians named as HOXA, HOXB, HOXC and HOXD, in each of them there are nearly 11 genes. • HOX gene expression combinations determine the developmental fate of some certain regions of embryo.
Developmental Genetics in Clinical Applications Dysmorphology: This is a branch of clinical genetics and deals with congenital malformations. Genetic principles, developmental mechanisms and various congenital malformations are combined together.
Isolated Congenital Defects, Syndromes and Sequences • Major congental defects usually (60%) affect only one system, for example heart or lips. The reasons are not defined. The others are called as malformation syndromes. • Some congenital malformations arise because of many factors, but they have common pathophysiological mechanisms. These are called as sequence or association. They differ from malformations that occur related to only one cause. (Example; Robin sequence)
Malformations, Deformations and Disruptions • Malformations are intrinsic abnormalities of development, they differ from deformations that occur by extrinsic factors. • Deformations are oftenly seen in second trimester of pregnancy. Fetus is stuck between amniotic sac and uterus. • Disruption occurs by the developmental pause in a developing tissue, the treatment is difficult because normal tissues are damaged.
