Medical genetics

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Mouse and human genome separated phylogenetically only one million years ago. Mice have nearly the same genes as humans, except organized in 40 chromosomes, and their genes grouped on the same chromosomes are similar to the grouping in man, except in man such group of genes is on a different chromosome.


Similar statement could be made about the genome of primates and humans, but nowadays for practical reasons mice are more important.


Genetic code is universal, i.e. the same for all organisms and non-repetitive. A partial exception is the genetic code of mitochondrial DNA, which is not universal, and is somewhat repetitive.


DNA in all eukaryotic cells is the same, that means that DNA in hepatocytes, myocytes, lymphocytes, etc., of the same organism is the same. Why is then the structure and function of these cells so different? Is it due to the character of genes, their expression and their end products specific for various types of cells? The transcription of some genes is active only during some stages of development of an organism.


One molecule of human DNA is substantially larger than that of any other protein.


Mutation is a process that causes permanent changes of DNA, positive or negative. Mutations can be major, i.e. loss, duplicity, structural change of chromosomes, or minimal, i.e. ‘point mutations’, when loss, duplicity or structural change applies to only one nucleotide, or a miniscule portion of DNA.


Spontaneous mutations outnumber the induced mutations many times over. It is believed to be the result of spontaneous errors during replication and repair of DNA, or during spontaneous chemical reactions. During human lifetime every gene is subject to 100 million to 10 billion of such mutations. But nearly all damage due to such mutations is repaired, or causes cell death without any consequences for other cells. But the danger of erroneous mitosis leading to cancer is always looming.


Radiation is 2 - 3 times more effective to induce mutation when delivered as an acute dose rather than chronic. The younger the ovaries and sperms are at the time of radiation exposure the less sensitive they are to the irradiation.


Chemicals are much more dangerous mutagens that radiation.


Types of mutation caused by viruses do not differ from those caused by chemicals or radiation. Mutagenic effect of named viruses is not specific.


Absolute majority of DNA mutations is immediately repaired in the organisms. In humans there are two major repair methods, that involve a complex of enzymatic steps:

1/ base excision repair, an excision of damaged purine or pyrimidine base;

2/ nucleotide excision repair, an excision of damaged nucleotide.


Gene mutations often take place only in some tissues. For example, a gene for Huntington chorea is expressed in many tissues but mutations take place only in certain parts of brain. Similarly retinoblastoma gene is expressed everywhere but genetic mutations occur only in retina.


Mutations can cause a gain of new function as often happens in cancer.


Overproduction of normal gene product can become pathologic, which is the usual mechanism for activation of protooncogens in cancer cells. The same is typical for hereditary sensory and motor neuropathy type 1A, known as Charcot-Marie-Tooth disease type 1A.


Identical phenotype can be caused by mutations of two or more different genes.


Different mutations in the same locus can sometimes cause similar phenotype, but sometimes completely different clinical signs. An example is congenital methemoglobinopathy, autosomal recessive disorder, where there are increased levels of hemoglobin with trivalent Fe3+-methemoglobin, with much stronger bond to oxygen than normal hemoglobin, so that oxygen cannot be released in the tissues as necessary. If level of methemoglobin reaches 15% of total hemoglobin, cyanosis becomes apparent, at 40% dyspnea, at higher levels ataxia, stupor and coma, and death at 85% concentration of methemoglobin.


Gene imprinting causes a completely different phenotype due to the same chromosomal damage depending on whether the inheritance is from father or mother, i.e. deletion of long arm of chromosome 15 will cause Prader-Willi syndrome, if inherited from father, i.e. already in infancy observed difficulty to drink, unique cry or a lack of cry, failure to thrive, delayed speech, round face without mimicry, genital hypoplasia, or Angelman syndrome, if inherited from mother, with psychomotor retardation, ataxia, hypertonia of extremities with hypotonia of trunk musculature, severe speech disturbance, attacks of laugh, spasms, typical EEG findings.