Mutatii Genetice Baze fiziopatologice

DNA Model by J. Watson and F. Crick Cold Spring Harbor Laboratory Archives

Exploring Our Molecular Selves

"Exploring Our Molecular Selves" is a 3D computer-animated video illustrating the basic components and principles of molecular biology. The video gives a sense of the scale of cells, chromosomes, and DNA and shows how the information in DNA is converted into the molecules necessary for life.
http://www.genome.gov/Pages/Education Kit/online.htm

The National Human Genome Research Institute with co-sponsorship of the Office of Biological and Environmental Research, US Department of Energy, Howard Hughes Medical Institute, Pharmaceutical Research and Manufacturers of America, Nature, Science and the American Society of Human Genetics.

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Human Genetic Disorders (I)

Chromosomal Disorders

Alteration of number or structure of chromosomes.

Contiguous Gene Deletion Syndromes

Deletion of a large continuous section of genetic material from a single chromosome. Mutation in a single gene. Influenced by multiple genetic and/or environmental factors.

Single Gene Disorders

Common Complex Disorders

National Center of Biotechnology Information, National Library of Medicine

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Human Genetic Disorders (II)

Pedigree Boxes represent males. Circles represent females. Diamond represents an individual of unspecified gender. Shading represents affected individuals. This example:

Autosomal dominant disorder. Single gene disorder.

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Mendelian Disorders (I)

Autosomal dominant inheritance A disorder appears in several generations of a family. Affected parents have a 50% risk of an affected child with each pregnancy. Variability and reduced penetrance can complicate predictions of prognosis.

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Mendelian Disorders (II)

Autosomal recessive inheritance

Disorders often appear in only one generation of a family. Carrier couples have a 25% risk of an affected child with each pregnancy.

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Mendelian Disorders (III)

X-linked inheritance X-linked dominant disorders are few in number. Male to male transmission of X-linked disorders is not seen. Carrier females may show mild to moderate symptoms of certain X-linked disorders.

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Maternal (Mitochondrial) Inheritance

Inheritance through the maternal lineage. Sperm do not contribute mitochondria to the embryo.

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Complex Mechanisms of Hereditary Disease (I)

Multifactorial Common Complex Disorders

New Mutation Found in the child, but not in either parent. Imprinting A form of gene silencing.
Fragile X syndrome is an example of a disorder involving a complex mechanism of inheritance called anticipation and results in a form of mental retardation known as Fragile X syndrome.
National Center for Biotechnology Information, National Library of Medicine

Anticipation Progressive severity of a disorder in successive generations.

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Complex Mechanisms of Hereditary Disease (II)

Genetic Heterogeneity Allelic different mutations in a single gene result in the same disorder. Locus mutations in different genes produce the same disorder.
Nonrandom X-inactivation

Barr Bodies (indicated by the arrows) are the highly compacted inactive X chromosomes.
Courtesy of Dr. Steven M. Carr.

In females, genes on one of the X chromosomes are turned off.

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The Molecular Basis of DNA Sequence Variations (I)

Wild type sequence: Nucleotide: ACTGAACTGATT Amino Acid: ThrGluLeu-Ile

Substitution: ACTGACCTGATT (Thr-Asp-Leu-Ile) Deletion: ACTCTGATT (Thr-Leu-Ile) Insertion: ACTGAACCTGAACTGATT (Thr-Glu-Pro-Gly-Leu-Ile) Frameshift: ACTGACTGATT (Thr-Asp-Stop) Inversion: ACTGGTCAAATT (Thr-Glu-Gln-Ile)
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The Molecular Basis of DNA Sequence Variations (II)

Nonsense mutations A single base pair substitution that prematurely codes for a stop codon. Results in complete or partial loss of functional capabilities of a protein derived from the mutated gene.

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The Molecular Basis of DNA Sequence Variations (III)

Missense mutations

Result in the substitution of one amino acid for another. May or may not affect a proteins function. Benign mutations can become prevalent in a population.
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The Molecular Basis of DNA Sequence Variations (IV)

Null mutations Result in the loss of a protein product from a gene. Repetitive elements Repeated sequences are found throughout the genome. Vary in size. Consequences depend on location.

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Mutations

Can occur at any point in a gene.

Can affect transcription, RNA processing, RNA stability, or amino acid sequence.
Can have a variety of consequences including:

Loss of function Gain of function Dominant negative

Center for Genetics Education

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Polymorphisms

DNA sequence variations are part of the genetic makeup of every species and every individual.

Not always associated with disease.

Polymorphisms can be used as markers to map disease genes.

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Causes of Mutations

Errors during DNA replication The proofreading capability of DNA polymerase corrects many, but not all errors. Exposure to mutagens

Ultraviolet light DNA damaging chemicals Radioactivity

DNA damage resulting in multiple broken chromosomes

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Mechanisms of DNA Repair

Cells have built-in mechanisms for DNA repair. These mechanisms protect against the consequences of errors during replication and exposure to mutagens.
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Excision of the damaged and surrounding nucleotides

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Visiscience Corporation. (2005). ScienceSlides. All rights reserved.

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Significance of DNA Sequence Variations

Normal variation: DNA sequence variations are part of what makes each of us unique.

Adaptation: DNA sequence variations provide the raw material for natural selection.
Speciation: DNA sequence variations are the basis for speciation in reproductively isolated populations. Genetic disease: DNA sequence variations can result in genetic disorders.

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DNA Sequence Variations as a Fossil Record

Understanding who we are. We are >99.9% genetically identical. Each of us is genetically unique, except for identical twins (maternal). Understanding where we came from. Africa

Human Genome Project, U.S. Department of Energy

Group of 10,000-80,000 50,000-100,000 years ago

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Summary

DNA sequence variation is a normal part of every species and is not always associated with disease.
DNA sequence variations provide a mechanism for mapping genes and tracing the genetic history of organisms. Understanding the genetic basis of diseases permits genetic testing and risk prediction, and research into treatments and cures.

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