The Molecular Basis of Heredity Part III The

The Molecular Basis of Heredity Part III: The Molecular Basis of Genetic Variation By Raye L. Alford, Ph. D Baylor College of Medicine DNA Model by J. Watson and F. Crick © Cold Spring Harbor Laboratory Archives Bio. Ed Online

Exploring Our Molecular Selves "Exploring Our Molecular Selves" is a 3 D 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/onli ne. htm Bio. Ed Online 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. www. Bio. Ed. Online. org

Human Genetic Disorders (I) n Chromosomal Disorders n n Contiguous Gene Deletion Syndromes n n Deletion of a large continuous section of genetic material from a single chromosome. Single Gene Disorders n n Alteration of number or structure of chromosomes. Mutation in a single gene. Common Complex Disorders n Influenced by multiple genetic and/or environmental factors. National Center of Biotechnology Information, National Library of Medicine Bio. Ed Online www. Bio. Ed. Online. org

Human Genetic Disorders (II) n Pedigree n Boxes represent males. n Circles represent females. n Diamond represents an individual of unspecified gender. n Shading represents affected individuals. n This example: n n Autosomal dominant disorder. Single gene disorder. P Bio. Ed Online www. Bio. Ed. Online. org

Mendelian Disorders (I) n Autosomal dominant inheritance A disorder appears in several generations of a family. n Affected parents have a 50% risk of an affected child with each pregnancy. n Variability and reduced penetrance can complicate predictions of prognosis. n Bio. Ed Online www. Bio. Ed. Online. org

Mendelian Disorders (II) n Autosomal recessive inheritance n n Disorders often appear in only one generation of a family. Carrier couples have a 25% risk of an affected child with each pregnancy. Bio. Ed Online www. Bio. Ed. Online. org

Mendelian Disorders (III) n X-linked inheritance X-linked dominant disorders are few in number. n Male to male transmission of Xlinked disorders is not seen. n Carrier females may show mild to moderate symptoms of certain X-linked disorders. n Bio. Ed Online www. Bio. Ed. Online. org

Maternal (Mitochondrial) Inheritance n Inheritance through the maternal lineage. n Sperm do not contribute mitochondria to the embryo. Bio. Ed Online www. Bio. Ed. Online. org

Complex Mechanisms of Hereditary Disease (I) n n Multifactorial n Common Complex Disorders New Mutation n Found in the child, but not in either parent. Imprinting n A form of gene silencing. Anticipation n Progressive severity of a disorder in successive generations. 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 Bio. Ed Online www. Bio. Ed. Online. org

Complex Mechanisms of Hereditary Disease (II) n Genetic Heterogeneity Allelic – different mutations in a single gene result in the same disorder. n Locus – mutations in different genes produce the same disorder. n n Nonrandom X-inactivation n In females, genes on one of the X chromosomes are turned off. Bio. Ed Online Barr Bodies (indicated by the arrows) are the highly compacted inactive X chromosomes. Courtesy of Dr. Steven M. Carr. www. Bio. Ed. Online. org

The Molecular Basis of DNA Sequence Variations (I) Wild type sequence: Nucleotide: ACTGATT Amino Acid: Thr–Glu–Leu-Ile n Substitution: ACTGACCTGATT (Thr-Asp-Leu-Ile) n Deletion: ACTCTGATT (Thr-Leu-Ile) n Insertion: ACTGAACTGATT (Thr-Glu-Pro-Gly-Leu-Ile) n Frameshift: ACTGATT (Thr-Asp-Stop) n Inversion: ACTGGTCAAATT (Thr-Glu-Gln-Ile) Bio. Ed Online www. Bio. Ed. Online. org

The Molecular Basis of DNA Sequence Variations (II) Nonsense mutations n A single base pair substitution that prematurely codes for a stop codon. n Results in complete or partial loss of functional capabilities of a protein derived from the mutated gene. Bio. Ed Online www. Bio. Ed. Online. org

The Molecular Basis of DNA Sequence Variations (III) Missense mutations Result in the substitution of one amino acid for another. n May or may not affect a protein’s function. n n Benign mutations can become prevalent in a population. Bio. Ed Online www. Bio. Ed. Online. org

The Molecular Basis of DNA Sequence Variations (IV) n n Null mutations n Result in the loss of a protein product from a gene. Repetitive elements n Repeated sequences are found throughout the genome. n Vary in size. n Consequences depend on location. Bio. Ed Online www. Bio. Ed. Online. org

Mutations n n n 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: n n n Loss of function Gain of function Dominant negative Bio. Ed Online Center for Genetics Education www. Bio. Ed. Online. org

Polymorphisms n DNA sequence variations are part of the genetic makeup of every species and every individual. n Not always associated with disease. n Polymorphisms can be used as markers to map disease genes. Bio. Ed Online www. Bio. Ed. Online. org

Causes of Mutations n Errors during DNA replication n n The proofreading capability of DNA polymerase corrects many, but not all errors. Exposure to mutagens n Ultraviolet light n DNA damaging chemicals n Radioactivity Bio. Ed Online DNA damage resulting in multiple broken chromosomes www. Bio. Ed. Online. org

Mechanisms of DNA Repair n n Cells have built-in mechanisms for DNA repair. These mechanisms protect against the consequences of errors during replication and exposure to mutagens. G A T C G C T A G C Damaged nucleotide shown by G A T C G C T A G C Excision of the damaged and surrounding nucleotides T A G C T G A T C G C T A G C Repair Visiscience Corporation. (2005). Science. Slides. All rights reserved. Bio. Ed Online www. Bio. Ed. Online. org

Significance of DNA Sequence Variations n n 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. Bio. Ed Online www. Bio. Ed. Online. org

DNA Sequence Variations as a Fossil Record n Understanding who we are. We are >99. 9% genetically identical. n Each of us is genetically unique, except for identical twins (maternal). n n Understanding where we came from. Human Genome Project, U. S. Department of Energy Africa n Group of 10, 000 -80, 000 n 50, 000 -100, 000 years ago n Bio. Ed Online www. Bio. Ed. Online. org

Summary n n n 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. Bio. Ed Online www. Bio. Ed. Online. org