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Genetic diseases Marin Vargas, Sergio Paul 2013 Genetic disease A genetic disease (genetic disorder or Mendelian disease) is an illness caused by one or more abnormalities in the genome, especially a condition that is present from birth (congenital). Most genetic disorders are quite rare and affect one person in every several thousands or millions. Genetic disorders are heritable, and are passed down from the parents' genes. Other defects may be caused by new mutations or changes to the DNA. In such cases, the defect will only be heritable if it occurs in the germ line. The same disease, such as some forms of cancer, may be caused by an inherited genetic condition in some people, by new mutations in other people, and by non genetic causes in still other people. Genetic disorder classification 1. Single gene disorder 1.1. Autosomal dominant 1.2. Autosomal recessive 1.3. X-linked dominant 1.4. X-linked recessive 1.5. Y-linked 1.6. Mitochondrial 2. Multifactorial and polygenic (complex) disorders SNV might cause a genetic disorder SNV: Single Nucleotide Variant At least 1% of population SNP (Single Nucleotide Polimorfism) Otherwise Mutation Here is part of the genome from two people who are both smokers and drinkers, but only one of them gets cancer. The zoom into the chromosomes of these two men shows just a sampling of the differences in variation that are responsible for their individual cancer risk. The variations themselves do not cause cancer. They only affect each person's susceptibility to tobacco smoke and alcohol after exposure. Protein folding The protein function depends on the 3D structure that depends on the sequence Amino acids Variations causing no changes Silent mutation or synonymous mutation When a SNP occurs within a coding region, it is possible that there is no effect. For example, when the DNA sequence GAC becomes GAG, the codon in the mRNA changes from CUG to CUC. Since both codons stand for the same amino acid leucine, there is no change in the protein. The change in the DNA is called a silent change. (Very high frequency mutation) Variations causing harmless changes Non synonymous harmless mutation There are also SNPs within coding regions that lead to very subtle changes in proteins. For example, if a SNP causes the codon GAU to change to GAG, the amino acid changes from aspartic acid to glutamic acid. These amino acids have very similar chemical properties, but glutamic acid is just a little bigger. If the SNP causes a change in a part of the protein that is not important to its function, the result may be very subtle or totally harmless. The cell continues to function normally. (High frequency mutation) Variations causing harmful changes Non synonymous harmful mutation There are also SNPs within coding regions that lead to very important changes in proteins. For example, the sequence GUA becomes GUU, and the amino acid called aspartic acid changes to valine in the protein. These two amino acids have very different chemical properties. The substitution of one for the other may, or may not, severely alter how the protein folds and functions, depending on where the change occurs in the protein. When the change in the protein does lead to disease symptoms in the patient, the SNP is harmful and is called a mutation. (Rare mutation low frequency) Gene expression and genetic disease Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA (rRNA), transfer RNA (tRNA) or small nuclear RNA (snRNA) genes, the product is a functional RNA. The process of gene expression is used by all known life to generate the macromolecular machinery for life. Conservation genetics Since sequence information is normally transmitted from parents to progeny by genes, a conserved sequence implies that there is a conserved gene. Highly conserved DNA sequences are thought to have functional value. A base preserved, most likely, indicates a region important for the protein structure, thus important for the protein functionality. Researcher goal Identification of pathogenic DNA sequence alterations in patients with inherited diseases. Understanding how a mutation affects the protein functionality, that is, whether the mutation is or not causative directly or indirectly of the genetic disorder (deleterious). Predict whether an amino acid substitution affects protein function The aim is to introduce single nucleotide variant found, into the protein’s structure and to predict the possible structural and functional consequences due to that variant.