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Genes and Genetic Disease Chapter 2 Genetic Perspective Microscopic studies – 1800s – nucleus might contain important information for inheritance Gregor Mendel 1865 Austrian monk Garden peas Dominant, recessive Homozygous, heterozygous “hallmark of understanding inheritance” Apparent –” chromosomes (nucleus) contain genes – basic unit of inheritance” Gregor Mendel 1822-1884 St. Thomas Abbey Brno Czech Rep. Mendelian Genetics Hugo de Vries & Carl Correns 1900 : independent duplication of 1865 work “acknowledged Mendel’s work” Lucky…working with characteristics that were coded by single genes Principles: Segregation : one gene(of a pair) per gamete(sperm/egg) Independent assortment : transmission of one gene does not affect the transmission of another Watson-Crick Model of DNA Molecule 1953 Genes = DNA (deoxyribonucleic acid) 3 basic components Pentose sugar – deoxyribose 2. Phosphate molecule 3. 4 types of nitrogen bases 1. pyrimidines: cytosine, thymine (C, T) purines: adenine, guanine (A, G) Double-helix model – “twisted ladder with chemical bands as the rungs” A –T rungs of the G–C ladder DNA subunit consists of Deoxyribose molecule Phosphate group One base (A, T, C or G) Called NUCLEOTIDE DNA Rosland Franklin: 1920-1958 DNA as the Genetic Code Proteins – structural, functional (receptors & enzymes) Amino acids → polypeptides → one/more → protein (tissues, enzymes, receptors) 20 different amino acids 4 bases (A-T, C-G) – specify which amino acid is placed into the polypeptide Group of 3 bases – each amino acid termed CODON DNA Replication Untwisting and unzipping of the DNA strand – template Complementary base pairing by DNA polymerase A –T C–G DNA Replication Mutation Any inherited alteration of genetic material “Chromosome aberrations” Base pair substitution (missense/stop) A-T………..G-C Frame shift mutation – deletion or insertion ATGCTACG……AT_CTACG or ATG G CTACG SO - insert the wrong amino acid(s) into the polypeptide chain(s) → abnormal proteins (MUTATION) Mutations Spontaneous – absence of known mutagen Hot spots – chromosome areas with ↑ rates cytosine followed by guanine → large percentage of disease – causing mutations Radiation & chemicals - ↑ frequency Genes to Proteins Dogma: Transcription DNA Translation RNA NUCLEUS RNA – 2 differences 1.- ribose sugar: added Oxygen 2.- uracil, rather than thymine A–U C–G Proteins CYTOPLASM Transcription Messenger RNA – synthesized from DNA template (RNA polyerase) single strand of DNA mRNA → cytoplasm Transcription Translation* RNA directs synthesis of polypeptides at the ribosome tRNA **contains a sequence of nucleotides (anticodon) complementary to the triad of nucleotides on the mRNA strand (codon) mRNA = UGC… tRNA = ACG remember:RNA- U:A, C:G DNA- T:A, C:G *Nobel Prize Chemistry 2009: Ramakrishnan, Steitz, Yonath “structure of ribosomes”…new antibiotics! **Transfer RNA Translation Chromosomes Abnormalities – leading cause mental retardation & miscarriage Somatic cells 46 chromosomes (23 pairs) – Diploid Gametes 23 chromosomes (1 member of pair) - Haploid Chromosomes Meiosis – haploid cells from diploid cells :sperms & eggs (reduction division) Mitosis – forms somatic cells :new cells Figure 2-9 Karyotype Ordered display of chromosomes Chromosome Aberrations Euploid cells Contains a multiple of the normal number of chromosomes (23) Haploid and diploid Polyploid cells Triploid – 3 copies of 23(haploid) → 69 chromosomes Tetraploid – 4 copies 23(haploid) → 92 chromosomes Chromosome Aberrations Aneuploidy Somatic cell does not contain a multiple of 23 chromosomes 3 copies of one → trisomy (may survive) 1 copy only → monosomy (lethal) “More is better” Chromosome Aberrations Disjunction – normal separation of chromosomes during cell division Non-disjunction – failure of homologous chromosomes to separate – meiosis / mitosis Usual cause of aneuploidy Chromosomes Autosomes First 22 of the 23 pairs Two members are identical and said to be homologous Sex chromosomes Remaining pair Females – XX – homologous Males – XY – non-homologous Nondisjunction Autosomal Aneuploidy Down Syndrome Trisomy 21 1:800 live births Mentally retarded, low nasal bridge, epicanthal folds, protruding tongue, poor muscle tone Risk ↑ with maternal age > 35 Down Syndrome Blood Test for Down Syndrome6/2011 Sex Chromosome Aneuploidy 1 in 500 males / 1 in 900 females Females trisomy X Females single X – total 45 chromosomes Turner Syndrome Males – two x and one Y (47 chromosomes) Klinefelter Syndrome Turner Syndrome -45X, monosomy Klinefelter Syndrome-47,XXY Abnormalities of Chromosome Structure Breakage – repair – may alter structure Loss – Cri du chat syndrome – deletion short arm #5 → low birth weight mental retardation and microcephaly Duplication – less serious Inversion – balanced – no apparent effect Translocation – interchange of material between two non-homologous chromosomes Robertsonian – fusion at centromere → single chromosome Abnormalities of Chromosome Structure Fragile sites – areas that develop breaks or gaps Fragile X syndrome – long arm X chromosome Mental retardation Male (XY) verses female (XX) Genetics Gregor Mendel – 1865 Austrian monk Garden peas Mendelian traits Genetics “trait caused by a single gene → mendelian trait” Locus – gene location on a chromosome Allele – different form of a particular gene at the given locus Example: Hgb A verses Hgb S Polymorphism – two or more alleles at a locus Genetics “humans are diploid – one chromosome from mom one from dad – 23 + 23 = 46” Homozygous – loci on a pair of chromosomes have identical genes Example: O blood type (OO) Heterozygous – loci on a pair of chromosomes have different genes Example: AB blood type (A & B genes on a pair of loci) Genetics Genotype – genetic makeup of the organism Phenotype – observable, detectable or outward appearance of the genetics of an organism Example: A blood type – could be AA or AO A – phenotype AA/AO – genotype Genetics Dominant/Recessive – two alleles are found together, observable allele is dominant, other allele is recessive and not observable A – large letter = dominant a – small letter = recessive Alleles can be co-dominant Example: AB blood type Genetics Carrier - one that has a disease gene but is phenotypically normal to demonstrate a recessive disease the pair of recessive genes must be inherited Example: Dd Heterozygous – carrier dd Homozygous _ disease Genetics Mendel 1865 Principle of segregation– homologous genes separate, reproductive cells carry only one gene (meiosis) Principle of independent assortment – hereditary transmission of one gene does not affect the transmission of another. Chromosome Theory of Inheritance “Single Gene Disease – 4 mode of inheritance” 1) Autosomal dominant 2) Autosomal recessive 3) X-linked dominant 4) X-linked recessive Pedigrees Used to study specific genetic disorders within families Begin with proband Pedigrees Single Gene Disorders Autosomal dominant – rare < 1:500 Normal parent x affected heterozygote “Rare” Single-Gene Disorders Autosomal dominant traits Single-Gene Disorders Autosomal dominant trait pedigree Single Gene Disorders Recurrence risk AD – one parent with disease, one without risk :50% risk Single Gene Disorders Autosomal dominant Achondroplasia 4p16.3…FGFR3 Gene …80% new mutations Marfan syndrome Neurofibromatosis Brachydactyly Noonan syndrome Huntington disease 15q 15-21 17q11 Wizard of Oz Review Delayed age of onset Penetrance expressivity Single Gene Disorders Autosomal recessive Abnormal allele – recessive so must have 2 copies (homozygous) for expression Recurrence risk 1:4 ↑ with consanguinity (2 related individuals) Autosomal Recessive Disorder Single Gene Disorders Autosomal recessive Albinism Cystic fibrosis 7q31 Phenylketnuria 12q21 Galactosemia Mucopolysaccharidosis Albinism Sex Linked Disorders X – chromosome,Y has only a few dozen genes Male expression (XY), females have another X (XX) Most disorders are recessive – fathers cannot transmit to sons, but can to daughters Disease: Duchenne’s Muscular Dystrophy Color Blindness Hemophilia Sex-Linked Disorders Review – Multi-factorial Inheritance Diseases Cleft lip & palate Neural tube defects Clubfoot Some congenital heart disease Figure 2-31 Example of Diseases: A Gene Map