Lecture4.pdf

Complications in Single Gene Pedigree Analysis and Non-Classical Inheritance Complications in Single Gene Pedigree Analysis ☛ Heterogeneity ☛ Pleiotropy, Penetrance and Expressivity ☛ Incomplete Dominance and Codominance ☛ Multiple alleles ☛ New Mutations and Mosaicism ☛ Sex-li...

Complications in Single Gene Pedigree Analysis and Non-Classical Inheritance Complications in Single Gene Pedigree Analysis ☛ Heterogeneity ☛ Pleiotropy, Penetrance and Expressivity ☛ Incomplete Dominance and Codominance ☛ Multiple alleles ☛ New Mutations and Mosaicism ☛ Sex-limited and Sex-influenced Traits ☛ Male lethality ☛ Maternal inheritance (mitochondrial diseases) Heterogeneity Principles of Medical Genetics (1998) Gelehrter, Collins, Ginsburg (eds)  Scheme of CFTR gene, transcript, and mutation distribution. F508 mutation causes defective folding and degradation Tsui L , and Dorfman R Cold Spring Harb Perspect Med 2013;3:a009472 ©2013 by Cold Spring Harbor Laboratory Press Deafness and locus heterogeneity  Mutations that exert effects on multiple aspects of physiology or anatomy are pleiotropic Pleitropy This is a common feature of human genes Marfan syndrome: Affects the eye, the skeleton and the cardiovascular system Albinism: Affects skin, eyes, and even hearing What all of this means is that individual genes typically are active within numerous tissues, and that a character often may be modified via different pathways and routes Marfan syndrome Pleiotropy – diverse phenotypic effects of a mutation Pleitropy Penetrance  Incomplete Penetrance Polydactyly - an AD pattern Some individuals do not express the phenotype dictated by their genotype. Expressivity  Variable Expressivity When the expression of a trait is not uniform Variable expressivity (range) of a given genotype is due to influences of environment and genetic background Waardenburg syndrome type 1 Codominance  Codominant Blood Group Alleles In heterozygotes, the molecules specified by both alleles are produced and generate a novel phenotype (here, AB blood type).  Multiple Blood Group Alleles there are 3 alleles in the population that specify ABO blood types but any one individual can carry only 2 alleles. New Mutations Can Arise Neurofibromatosis type I is usually inherited as a dominant trait Germline mosaicism Germline mosaicism  Germline Mosaicism amelogenesis imperfecta ü Both children have the same mutation ü No evidence of mutation in father’s somatic tissue Germline mosaicism recurrence Somatic mosaicism  Male Pattern Baldness : A Sex-Influenced Trait John Adams John Quincy Adams Charles Francis Adams Henry Adams Autosomal mutation; dominant in men and recessive in females - Hemochromatosis (iron overload disease) is also a sex-influenced trait (autosomal recessive); women are less affected because of menstruation. A Few X-linked Dominant Mutations are Lethal to Males in Utero Incontinentia pigmenti type 2 ü Trait occurs exclusively in females Single Gene Inheritance (Mendelian) Segregation of characters is based on meiosis: üalleles of one gene are never found on the same gamete but segregate and end up in different gametes Expression of genes (or alleles) is NOT determined by whether the gene is inherited from the father or mother  Non-Classical Inheritance Ratios typical of Mendelian segregation do not occur because meiotic segregation is not involved. Expression of genes (or alleles) is determined by whether the gene is inherited from the father or mother Non-Classical Inheritance Mosaicism Imprinting Uniparental Disomy Trinucleotide Repeat Disorders Mitochondrial/Maternal Inheritance Non-Classical Inheritance Mosaicism Imprinting Uniparental Disomy Trinucleotide Repeat Disorders Mitochondrial/Maternal Inheritance  Non-Classical Inheritance Uniparental Disomy ü Uniparental disomy: both homologues come from the same parent, none from the other eg: 2 #7 chromosomes from mom, none from dad Non-Classical Inheritance Mosaicism Imprinting Uniparental Disomy Trinucleotide Repeat Disorders Mitochondrial/Maternal Inheritance  Mutations are the ultimate source of genetic variation. Some mutations result in genetic disease, whereas others have no physical effects. The principal types of mutations include missense, nonsense, frameshift, deletion, duplication, promoter, and splice site mutations. There is also evidence for mutations caused by the random insertion of mobile elements, and some genetic disease are known to be caused by expanded repeats.  Non-Classical Inheritance Trinucleotide Repeat Disorders ü Dynamic mutations: heritable, unstable DNA v “…the capability of a trinucleotide to expand into multiple copies within one generation… the ability to increase in copy number over several generations…” ü Anticipation: v the observation that a disease becomes progressively worse and demonstrates earlier onset in subsequent generations  Non-Classical Inheritance Trinucleotide Repeat Disorders ü TNR: a feature normally present in the genome ü repeat of 3 (tri) nucleotides (e.g. CAG, CTG or CGG) from 30 to 100s of copies (e.g: CGGCGGCGGCGGCGGCGG) ü premutation: 50 - 230 repeats ü full mutation: > 230 repeats  Non-Classical Inheritance Trinucleotide Repeat Disorders Fragile X Syndrome Huntington’s Disease Myotonic dystrophy  Fragile X Syndrome Major Features X- linked: most common mental retardation Mutations in FMR1 gene on Xq27.3 FMR1 mutations: Expansions of a (CGG) TNR in the 5’UTR of the FMR1 >230 TNR: FMR1 inactivation by hypermethylation Non-Classical Inheritance Mosaicism Imprinting Uniparental Disomy Trinucleotide Repeat Disorders Mitochondrial/Maternal Inheritance Mitochondria 3 majors tasks: ý Production of energy [ATP] for the cell: ý Krebs cycle ý Oxidative phosphorylation ý Production of toxic reactive oxygen species (ROS) ý Regulation of the initiation of apoptosis Nuclear DNA vs Mitochondrial DNA Somatic cells (diploid) contain only 2 copies of the genome per cell : only two possible versions of each gene (“alleles”) An average 5 genomes per mitochondrion, and ~100 to 1,000 mitochondrial per cell. Mature mammalian oocytes have ~100,000 mtDNA copies/cell Sperm cells have ~100 mtDNA copies/cell  The human mitochondrial genome One molecule of circular DNA: 16,659 bp Dense gene packing (1 every 0.45 kb) 37 intronless genes: 13 encoding peptides of the respiratory chain 22 tRNA and 2 rRNA genes. Higher mutation rate than that of chromosomal DNA Genetic code is different for mtDNA  Mitochondrial Inheritance Mitochondria and their genome are transmitted from a mother to all of her offspring. The children of an affected mother might be affected. None of the children of an affected father will be affected  Heteroplasmy Heteroplasmy is the condition where a particular mutation may be present in some mitochondrial chromosomes but not others Can affect the severity of disease Heteroplasmy  Mitochondrial Disorders ü Affect tissues that are highly energy demanding: CNS, muscle, liver, kidney ü Disease phenotype dependent upon: gene(s) involved type of mutation (missense/nonsense/deletion) % normal vs abnormal mitochondria tissue involved  Mitochondrial Disorders MILD Asymptomatic Clinical features: very heterogenous LHON Single tissues or system may be affected (eg. Optic nerve damage in LHON) MELAS, MERRF Multi-system syndromes, Leigh Syndrome onset ranging from neonatal to adult Fetal non-viable SEVERE