遗传学英文课件：Learning Objectives

1、Learning Objectives,Mutations in mitochondrial genes (one of non-Mendelian patterns of inheritance).,What is Life?,LIFE = Structure + Energy + Information,An adult organism has an estimated 1014 cells. Cells =2 organisms:nucleus-cytosol + mitochondria. Mitochondria are bacterial symbionts, 2-3 109 Y

2、RA. Mitochondrial genome 1500 genes (mtDNA + nDNA). Each cell has 100s of mitochondria and 1000s mtDNA. Mutations in mtDNA can be inherited maternally or acquired as somatic mutations.,A small but important subset of genes encoded in the human genome residues in the cytoplasm in the mitochondria.,EN

3、ERGY: Fats + Sugars + Oxygen = Energy (heat + work) + CO2 + H2O REACTIVE OXYGEN SPECIES: Mitochondrial Combustion Oxygen Radical APOPTOSIS: Energy + ROS = mtPTP Activated Cell Death (Apoptosis),LIFE = STRUCTURE + ENERGY + INFORMATION,The physiology of mitochondria,16569 bp; heavy (H) and a light (L)

4、 single strand; 37 genes. / (16568 bp in fact! 3107del is maintained in the sequence as a gap, “X”),Organization of the mt genome,Mitochondrial genome Small (16.5 kb) circular DNA 1 gene/0.45 kb Very few repeats No introns 93% coding Heavy and Light strands,Organization of the m

5、t genome,Mitochondrial genes rRNA, tRNA and protein encoding genes (37) 28 encoded by the heavy strand 22 tRNAs, 2 rRNAs (23S rRNA, 16S rRNA) and 13 protein coding genes (OXPHOS subunits),Nuclear human genome,Special features of mitochondrial genetics,1. mtDNA is maternally inherited.,Paternal inher

6、itance of mtDNA disease has been documented in only 1 instance. Schwartz M, Vissing J. NEJM, 2002;347:576580,Y chromosomal haplogroup distribution,Wallace D C. Annu Rev Genet, 2005;39:259-407 Wallace D C. Annu Rev Biochem, 2007;76:781-821 Wallace D C. Annu Rev Pathol, 2010;5:297-348,2. mtDNA genes h

7、ave a much higher mutation rate than nuclear DNA genes. Mutation rate is 10 fold than nuclear DNA genes,3. Many of the pathogenic mtDNA mutations are heteroplasmic. For expression of a disease it is required that a certain threshold level of mutant mtDNA should be exceeded.,3. Homoplasmy 111: 303-31

8、2,mtDNA genome mutates at a rate about 10-fold greater than does nuclear DNA. Three Types of mutations:(1) missense mutations in the coding regions of genes that alter the activity of an OXPHOS protein; (2) point mutations in tRNA or rRNA genes that impair mitochondrial protein synthesis; (3) rearra

9、ngements that generate deletions or duplications of the mtDNA molecule. Chan DC. Cell, 2006; 125:1241-1252,Mutation of mtDNA (LHON, MERRF，etc.),Examples of diseases due to mutations and deletions in mtDNA Abbreviation OMIM# Designation LHON 535000 Leber hereditary optical neuropathy MELAS 540000 Mit

10、ochondrial encephalomyopathy 540050 Lactic acidosis with stroke-like signs MERRF 545030 Myoclonic epilepsy and ragged red fibers,Leber hereditary optical neuropathy, LHON,Rapid optic nerve death, leading to blindness in young adult life.,MZ with LHON,Leber hereditary optic neuropathy,The diagnosis o

11、f Leber disease is strongly supported by finding typical microangiopathy in symptomatic or asymptomatic family members.,LHON,Incomplete penetrance - approximately 50% males and 10% females with a pathogenic mtDNA mutation develop the optic neuropathy Genetic heterogeneity The majority of patients (9

12、5%) have 1 of 3 mtDNA point mutations (G3460A, G11778A, or T14484C),Interaction Between the mtDNA and nDNA,A more direct relationship exists between the nuclear and mtDNA genomes. As most mt proteins, including subunits involved in electron transport, are encoded by nuclear genes, these most often f

13、ollow AR. mtDNA: “The slave of nuclear DNA”,Interaction Between the mtDNA and nDNA,Autosomally transmitted deletions in mtDNA: mtDNA depletion syndrome: Mitochondrial gastrointestinal encephalomyopathy:,Nuclear Genes Can Modify the Phenotype of mtDNA Diseases,About 50% of male carriers but only about 10% of female carriers of a LHON mutation develop symptoms. The variation in penetrance and the male bias of the phenotype have been shown to be determined by a haplot