Salinas, D.

Universitat Autònoma de Barcelona. Facultat de Biociències

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THE INHERITANCE OF MITOCHONDRIAL HETEROPLASMYSalinas.D, Genetics Degree, Facultat de Biociències, Universitat Autònoma de Barcelona.  Barcelona. Catalonia. Spain 2013INTRODUCTIONThe mammalian mitochondrial genome (mtDNA) is a small double‐stranded molecule that is exclusively transmitted down the maternal line. The existence of a mixture of mutant and wild‐type mtDNAwithin the same organism is called heteroplasmy and, although not necessarily, this event can be associated with pathogenic effects. However, the exact mechanism of inheritance that controls the amountof mutant mtDNA that is going to be transmitted from a mother to her offspring is still unknown. Therefore, understanding the biological basis of this uncertainty is one of the principal challenges facingscientists in the field of mitochondrial genetics. In this review the main goal is to shed light on the factors responsible for inheritance through the different theories about when and how the mitochondrialgenetic bottleneck is produced and whether selection, random drift or both are influencing in the segregation patterns.High copy numberLack of recombinationMaternal inheritanceHigh mutation rateHETEROPLASMYPOINT LENGTHSporadic MaternalINHERITANCESELECTION?Different types of mtDNA withinthe same organism.?More frequent in control region.? 62,37% population.?50‐85% of affectation to causephenotypic effect.? Different rates among tissuesand offspring.?More than 100 different types of pathological mutations in mtDNA have been described butheteroplasmy itself can appear equally in healthy individuals. Only rates over 50‐80% will showphenotypic affectation.? There are different levels of heteroplasmy among tissues produced by somatic mutations thatdescribe a non‐randomly pattern of inheritance. This is influenced by selection at the level of organismassociated with the phenotypic affectation.?The inheritance of heteroplasmy can be explained by the bottleneck theory. A physical reduction ofunits in the early oogenesis is evident but the bottleneck responsible for the genetic variance occursduring folliculogenesis, when mutations that escape from purifying selection in early oogenesis arerapidly segregated and exposed to selection at the level of organism.? 200 is the approximate number of segregating units which are going to contribute to nextgeneration’s genetic variance.?In the transmission of heteroplasmy it is evident the action of random drift although selection actsover pathogenic mutations. Below the threshold of 80% affectation mutations would be invisible toselection and would segregate randomly.Early embryo Fertilized zygote Non‐random segregationNon proliferative tissuesProliferative tissuesHETEROPLASMYRANDOM INTRACELLUAR GENETIC DRIFTExpansion and accumulation of somatic mutationsAging Neurodegenerative diseases HETEROPLASMYDeleterious mutations will be lost through replicationTHE HUMAN MITOCHONDRIAL GENOME GENETIC BOTTLENECKEARLY  OOGENESIS   POSTNATAL FOLLICULOGENESIS  Mitochondrial genetic bottleneckFertilized oocyte Primordial germ cellsOogonia Primordial folliclePrimary oocyteSecondary oocyteMature oocyteFilter for purifying selectionmtDNA GenotypicVariance Oogenesis FolliculogenesisNon replicating Replicating Primordial germ cellsPurifying selection event against deleterious mutationsGENETIC VARIANCESelective replication of random subset of mtDNA templates1. Cao, L. et al. New evidence confirms that the mitochondrial bottleneck is generated without reduction of mitochondrial DNA content inearly primordial germ cells of mice. PLoS genetics 5, e1000756 (2009).2. Chinnery, P. F. Modulating heteroplasmy. Trends in genetics : TIG 18, 173–6 (2002).3. Jenuth, J. P., Peterson, A. C., Fu, K. & Shoubridge, E. A. Random genetic drift in the female germline explains the rapid segregation ofmammalian mitochondrial DNA. Nature genetics 14, 146–151 (1996).4. Li, M., Schönberg, A. & Schaefer, M. Detecting heteroplasmy from high‐throughput sequencing of complete human mitochondrial DNAgenomes. Journal of Human Genetics87, 237–49 (2010).5. Lightowlers, R. N., Chinnery, P. F., Turnbull, D. M. & Howell, N. Mammalian mitochondrial genetics: heredity, heteroplasmy and disease.Trends in genetics : TIG 13, 450–5 (1997).6. Ramos Reche, A. Freqüència i patró d’heteroplasmia mitocondrial humana. (2012).7. Wai, T., Teoli, D. & Shoubridge, E. a The mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes.Nature genetics 40, 1484–8 (2008).Very small number of mtDNAs, or even a single one, serve astemplates for replication to populate the oocytes from whichmtDNA is transmitted to the offspring.Human Ovum 200,000 mtDNAsFertilized oocyteRapid zygotic divisionsNo mtDNAreplication100 mtDNAs/cellEarly embryonic development Primordial germ cellsPGC migrate to the ovary and asubpopulation of diploid cells(oogonia) are formed by mitoticdivisions.10 mtDNAs Mitochondrial DNA multiplicationPHYSICAL  BOTTLENECK NUMBER OF SEGREGATING UNITSVariance in primary oocyte issufficient to explain variance inmtDNA frequencies in adults ofnext generationNo differences were observed whenheteroplasmy was measured in primaryoocytes and mature oocytes from adultmice.RANDOM DRIFTGENETIC BOTTLENECKVn =p0(1‐p0) [1‐(1‐1/N)gn]Initial frequency Variance in nth generationCell divisions in germline N ≈ 200DISCUSSIONBIBLIOGRAPHY Selection at different levels of organizationInitial proportions of mtDNA variants in the motherMoment in which mutation arises BeforeAfterDuringPosition of mutated mitochondria PeripheralPerinuclearNuclear genetic backgroundBottleneckDRIFT + SELECTIONRAPID SEGREGATION(2‐3 generations)Heteroplasmy HomoplasmyPathogenic mutationsSmall pedigreesPURIFYING SELECTIONLost from maternal lineSeverity prevents further transmissionNucleoidsmtDNAs replicate as a unit Physical bottleneckSelective pressureRANDOM DRIFT Random genetic drift isthe main mechanism ofsegregation acting in thefemale germ lineExplains the different proportions of heteroplasmy among the offspringNeutral and polymorphic variantsBelow80% Mutant mtDNA escapes from selectionRANDOM SEGREGATION

The inheritance of mitochondrial heteroplasmy

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The inheritance of mitochondrial heteroplasmy

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