Archiver > GENEALOGY-DNA > 2008-02 > 1202032495

From: "Ian Logan" <>
Subject: Re: [DNA] Strong purifying selection in transmission ofMammalianmitochondrial DNA
Date: Sun, 3 Feb 2008 09:58:54 -0000
References: <>

Sasson wrote:
How do we know that previous generations of humans were not 'enzyme
deficient' ?

If they were, then it wouldn't take "ten thousand generations" to get to the
degree of overall genetic diversity observed today.


An interesting point.

Below is the abstract to the previous paper from Trifunovic.

It really is a very special paper as it shows how their enzyme-deficient mice
were produced - and then shows the severe health problems suffered by the
mice in just a few weeks.

The enzyme involved in 'Polymerase gamma' (Polg) which in some way
proof-reads new mtDNA.

I certainly wonder if the familiar mutations in the human phyllogentic tree
are the result of their occurring in persons with this time of 'enzyme deficiency'.

I.e. 'In normal persons mutations never occur', and a mutation is a sign
of decreased enzyme functioning.

Certainly there are diseases linked to mutations in this enzyme, so its
normal functioning is very important.


Premature ageing in mice expressing defective mitochondrial DNA polymerase

Aleksandra Trifunovic Anna Wredenberg Maria Falkenberg Johannes N.
Spelbrink Anja T. Rovio Carl E. Bruder Mohammad Bohlooly-Y Sebastian
Gidlöf Anders Oldfors Rolf Wibom Jan Törnell Howard T. Jacobs &
Nils-Göran Larsson
Nature 429, 417 - 423 (2004).

Point mutations and deletions of mitochondrial DNA (mtDNA) accumulate
in a variety of tissues during ageing in humans, monkeys and
rodents. These mutations are unevenly distributed and can accumulate
clonally in certain cells, causing a mosaic pattern of respiratory
chain deficiency in tissues such as heart, skeletal muscle and
brain. In terms of the ageing process, their possible causative
effects have been intensely debated because of their low abundance and
purely correlative connection with ageing. We have now addressed
this question experimentally by creating homozygous knock-in mice that
express a proof-reading-deficient version of PolgA, the
nucleus-encoded catalytic subunit of mtDNA polymerase. Here we show
that the knock-in mice develop an mtDNA mutator phenotype with a
threefold to fivefold increase in the levels of point mutations, as
well as increased amounts of deleted mtDNA. This increase in somatic
mtDNA mutations is associated with reduced lifespan and premature
onset of ageing-related phenotypes such as weight loss, reduced
subcutaneous fat, alopecia (hair loss), kyphosis (curvature of the
spine), osteoporosis, anaemia, reduced fertility and heart
enlargement. Our results thus provide a causative link between mtDNA
mutations and ageing phenotypes in mammals.

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