Transcript Document

Number of mitoses in females = 22
Number of mitoses in
males is age dependent.
23 more
cell
divisions
per
year…
Because mammalian oogenesis differs
fundamentally from the process of spermatogenesis,
the number of germ-cell divisions from one
generation to the next in males, nm, is usually much
larger than that in females, nf.
In mice, nm = 57 and nf = 28.
In rats, nm = 58 and nf = 29.
The duration of meiosis is much longer in female
germ cells (order of tens of years) than that
observed during spermatogenesis (only weeks).
It is predicted that these differences will be
reflected in different mutation rates in males and
females.
J. B. S. Haldane (1947):
“… if mutation is due to faulty
copying of genes at the nuclear
division, we might expect it to be
commoner in males than in females.”
“[I]t is almost certain that the
mutation rate per gene is less in
women than in men.”
“It is difficult to see how this could
be proved or disproved for many
years to come.”
Takashi Miyata et al (1987)
Male-driven molecular evolution: a model and
nucleotide sequence analysis.
Miyata T et al. (1987). Cold Spring Harbor
Symp. Quant. Biol. 52:863-867.
Autosomal sequences are carried one half of the
time by females and one half of the time by males.
X-linked sequences are carried two-thirds of the
time by females and one third of the time by
males.
Y-linked sequences are only carried by males.
Let um and uf be the mutation rates in males
and females, respectively, and  be the ratio of
male to female mutation rates. That is
um

uf
um  u f
A
2
X
um
3

2u f
3
Y  um
2
Y/A 
1 
2(2   )
X/A 
3(1  )
3
Y/X 
2 
2(2   )
X/A 
3(1  )
When alpha approaches infinity, the ratio is 2/3.
Miyata et al. (1987) compared Ks values between
autosomal and X-linked genes (human vs. mouse and
rat). He estimated the ratio to be 0.6: relatively close
to the expectation.
Ks in X-linked
genes is lower
The zinc-finger protein-coding genes are a good case for
studying the ratio of male to female mutation rates
because in all mammals there are two homologous
genes, an X-linked one (Zfx) and a Y-linked gene (Zfy).
Shimmin et al. (1993) sequenced the last intron of Zfx
and Zfy genes in human, orangutan, baboon, and
squirrel monkey. There are only few functional
constraints on introns and, therefore, we may disregard
selective forces in this case.
For all pairwise comparisons, Shimmin et al. (1993)
found that the Y sequences were more divergent, i.e.,
have evolved faster, than their X-linked homologues.
The mean Y/X ratio was 2.25, which by using
3
Y/X 
2 
translates into an estimate of  = ~ 6.
Interestingly, the ratio nm/nf, is 200/33  6.
In rat, mouse, hamster, and fox, the mutation
rates in males were found to be twice as large as
those in females, which agrees with the nm/nf =2
ratio in these species.
This phenomenon was dubbed:
“MALE DRIVEN EVOLUTION”
Complication:
MALE DRIVEN EVOLUTION
may be explained by:
1. Number of replications: There are more
mutations in males than in females because of
differences in the number of replications in
spermatogenesis vs. oogenesis.
Complication:
MALE DRIVEN EVOLUTION
may be explained by:
2. Differences in mutation rate due to selection
against high mutation rate in the X
chromosome:
Since mutations in the X have more potential to be
deleterious, evolution selected in favor of low
mutation rate in X.
How to separate sex from
sex chromosomes?
ZW ZZ
XX XY
A
ZW ZZ
um  u
f
2
um

uf
W  uf
1
2
Z  u f  um
3
3
3
W /Z 
2  1
2(1  2 )
Z/ A
3(1   )
2
W /A
1 
Mutation rates vs. alpha
Ellegren and Fridolfsson
(1997) studied rates of
mutation in birds.
Male-to-female ratio in
mutation rates ranged from
4 to 7.
The vast majority of mutations
derive from the male germline.
Nothing happens, but if it does,
blame your husband.
Male driven evolution
The debate continues…
Headlines
Men are not in Driver's Seat of Human
Evolution
Whitehead Institute (August 9, 2000)
Men regain evolutionary driver's seat:
Mutation study confirms strong maledriven evolution among humans and
apes
University of California Hospitals (April
10, 2002)
Effect of age on mutations was studied for
achondroplasia and for Apert syndrome (dwarfism).
These diseases are autosomal dominant of full
penetrance. They are the result of mutations in
fibroblast growth factor 3 and 2 (FGRP3 & FGRP2).
achondroplasia
Apert syndrome
In almost all cases,
the father is the source
of the mutation
The average age of fathers at the time of birth of
affected children (>35y) is significantly higher
compared to average age of fathers (30.1).
The risk of a male aged > 50 is 7.8-fold higher than
that of a 25-29 year old male to be a father of an
affected child… [exponential increase in risk].