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Male-Driven Male-Driven Evolution:Evolution:

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The Rate of Substitution is Positively Correlated with the Rate of Mutation and Negatively Correlated with the Degree of Purifying Selection

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J. B. S. Haldane. 1947. The mutation rate of the gene for haemophilia and its segregation ratios in males and females. Annals of Eugenics 13:262-271.  “The primordial oocytes are mostly if not all formed at birth, whereas spermatogonia go on dividing throughout the sexual life of a male. So if mutation is due to faulty copying of genes at a nuclear division, we might expect it to be commoner in malesmales than femalesfemales.”

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J. B. S. Haldane. 1947. The mutation rate of the gene for haemophilia and its segregation ratios in males and females. Annals of Eugenics 13:262-271.

“… we should expect higher mutability in the male to be a general property of human and perhaps other vertebrate genes.”

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Because mammalian oogenesis differs fundamentally from the process of spermatogenesis, the number of germ-cell divisions from one generation to the next in males is usually much larger than that in females.

nm >> nf

6Number of divisions in females = 33

From human ovum to human ovum

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Number of divisions in males is age dependent.

From human sperm to human sperm

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Age (years) Number of cell divisions

Puberty (~10-16)

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20 ~150

30 ~380

40 ~610

50 ~840

An old father = 67 years A young father = 13 years

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In mice, nm = 57 and nf = 28.

In rats, nm = 58 and nf = 29.

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J. B. S. Haldane (1947):

“It is difficult to see how this could be proved or disproved for many years to come.”

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Takashi Miyata (1987): Takashi Miyata (1987):

Autosomal seAutosomal seqquencesuences are carried are carried one half of the time by females one half of the time by females and one half of the time by and one half of the time by males. males.

X-linked seX-linked seqquencesuences are carried are carried two-thirds of the time by two-thirds of the time by females and one third of the females and one third of the time by males. time by males.

Y-linked seY-linked seqquencesuences are only are only carried by males.carried by males.

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umu f

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

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A um uf

2

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X um

3

2u f

3

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Y = um

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Y / A 2

1

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X / A 2(2 )

3(1 )

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Y / X 3

2

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If indeed males have a higher mutation rate than females, then…

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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 an 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 almost no 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.

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The mean Y/X ratio was 2.25, which by using

translates into an estimate of = ~ 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.

Y / X 3

2

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This phenomenon was dubbed:

““MALE DRIVEN EVOLUTION”MALE DRIVEN EVOLUTION”

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Complication:

MALE DRIVEN EVOLUTIONMALE DRIVEN EVOLUTION may be explained by two factors:

1. Mutation: There are more mutations in males than in females.

2. Selection: Exposure of alleles to purifying selection on hemizygous X chromosomes in males.

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How to separate How to separate sex from sex sex from sex chromosomes?chromosomes?

WZ WW XX XY

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Ellegren and Fridolfsson (1997) studied rates of mutation in birds.

Male-to-female ratio in mutation rates ranged from 4 to 7.

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The vast majority of The vast majority of mutations derive from mutations derive from the male germline.the male germline.

If your child is a If your child is a mutant, mutant, blame your husband.blame your husband.

• Mutations can occur due to errors during DNA replication (replication-dependent mutations)– Point mutations– Indels– Gene conversion events

• Mutations can also occur independently of DNA replication (replication-independent mutations or non-replication-dependent mutations or shelf-life mutations).– Mutations in methylated CpG sites (increased vulnerability of methylcytosines to mutate).

– Induced mutations (e.g., exposure to mutagens)

– Chromosomal abnormalities.

Male-driven evolution

•Only replication-dependent mutations exhibit characteristics of “male-driven evolution.”

Male-driven evolution