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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].