Date of Award

1993

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Sciences

First Advisor

William R. Lee

Abstract

Germline mutation rates measured per generation per locus in three species of Metazoa are used to address questions of the constancy of mutation rates per generation, per year and per germcell division. Null mutation rates per generation are: 3.6 $\times$ 10$\sp{-6}$ for human X-linked disease, 8.9 $\times$ 10$\sp{-6}$ for Specific Locus Test (SLT) in male mice, 3.2 $\times$ 10$\sp{-6}$ for SLT in female mice, 8.0 $\times$ 10$\sp{-6}$ for SLT in male Drosophila melanogaster (D.m.), 1.6 $\times$ 10$\sp{-6}$ for SLRL test in male D.m. and 2.0 $\times$ 10$\sp{-6}$ for SLRL test in female D.m. They were found to be very similar across the species with some variation between loci and tests. Using much of the same data and estimates of male generation time of 30 years for humans, 9 months for mouse, and 18 days for D.m., male mutation rates per year are calculated. Varying over 3 orders of magnitude, the results do not support a time-dependent mechanism for mutation rates. These germlines are described in detail and estimations of numbers of germcell divisions per generation are made. They are 399 for a 30-year-old human male, 31 for a human female, 62 for a 9-month-old mouse male, 25 for a mouse female, 35.5 for an 18-day-old D.m. male and 36.5 for a 25-day-old D.m. female. Comparisons of mutation rates per cell division, along with data regarding parental origin of human mutations and male-driven molecular evolution, provide support for an effect of cell division upon mutation rates, but with additional factors which cause male mutation rates in humans to be higher, relative to female rates, than predicted based on cell division alone. The remarkable agreement among mutation data for these three species measured per generation supports generation-dependent mutation rates. Mechanisms proposed based upon the present studies of the germlines involve germline events occurring once per generation, between meiosis and the end of cleavage, which contribute disproportionately to the total mutation rate. The present study was supported by NIH grant $\sp\#$ESO3347-09.

Pages

135

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