Our major goals are: (1) To estimate the male-to-female ratio of substitution mutation (a) and that of index (insertion and deletion) mutation (b) in primates and rodents, and to test three hypotheses: (i) the rate of index mutation is the same in the two sexes (i.e. B= 1); (ii) the rate of index mutation is the same in the two sexes (i.e. B=1); (ii) alpha is extremely large (say>50) in both humans and rodents; and (iii) alpha increases with generation time (i.e., generation-time effect). (2) To test the hypothesis that errors in DNA replication during germ-cell division are the primary sources of mutation. (3) To test the hypothesis that mutation rates differ among regions of the mammalian genome. (4) To test the molecular clock hypothesis. To achieve these goals, we propose to investigate: 1. Argininosuccinate synthetase (AS) processed pseudogenes: sequence the entire sequence of one Y-linked, two X-linked and two autosomal AS pseudogenes in human, orangutan, baboon and squirrel monkey. 2. Actin processed pseudogenes: sequence the entire sequence of one Y- linked, one X-linked and three autosomal gamma actin pseudogenes in human, orangutan, baboon and squirrel monkey. 3. Zinc finger (ZF) genes: sequence the last intron (1.1 Kb), the last exon (1.2 Kb) and the 3' flanking region (2 Kb) of the X-linked and Y- linked ZF genes in human, organutan, baboon, squirrel monkeys, mouse and rat. 4. Ubiquitin activating enzyme E1 (Ube1) genes: sequence three introns (900 bp) and two exons (300 bp) of the X-linked and Y-linked Ubel genes in mouse and rat. 5. Statistical analyses: conduct analyses of the new and published sequences to estimate alpha and beta and to test the hypotheses stated above. We shall also analyze published data on embryogenesis, oogenesis and spermatogenesis to estimate the ration (c) of the numbers of germ- cell division per generation in males and females in humans, mice and rats. A comparison of alpha and c may indicate whether substitution mutation is primarily due to errors in DNA replication.
| Huang, W; Fu, Y X; Chang, B H et al. (1998) Sequence variation in ZFX introns in human populations. Mol Biol Evol 15:138-42 |
