Germline mutations provide the substrate for evolution, whether mediated by natural selection or random genetic drift. The inheritance of advantageous mutations increases the chance of survival and reproduction while the inheritance of deleterious mutations causes or predisposes to illness. Germline mutations in humans can neither be observed directly nor manipulated experimentally. However, inferences about the germline mutational process are possible by detailed analysis with attention to defining and correcting for biases in the data. The human factor IX gene is an advantageous system for examining the mutational process in the human germline. The goal of this grant application is to extend the analysis of the factor IX gene in order to gain further novel insights into the mutational process during both the recent and the more distant past. Molecular analysis of the factor IX gene in patients with hemophilia B will define germline mutations that generally have occurred within the past 150 years. In contrast to most genes, the observed pattern of mutation in patients with hemophilia B is similar to the underlying pattern of mutation. In addition, molecular analyses of: (i) intronic sequence changes in humans, (ii) intronic sequence changes in primates, and (iii) exonic sequence changes in nonmammals will define essentially neutral mutations that generally have occurred thousands, millions, and hundreds of millions of years ago, respectively. In the present application, the following questions will be addressed: (i) How does the sex ratio of recent germline mutation depend on the type of mutation and the age of the parent?; (ii) How frequent is somatic mosaicism and how likely is it to occur at a frequency of 10-1, 10-2, and 10-3?; (iii) Does the pattern of recent human factor IX germline mutation vary with ethnicity or geography?; (iv) What is the nature of the mutations that affect both factor IX mRNA structure and occur outside the regions of likely functional significance?; (v) Do germline mutations tend to arise in clusters?; (vi) Is the pattern of intronic polymorphism in Caucasians, Asians, Blacks, and Amerindians the same as the inferred underlying pattern of germline mutation during the past 150 years?; (vii) Is the average pattern of fixed germline mutations in the factor IX gene in eight great apes and Old World monkeys the same in each lineage?; and (viii) Are the amino acids conserved in factor IX during nonmammalian evolution the same amino acids that are mutated in humans with hemophilia B?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL039762-07
Application #
2392642
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1989-07-01
Project End
2000-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
7
Fiscal Year
1997
Total Cost
Indirect Cost
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
City
Duarte
State
CA
Country
United States
Zip Code
91010
Feng, Jinong; Drost, Joni B; Scaringe, William A et al. (2002) Mutations in the factor IX gene (F9) during the past 150 years have relative rates similar to ancient mutations. Hum Mutat 19:49-57
Hill, Kathleen A; Sommer, Steve S (2002) p53 as a mutagen test in breast cancer. Environ Mol Mutagen 39:216-27
Sommer, S S; Scaringe, W A; Hill, K A (2001) Human germline mutation in the factor IX gene. Mutat Res 487:1-17
Li, X; Scaringe, W A; Hill, K A et al. (2001) Frequency of recent retrotransposition events in the human factor IX gene. Hum Mutat 17:511-9
Li, X; Drost, J B; Roberts, S et al. (2000) Factor IX mutations in South Africans and African Americans are compatible with primarily endogenous influences upon recent germline mutations. Hum Mutat 16:371
Liu, J Z; Li, X; Drost, J et al. (2000) The human factor IX gene as germline mutagen test: samples from Mainland China have the putatively endogenous pattern of mutation. Hum Mutat 16:31-6
Drost, J B; Scaringe, W A; Jaloma-Cruz, A R et al. (2000) Novel hotspot detector software reveals a non-CpG hotspot of germline mutation in the factor IX gene (F9) in Latin Americans. Hum Mutat 16:203-10
Feng, J; Buzin, C H; Tang, S H et al. (1999) Highly sensitive mutation screening by REF with low concentrations of urea: A blinded analysis of a 2-kb region of the p53 gene reveals two common haplotypes. Hum Mutat 14:175-80
Heit, J A; Ketterling, R P; Zapata, R E et al. (1999) Haemophilia B Brandenberg-type promoter mutation. Haemophilia 5:73-5
Thorland, E C; Drost, J B; Lusher, J M et al. (1999) Anaphylactic response to factor IX replacement therapy in haemophilia B patients: complete gene deletions confer the highest risk. Haemophilia 5:101-5

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