A germ-line-selective advantage rather than an increased mutation rate can explain some unexpectedly common human disease mutations.

A germ-line-selective advantage rather than an increased mutation rate can explain some unexpectedly common human disease mutations. Research Abstract Details 

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A germ-line-selective advantage rather than an increased mutation rate can explain some unexpectedly common human disease mutations. Abstract Text:

Two nucleotide substitutions in the human FGFR2 gene (C755G or C758G) are responsible for virtually all sporadic cases of Apert syndrome. This condition is 100-1,000 times more common than genomic mutation frequency data predict. Here, we report on the C758G de novo Apert syndrome mutation. Using data on older donors, we show that spontaneous mutations are not uniformly distributed throughout normal testes. Instead, we find foci where C758G mutation frequencies are 3-4 orders of magnitude greater than the remaining tissue. We conclude this nucleotide site is not a mutation hot spot even after accounting for possible Luria-Delbruck "mutation jackpots." An alternative explanation for such foci involving positive selection acting on adult self-renewing Ap spermatogonia experiencing the rare mutation could not be rejected. Further, the two youngest individuals studied (19 and 23 years old) had lower mutation frequencies and smaller foci at both mutation sites compared with the older individuals. This implies that the mutation frequency of foci increases as adults age, and thus selection could explain the paternal age effect for Apert syndrome and other genetic conditions. Our results, now including the analysis of two mutations in the same set of testes, suggest that positive selection can increase the relative frequency of premeiotic germ cells carrying such mutations, although individuals who inherit them have reduced fitness. In addition, we compared the anatomical distribution of C758G mutation foci with both new and old data on the C755G mutation in the same testis and found their positions were not correlated with one another.

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A germ-line-selective advantage rather than an increased mutation rate can explain some unexpectedly common human disease mutations. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Proceedings of the National Academy of Sciences of

VOLUME: 105

Page Numbers: 10143-8

Journal Abbreviation: Proc. Natl. Acad. Sci. U.S.A.

ISSN: 1091-6490

DAY: 16

MONTH: 07

YEAR: 2008

A germ-line-selective advantage rather than an increased mutation rate can explain some unexpectedly common human disease mutations. Information

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LANGUAGE: eng

NlmUniqueID: 7505876

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Grant and Affiliation Information for A germ-line-selective advantage rather than an increased mutation rate can explain some unexpectedly common human disease mutations.

AFFILIATION: Molecular and Computational Biology Program, University of Southern California, 1050 Childs Way, Los Angeles, CA 90089-2910.

Country: United States

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MEDLINETA: Proc Natl Acad Sci U S A

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