Early postzygotic mutations contribute to de novo variation in a healthy monozygotic twin pair
Author
Dal, Gülşah Merve
Advisor
Özçelik, Tayfun
Date
2014Publisher
Bilkent University
Language
English
Type
ThesisItem Usage Stats
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Abstract
Characterizing the patterns and rate of de novo mutations is crucial for our perception
of evolution and genetic basis of human disease. Direct observation of de novo single
nucleotide variation (SNV) rate in healthy individuals revealed a rate in a range of
0.82 – 1.70 ×10-8
base pair per generation. However, the developmental timing of the
de novo mutations is unknown and thus, contribution of the early post-zygotic
mutations to the human de novo SNV rate remained unknown. In an attempt to
estimate the rate of de novo mutations regarding the developmental timing of
mutagenesis, we sequenced the whole genomes of a healthy monozygotic twin pair
and their parents with a total of 170 fold coverage. We identified the de novo SNVs
through examination of the genotypes of each individual for each of the variants in a
synchronous manner. Subsequent to the Sanger sequencing based validation, we
conservatively characterized a total of 32 de novo SNVs. Of these 23 were shared by
the twin pair, 8 were specific to twin I, and 1 was specific to twin II. We estimated
the overall de novo SNV rate of 1.31 × 10-8
for twin I and 1.01 × 10-8
for twin II. The
rate of the early post-zygotic de novo SNVs was calculated to be 0.34 × 10-8
and 0.04
× 10-8
for twin I and twin II, respectively. These data indicate the growing
importance of genome mosaicism which might be resulted from de novo mutations
of early post-zygotic origin in disease pathogenesis.
Keywords
Mutation ratede novo SNV
monozygotic twins
somatic mosaicism
early post-zygotic
next generation sequencing