Mutations are the cause of many human genetic diseases and the main source of genetic variation in natural populations. Thus, elucidating the mechanisms of mutagenesis is of great significance. The fact that, in mammals, the number of germline cell divisions (and of DNA replications) is higher in males than in females provides an opportunity to test whether mutations result from errors in DNA replication. If this hypothesis is true, we expect higher mutation rate in males than in females (male mutation bias) and higher mutation rate in older males than in younger males (paternal age effect). Here we will employ the tools of comparative genomics and bioinformatics to analyze available mammalian genomic sequences and generate additional data experimentally to test the following specific hypotheses: 1. Errors in DNA replication are the primary sources of insertions and deletions (indels). 2. Nucleotide substitutions, particularly at CpG dinucleotides, depend on the number of germline cell divisions. To test these first two hypotheses we will estimate mutation rates from mammalian whole-genome alignments and compare these rates between sex chromosomes and autosomes. 3. Microsatellite repeat expansions and contractions are caused by errors in DNA replication. This will be tested by observing de novo mutations in single sperm of human males of different ages. 4. The magnitude of male mutation bias and generation time are positively correlated in mammals. To investigate this, we will sequence introns of genes homologous between X and Y in mammals with long generation time (Cetacea and Perissodactyla) and analyze additional data from the literature. The proposed research has direct relevance to issues of public health and clinical genetics. The overwhelming majority of mutations causing human genetic diseases are indels, nucleotide substitutions, and microsatellite repeat expansions/contractions. Moreover, single nucleotide polymorphisms (SNPs), an outcome of nucleotide substitutions, and microsatellites are widely used markers for mapping diseases and traits in association studies. Thus, it is critical to know whether mutations at these loci are driven by replication-dependent or by replication-independent factors (e.g., environmental agents such as free radicals). Additionally, the conclusions of this project will be important for genetic counseling. Namely, our results will indicate whether the age of a father at the time of conception represents a risk factor for pathology in the offspring.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM072264-05S1
Application #
7913976
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Eckstrand, Irene A
Project Start
2009-09-09
Project End
2011-06-30
Budget Start
2009-09-09
Budget End
2011-06-30
Support Year
5
Fiscal Year
2009
Total Cost
$87,133
Indirect Cost
Name
Pennsylvania State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802
Dickins, Benjamin; Rebolledo-Jaramillo, Boris; Su, Marcia Shu-Wei et al. (2014) Controlling for contamination in re-sequencing studies with a reproducible web-based phylogenetic approach. Biotechniques 56:134-141
Wilson Sayres, Melissa A; Makova, Kateryna D (2013) Gene survival and death on the human Y chromosome. Mol Biol Evol 30:781-7
Wagstaff, Bradley J; Hedges, Dale J; Derbes, Rebecca S et al. (2012) Rescuing Alu: recovery of new inserts shows LINE-1 preserves Alu activity through A-tail expansion. PLoS Genet 8:e1002842
Afgan, Enis; Baker, Dannon; Coraor, Nate et al. (2011) Harnessing cloud computing with Galaxy Cloud. Nat Biotechnol 29:972-4
Wilson Sayres, Melissa A; Venditti, Chris; Pagel, Mark et al. (2011) Do variations in substitution rates and male mutation bias correlate with life-history traits? A study of 32 mammalian genomes. Evolution 65:2800-15
Wilson Sayres, Melissa A; Makova, Kateryna D (2011) Genome analyses substantiate male mutation bias in many species. Bioessays 33:938-45
Kvikstad, Erika M; Makova, Kateryna D (2010) The (r)evolution of SINE versus LINE distributions in primate genomes: sex chromosomes are important. Genome Res 20:600-13
Wilson, Melissa A; Makova, Kateryna D (2009) Evolution and survival on eutherian sex chromosomes. PLoS Genet 5:e1000568
Kvikstad, Erika M; Chiaromonte, Francesca; Makova, Kateryna D (2009) Ride the wavelet: A multiscale analysis of genomic contexts flanking small insertions and deletions. Genome Res 19:1153-64
Tyekucheva, Svitlana; Makova, Kateryna D; Karro, John E et al. (2008) Human-macaque comparisons illuminate variation in neutral substitution rates. Genome Biol 9:R76

Showing the most recent 10 out of 16 publications