Chromosome-wide Mapping of Recombination Activity
Mammalian recombination is not distributed randomly along the chromosomes; most recombination events are concentrated in 1-2 kb genomic regions termed recombination hotspots. Our goal is to generate the first high-resolution maps of mammalian recombination activity for an entire chromosome as a representative of the genome as a whole, including the variation in hotspot location and activity within and between species, and how this differs in F1 animals from reciprocal crosses and between male and female meiosis. For this we are mapping recombinants arising in 3000 or 6000 meioses from each of six genetic crosses at under 50-Kb resolution, enabling us to distinguish individual hotspots and detect activities as low as 0.03 cM/hotspot. These data will go far in helping us understand mammalian recombination as a biological process as well as relationships between parameters of recombination and other aspects of chromosome dynamics..
Specifically we are:
- Mapping the location of every crossover on Chromosome 11 arising in six genetic crosses, 6000 offspring each of C57BL/6J x CAST/EiJ and WSB/EiJ x PWD/PhJ and 3000 offspring each of C57BL/6J x PWD/PhJ, WSB/EiJ x CAST/EiJ, C57BL/6J x WSB/EiJ and PWD/PhJ x CAST/EiJ, for a total of 24,000 meioses, at under 50 kb resolution. In all crosses, half of the progeny is derived from female F1 and the other half from male F1 hybrids which are backcrossed to C57BL/6J. This design is optimal for gathering data on genetic variability, sex specificity, and possible imprinting effects in these crosses.
- Using these data, we are analyzing the strain, sex and cross direction specificity of the location, distribution and activity of the recombination hotspots along the length of Chromosome 11.
- Making the 24,000 backcross DNA samples available to the scientific community via a repository, and the 3000 SNP assays that are being newly developed on Chromosome 11 are being posted on our website and made available to others for QTL and gene mapping studies.
Our results so far have shown at least three levels of regulation of recombination activity that differ between the two sexes – chromosome-wide, regional (megabase scale), and local (hotspot scale). Genetic background plays a crucial role in determining the positions of individual hotspots, as most hotspots are active when a particular strain is involved in the corresponding cross and inactive when the strain is not involved. This pattern is consistent with the presence of different alleles of Prdm9, the first mammalian gene regulating recombination positioning we have recently identified, in each of the four strains involved in our crosses. We also found a number of hotspots in which differences in recombination rates between crosses involving the same parental strain were statistically significant, as well as intervals where recombination activity was present in only one cross. We are now focusing our attention to mapping individual hotspots that show strain, sex or cross specificity, and identifying the genes that regulate them. We are now developing a phenotyping approach for quantitative measurement of hotspot activity using massive parallel sequencing in sperm of individual males.
Center related publications
Patterns of recombination activity on mouse chromosome 11 revealed by high resolution mapping
Billings T, Sargent EE, Szatkiewicz JP, Leahy N, Kwak IY, Bektassova N, Walker M, Hassold T, Graber JH, Broman KW, Petkov PM.
PLoS One. 2010 Dec 8;5(12):e15340. PMCID: PMC2999565. [ Full Text ]
Mammalian recombination hot spots: properties, control and evolution
Paigen K, Petkov P.
Nat Rev Genet. 2010 Mar;11(3):221-33.
Prdm9 controls activation of mammalian recombination hotspots
Parvanov ED, Petkov PM, Paigen K.
Science. 2010 Feb 12;327(5967):835. PMCID: PMC2821451. [ Full Text ]
Parental origin of chromosomes influences crossover activity within the Kcnq1 transcriptionally imprinted domain of Mus musculus
Ng SH, Madeira R, Parvanov ED, Petros LM, Petkov PM, Paigen K.
BMC Mol Biol. 2009 May 13;10:43. PMCID: PMC2689222. [ Full Text ]
Trans-regulation of mouse meiotic recombination hotspots by Rcr1
Parvanov ED, Ng SHS, Petkov PM, Paigen K.
PLoS Biol. 2009 Feb 17;7(2):e36. PMCID: PMC2642880. [ Full Text ]
A quantitative assay for crossover and noncrossover molecular events at individual recombination hotspots in both male and female gametes
Ng SH, Parvanov E, Petkov PM, Paigen K.
Genomics. 2008 Oct;92(4):204-9. PMCID: PMC2610674 [ Full Text ]
The recombinational anatomy of a mouse chromosome
Paigen K, Szatkiewicz JP, Sawyer K, Leahy N, Parvanov ED, Ng SH, Graber JH, Broman KW, Petkov PM.
PLoS Genet. 2008 Jul 11;4(7):e1000119. PMCID: PMC2440539 [ Full Text ]
Crossover interference underlies sex differences in recombination rates
Petkov PM, Broman KW, Szatkiewicz JP, Paigen K.
Trends Genet. 2007 Nov;23(11):539-42.
Evidence of a large-scale functional organization of mammalian chromosomes
Petkov PM, Graber JH, Churchill GA, DiPetrillo K, King BL, Paigen K.
PLoS Biol. 2007 May;5(5):e127; author reply e128. PMCID: PMC1868061 [ Full Text ]
Patterns and mechanisms of genome organization in the mouse
Graber JH, Churchill GA, Dipetrillo KJ, King BL, Petkov PM, Paigen K.
J Exp Zoolog A Comp Exp Biol. 2006 Sep 1;305(9):683-8.