Fernando Pardo-Manuel de Villena

Population Genetics of Inbred Strains

 

The fundamental paradigm of the work at the Center for Genome Dynamics derives from our understanding that the physical and functional organization of the genome is a consequence of its evolution, and that this organization can be deciphered by exploiting the unique evolutionary experiment inbred strains of mice provide (Yang et al. Nature Genetics 2007). Doing so requires that the genomic markers (SNPs) we use for mapping and the functional allelic variation they tag arose in the same branches of the evolutionary tree, that the density of our markers approximates average gene densities, and that we can carry out the requisite genotyping in a cost effective manner. Because the SNPs described in existing databases do not meet these requirements, we have used 109 million genotypes obtained by microarray resequencing of 15 inbred strains, including representatives from each of the three major mouse subspecies to generate two sets of 25,400 phylogenetic trees. Each sets contain the tree for each consecutive 100 kb interval, and the second set is displaced 50 kb with respect to the first. In each interval we determined all the strain distribution patterns (SDPs) represented in the tree and their respective frequencies. This SDP database was then used to select 400,000 SNPs representing each one of the phylogenetic branches observed in the local trees. Computationally, each segment represents a polyallelic system in which we know the time in evolution when the alleles arose, and we have an efficient means of typing these alleles across an extensive sample of inbred strains. The resulting data will 1) provide considerably improved maps of linkage disequilibrium (LD) domains and networks, 2) allow us to investigate the evolutionary forces responsible for the assembly of the LD domains and networks, 3) improve the reliability/resolution of in silico QTL mapping, 4) identify and map historical recombination events and relate these to current maps of recombination hotspots, and 5) address several basic evolutionary questions for which the genus Mus is exceptionally well suited, primary among them being the validity of Wright’s Shifting Balance theory.

Specifically, we are:

  1. Establishing a collection of DNA from a comprehensive set of inbred strains.

  2. Identifying an unbiased set of 400,000 SNPs representing the diversity present among four mouse subspecies, M. m. domesticus, M. m. musculus, M. m. castaneus and M. m. molossinus.

  3. Genotyping these SNPs on 2,000 mouse strains and individual samples.

  4. Generating a genome-wide map of the phylogenetic origin of each genomic region in each strain.

Center related publications

Genetic analysis of complex traits in the emerging collaborative cross
Aylor DL, Valdar W, Foulds-Mathes W, Buus RJ, Verdugo RA, Baric RS, Ferris MT, Frelinger JA, Heise M, Frieman MB, Gralinski LE, Bell TA, Didion JD, Hua K, Nehrenberg DL, Powell CL, Steigerwalt J, Xie Y, Kelada SN, Collins FS, Yang IV, Schwartz DA, Branstetter LA, Chesler EJ, Miller DR, Spence J, Liu EY, McMillan L, Sarkar A, Wang J, Wang W, Zhang Q, Broman KW, Korstanje R, Durrant C, Mott R, Iraqi FA, Pomp D, Threadgill D, Pardo-Manuel de Villena F, Churchill GA.
Genome Res. 2011 Aug;21(8):1223-38. PMCID: PMC3149489 [ Full Text ] [ Highlight in Nature Reviews Genetics ] [ datasets ]

Architecture of energy balance traits in emerging lines of the Collaborative Cross
Mathes WF, Aylor DL, Miller DR, Churchill GA, Chesler EJ, de Villena FP, Threadgill DW, Pomp D.
Am J Physiol Endocrinol Metab. 2011 Jun;300(6):E1124-34. PMCID: PMC3118585 [ Full Text ] [ datasets ]

Subspecific origin and haplotype diversity in the laboratory mouse
Yang H, Wang JR, Didion JP, Buus RJ, Bell TA, Welsh CE, Bonhomme F, Yu AH, Nachman MW, Pialek J, Tucker P, Boursot P, McMillan L, Churchill GA, de Villena FP.
Nat Genet. 2011 May 29;43(7):648-55. PMCID: PMC3125408 [ Full Text ] [ News Article ] [ datasets ]

CGDSNPdb: a database resource for error-checked and imputed mouse SNPs
Hutchins LN, Ding Y, Szatkiewicz JP, Smith RV, Yang H, de Villena FP, Churchill GA, Graber JH.
Database (Oxford). 2010 Jul 6;2010:baq008. Print 2010. PMCID: PMC2911843. [ Full Text ] [ datasets 1 ] [ datasets 2 ]

Genetic architecture of voluntary exercise in an advanced intercross line of mice
Kelly SA, Nehrenberg DL, Peirce JL, Hua K, Steffy BM, Wiltshire T, Pardo-Manuel de Villena F, Garland T Jr, Pomp D.
Physiol Genomics. 2010 Jul 7;42(2):190-200. PMCID: PMC3032284 [ Full Text ]

Efficient genome ancestry inference in complex pedigrees with inbreeding
Liu EY, Zhang Q, McMillan L, de Villena FP, Wang W.
Bioinformatics. 2010 Jun 15;26(12):i199-207. PMCID: PMC2881372. [ Full Text ]

Genomic mapping of social behavior traits in a F2 cross derived from mice selectively bred for high aggression
Nehrenberg DL, Wang S, Buus RJ, Perkins J, de Villena FP, Pomp D.
BMC Genet. 2010 Dec 31;11:113. PMCID: PMC3022667 [ Full Text ]

TreeQA: quantitative genome wide association mapping using local perfect phylogeny trees
Pan F, McMillan L, Pardo-Manuel De Villena F, Threadgill D, Wang W.
Pac Symp Biocomput. 2009:415-26. PMCID: PMC2739990. [ Full Text ]

A customized and versatile high-density genotyping array for the mouse
Yang H, Ding Y, Hutchins LN, Szatkiewicz J, Bell TA, Paigen BJ, Graber JH, de Villena FP, Churchill GA.
Nat Methods. 2009 Sep;6(9):663-6. PMCID: PMC2735580. [ Full Text ] [ datasets ]

Inferring genome-wide mosaic structure
Zhang Q, Wang W, McMillan L, Pardo-Manuel De Villena F, Threadgill D.
Pac Symp Biocomput. 2009:150-61. PMCID: PMC2736068. [ Full Text ]

An imputed genotype resource for the laboratory mouse
Szatkiewicz JP, Beane GL, Ding Y, Hutchins L, Pardo-Manuel de Villena F, Churchill GA.
Mamm Genome. 2008 Mar;19(3):199-208. PMCID: PMC2725522. [ Full Text ] [ datasets ]

The polymorphism architecture of mouse genetic resources elucidated using genome-wide resequencing data: implications for QTL discovery and systems genetics
Roberts A, Pardo-Manuel de Villena F, Wang W, McMillan L, Threadgill DW.
Mamm Genome. 2007 Jul;18(6-7):473-81. PMCID: PMC1998888 [ Full Text ]

Three male germline-specific aldolase A isozymes are generated by alternative splicing and retrotransposition
Vemuganti SA, Bell TA, Scarlett CO, Parker CE, de Villena FP, O'Brien DA.
Dev Biol. 2007 Sep 1;309(1):18-31. NIHMSID30168.

On the subspecific origin of the laboratory mouse
Yang H, Bell TA, Churchill GA, Pardo-Manuel de Villena F.
Nat Genet. 2007 Sep;39(9):1100-7.