Fernando Pardo-Manuel de Villena

Research Interests:

The large investments of the past decade in genome projects and more recently in genetic diversity (hapmap) projects are now bearing their first fruits. Genome wide association studies in humans and comparative genomics studies are two areas in which extraordinary advances are currently been made. The laboratory mouse has been the most popular, and arguably the successful, mammalian model to investigate human physiology and disease, while its feral counterpart is an exceptional model to address evolutionary questions. However, within the mouse community the paradigm shift required to switch from single genes to systems genetics and the full incorporation of new genetic/genomic/evolutionary data and tools to investigate every biological process has not yet taken broad hold (Churchill et al. Nature Genetics 2004). Given the privileged position of the mouse among mammalian systems it is difficult to overstate the potential for such a paradigm shift to revolutionize biomedical research. My contribution to this paradigm shift is to incorporate state-of-the-art evolutionary approaches and to include evolutionary considerations to propose, design and interpret all aspects of biomedical research in the mouse. The overall goal of the research in my laboratory is to advance science in a non-incremental fashion by re-examining some of the basic assumptions build-in our models (questions that in many cases could not be answered a few years ago). These assumptions span the gamut from the expectation for the universal operation of Mendel’s laws to the structure, levels and origin of the genetic variation present in the most basic tool for mouse genetics, the inbred strains. I expect that this research will be instrumental in building a better mouse model for biomedical research. The selected publications provided below provide examples of our research interests which include:

Generating a genome-wide map of the phylogenetic origin of each genomic region in a comprehensive set of inbred strains. This provides a natural extension into two questions of particular interest to us, the dynamics of speciation in mammals and the evolutionary dynamics of the highest order of genome organization, i.e. the karyotype. We have recently proposed the centromeric drive theory to explain centromere/karyotype evolution (Pardo-Manuel de Villena and Sapienza Genetics 2001). The different M. musculus subspecies provide a unique experimental setting in which to test this theory and to uncover the genetic basis of variation in centromere function.
Examine the scope and form of epistatic selection during population admixture and inbreeding. Through our involvement with the Collaborative Cross (CC) (Churchill et al., Nature Genetics, 2004), we will measure several aspects of the form and magnitude of epistatic selection operating in the derivation of the Recombinant Inbred Lines (RI lines). These crosses bring together unfavorable heterospecific combinations of alleles in the mixing generations which are purged from the population in the inbreeding generations. When this occurs, gametic disequilibrium ensues, allowing us to detect the action of epistatic selection and reconstruct networks of co-adapted alleles. In addition, using the same resource we will also study the role of selfish systems, in which selection operates directly on components of the genome, independently of Darwinian fitness, and determine how epistatic selection, meiotic drive, and poor reproductive performance shape the genetic landscape in the surviving RI lines.

Selected Publications:

Wright FA, Huand H, Guan X, Gamiel K, Jeffries C, Barry WT, Pardo-Manuel F, Sullivan PF, Wilhelmsen KC, Zhou F (2007) Simulating association studies: a data-based resampling method for candidate regions or whole genome scans. Bioinformatics (in press)

Roberts A, Pardo-Manuel de Villena F, Wang W, McMillan L, Threadgill D (2007) The polymorphism architecture of mouse genetic resources elucidated using genome-wide resequencing data: implications for QTL discovery and systems genetics. Mamm. Genome. 2007 Jul;18(6-7):473-81. Epub 2007 Aug 3.

Yang H, Bell TA, Churchill GA, Pardo-Manuel de Villena F (2007) On the subspecific origin of the laboratory mouse. Nature Genetics. 2007 Sep;39(9):1100-7. Epub 2007 Jul 29.

Vemuganti SA, Bell TA, Scarlett CO, Parker CE, Pardo-Manuel de Villena F, O'Brien DA (2007) Three male germline-specific aldolase A isozymes are generated by alternative splicing and retrotransposition. Developmental Biology 2007 Jun 18; [Epub ahead of print]

Ideraabdullah F, Kim K, Pomp D, Moran JL, Beier D, Pardo-Manuel de Villena F (2007) Rescue of the Mouse DDK Syndrome by Parent-of-Origin-Dependent Modifiers. Biol. Reprod. 7, 286-293.

Bell TA, de la Casa-Esperon E, Doherty HE, Ideraabdullah F, Kim K, Wang Y, Lange LA, Wilhemsen K, Lange EM, Sapienza C, Pardo-Manuel de Villena F (2006) The paternal gene of the DDK syndrome maps to the Schlafen gene cluster on mouse chromosome 11. Genetics 172, 411-423.

Ideraabdullah FY, De la Casa-Esperon E, Bell TA, Detwiler DA, Magnuson T, Sapienza C, Pardo-Manuel de Villena F (2004) Genetic and haplotype diversity among wild derived mouse inbred strains. Genome Res. 14, 1880-1887.

Churchill GA, Airey DC, Allayee H, Angel JM, Attie AD, Beatty J, Beavis WD, Belknap JK, Bennett B, Berrettini W, Bleich A, Bogue M, Broman KW, Buck KJ, Buckler E, Burmeister M, Chesler EJ, Cheverud JM, Clapcote S, Cook MN, Cox RD, Crabbe JC, Crusio WE, Darvasi A, Deschepper CF, Doerge RW, Farber CR, Forejt J, Gaile D, Garlow SJ, Geiger H, Gershenfeld H, Gordon T, Gu J, Gu W, de Haan G, Hayes NL, Heller C, Himmelbauer H, Hitzemann R, Hunter K, Hsu HC, Iraqi FA, Ivandic B, Jacob HJ, Jansen RC, Jepsen KJ, Johnson DK, Johnson TE, Kempermann G, Kendziorski C, Kotb M, Kooy RF, Llamas B, Lammert F, Lassalle JM, Lowenstein PR, Lu L, Lusis A, Manly KF, Marcucio R, Matthews D, Medrano JF, Miller DR, Mittleman G, Mock BA, Mogil JS, Montagutelli X, Morahan G, Morris DG, Mott R, Nadeau JH, Nagase H, Nowakowski RS, O'Hara BF, Osadchuk AV, Page GP, Paigen B, Paigen K, Palmer AA, Pan HJ, Peltonen-Palotie L, Peirce J, Pomp D, Pravenec M, Prows DR, Qi Z, Reeves RH, Roder J, Rosen GD, Schadt EE, Schalkwyk LC, Seltzer Z, Shimomura K, Shou S, Sillanpaa MJ, Siracusa LD, Snoeck HW, Spearow JL, Svenson K, Tarantino LM, Threadgill D, Toth LA, Valdar W, de Villena FP, Warden C, Whatley S, Williams RW, Wiltshire T, Yi N, Zhang D, Zhang M, Zou F (2004) Complex Trait Consortium. The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nature Genetics 36, 1133-1137.




			Research Interests: The large investments of the past decade in genome projects and more recently in genetic diversity (hapmap) projects are now bearing their first fruits. Genome wide association studies in humans and comparative genomics studies are two areas in which extraordinary advances are currently been made. The laboratory mouse has been the most popular, and arguably the successful, mammalian model to investigate human physiology and disease, while its feral counterpart is an exceptional model to address evolutionary questions. However, within the mouse community the paradigm shift required to switch from single genes to systems genetics and the full incorporation of new genetic/genomic/evolutionary data and tools to investigate every biological process has not yet taken broad hold (Churchill et al. Nature Genetics 2004). Given the privileged position of the mouse among mammalian systems it is difficult to overstate the potential for such a paradigm shift to revolutionize biomedical research. My contribution to this paradigm shift is to incorporate state-of-the-art evolutionary approaches and to include evolutionary considerations to propose, design and interpret all aspects of biomedical research in the mouse. The overall goal of the research in my laboratory is to advance science in a non-incremental fashion by re-examining some of the basic assumptions build-in our models (questions that in many cases could not be answered a few years ago). These assumptions span the gamut from the expectation for the universal operation of Mendel’s laws to the structure, levels and origin of the genetic variation present in the most basic tool for mouse genetics, the inbred strains. I expect that this research will be instrumental in building a better mouse model for biomedical research. The selected publications provided below provide examples of our research interests which include: Generating a genome-wide map of the phylogenetic origin of each genomic region in a comprehensive set of inbred strains. This provides a natural extension into two questions of particular interest to us, the dynamics of speciation in mammals and the evolutionary dynamics of the highest order of genome organization, i.e. the karyotype. We have recently proposed the centromeric drive theory to explain centromere/karyotype evolution (Pardo-Manuel de Villena and Sapienza Genetics 2001). The different M. musculus subspecies provide a unique experimental setting in which to test this theory and to uncover the genetic basis of variation in centromere function. Examine the scope and form of epistatic selection during population admixture and inbreeding. Through our involvement with the Collaborative Cross (CC) (Churchill et al., Nature Genetics, 2004), we will measure several aspects of the form and magnitude of epistatic selection operating in the derivation of the Recombinant Inbred Lines (RI lines). These crosses bring together unfavorable heterospecific combinations of alleles in the mixing generations which are purged from the population in the inbreeding generations. When this occurs, gametic disequilibrium ensues, allowing us to detect the action of epistatic selection and reconstruct networks of co-adapted alleles. In addition, using the same resource we will also study the role of selfish systems, in which selection operates directly on components of the genome, independently of Darwinian fitness, and determine how epistatic selection, meiotic drive, and poor reproductive performance shape the genetic landscape in the surviving RI lines. Selected Publications: Wright FA, Huand H, Guan X, Gamiel K, Jeffries C, Barry WT, Pardo-Manuel F, Sullivan PF, Wilhelmsen KC, Zhou F (2007) Simulating association studies: a data-based resampling method for candidate regions or whole genome scans. Bioinformatics (in press) Roberts A, Pardo-Manuel de Villena F, Wang W, McMillan L, Threadgill D (2007) The polymorphism architecture of mouse genetic resources elucidated using genome-wide resequencing data: implications for QTL discovery and systems genetics. Mamm. Genome. 2007 Jul;18(6-7):473-81. Epub 2007 Aug 3. Yang H, Bell TA, Churchill GA, Pardo-Manuel de Villena F (2007) On the subspecific origin of the laboratory mouse. Nature Genetics. 2007 Sep;39(9):1100-7. Epub 2007 Jul 29. Vemuganti SA, Bell TA, Scarlett CO, Parker CE, Pardo-Manuel de Villena F, O'Brien DA (2007) Three male germline-specific aldolase A isozymes are generated by alternative splicing and retrotransposition. Developmental Biology 2007 Jun 18; [Epub ahead of print] Ideraabdullah F, Kim K, Pomp D, Moran JL, Beier D, Pardo-Manuel de Villena F (2007) Rescue of the Mouse DDK Syndrome by Parent-of-Origin-Dependent Modifiers. Biol. Reprod. 7, 286-293. Bell TA, de la Casa-Esperon E, Doherty HE, Ideraabdullah F, Kim K, Wang Y, Lange LA, Wilhemsen K, Lange EM, Sapienza C, Pardo-Manuel de Villena F (2006) The paternal gene of the DDK syndrome maps to the Schlafen gene cluster on mouse chromosome 11. Genetics 172, 411-423. Ideraabdullah FY, De la Casa-Esperon E, Bell TA, Detwiler DA, Magnuson T, Sapienza C, Pardo-Manuel de Villena F (2004) Genetic and haplotype diversity among wild derived mouse inbred strains. Genome Res. 14, 1880-1887. Churchill GA, Airey DC, Allayee H, Angel JM, Attie AD, Beatty J, Beavis WD, Belknap JK, Bennett B, Berrettini W, Bleich A, Bogue M, Broman KW, Buck KJ, Buckler E, Burmeister M, Chesler EJ, Cheverud JM, Clapcote S, Cook MN, Cox RD, Crabbe JC, Crusio WE, Darvasi A, Deschepper CF, Doerge RW, Farber CR, Forejt J, Gaile D, Garlow SJ, Geiger H, Gershenfeld H, Gordon T, Gu J, Gu W, de Haan G, Hayes NL, Heller C, Himmelbauer H, Hitzemann R, Hunter K, Hsu HC, Iraqi FA, Ivandic B, Jacob HJ, Jansen RC, Jepsen KJ, Johnson DK, Johnson TE, Kempermann G, Kendziorski C, Kotb M, Kooy RF, Llamas B, Lammert F, Lassalle JM, Lowenstein PR, Lu L, Lusis A, Manly KF, Marcucio R, Matthews D, Medrano JF, Miller DR, Mittleman G, Mock BA, Mogil JS, Montagutelli X, Morahan G, Morris DG, Mott R, Nadeau JH, Nagase H, Nowakowski RS, O'Hara BF, Osadchuk AV, Page GP, Paigen B, Paigen K, Palmer AA, Pan HJ, Peltonen-Palotie L, Peirce J, Pomp D, Pravenec M, Prows DR, Qi Z, Reeves RH, Roder J, Rosen GD, Schadt EE, Schalkwyk LC, Seltzer Z, Shimomura K, Shou S, Sillanpaa MJ, Siracusa LD, Snoeck HW, Spearow JL, Svenson K, Tarantino LM, Threadgill D, Toth LA, Valdar W, de Villena FP, Warden C, Whatley S, Williams RW, Wiltshire T, Yi N, Zhang D, Zhang M, Zou F (2004) Complex Trait Consortium. The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nature Genetics 36, 1133-1137.

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