RESUMO
Meiotic recombination events cluster into narrow segments of the genome, defined as hotspots. Here, we demonstrate that a major player for hotspot specification is the Prdm9 gene. First, two mouse strains that differ in hotspot usage are polymorphic for the zinc finger DNA binding array of PRDM9. Second, the human consensus PRDM9 allele is predicted to recognize the 13-mer motif enriched at human hotspots; this DNA binding specificity is verified by in vitro studies. Third, allelic variants of PRDM9 zinc fingers are significantly associated with variability in genome-wide hotspot usage among humans. Our results provide a molecular basis for the distribution of meiotic recombination in mammals, in which the binding of PRDM9 to specific DNA sequences targets the initiation of recombination at specific locations in the genome.
Assuntos
Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Meiose/genética , Recombinação Genética , Alelos , Sequência de Aminoácidos , Animais , Sequência de Bases , Sítios de Ligação , DNA/química , DNA/metabolismo , Quebras de DNA de Cadeia Dupla , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Genoma , Genoma Humano , Genótipo , Histona-Lisina N-Metiltransferase/química , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Fenótipo , Dedos de Zinco/genéticaRESUMO
We describe a new approximate likelihood for population genetic data under a model in which a single ancestral population has split into two daughter populations. The approximate likelihood is based on the 'Product of Approximate Conditionals' likelihood and 'copying model' of Li and Stephens [Li, N., Stephens, M., 2003. Modeling linkage disequilibrium and identifying recombination hotspots using single-nucleotide polymorphism data. Genetics 165 (4), 2213-2233]. The approach developed here may be used for efficient approximate likelihood-based analyses of unlinked data. However our copying model also considers the effects of recombination. Hence, a more important application is to loosely-linked haplotype data, for which efficient statistical models explicitly featuring non-equilibrium population structure have so far been unavailable. Thus, in addition to the information in allele frequency differences about the timing of the population split, the method can also extract information from the lengths of haplotypes shared between the populations. There are a number of challenges posed by extracting such information, which makes parameter estimation difficult. We discuss how the approach could be extended to identify haplotypes introduced by migrants.
Assuntos
Funções Verossimilhança , Modelos Teóricos , Dinâmica Populacional , Recombinação Genética , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo ÚnicoRESUMO
When performing association studies in populations that have not been the focus of large-scale investigations of haplotype variation, it is often helpful to rely on genomic databases in other populations for study design and analysis - such as in the selection of tag SNPs and in the imputation of missing genotypes. One way of improving the use of these databases is to rely on a mixture of database samples that is similar to the population of interest, rather than using the single most similar database sample. We demonstrate the effectiveness of the mixture approach in the application of African, European, and East Asian HapMap samples for tag SNP selection in populations from India, a genetically intermediate region underrepresented in genomic studies of haplotype variation.
