Nila Patil

Fine-scale recombination patterns differ between chimpanzees and humans

Recombination rates seem to vary extensively along the human genome. Pedigree analysis suggests that rates vary by an order of magnitude when measured at the megabase scale, and at a finer scale, sperm typing studies point to the existence of recombination hotspots. These are short regions (1–2 kb) in which recombination rates are 10–1,000 times higher than the background rate. Less is known about how recombination rates change over time. Here we determined to what degree recombination rates are conserved among closely related species by estimating recombination rates from 14 Mb of linkage disequilibrium data in central chimpanzee and human populations. The results suggest that recombination hotspots are not conserved between the two species and that recombination rates in larger (50 kb) genomic regions are only weakly conserved. Therefore, the recombination landscape has changed markedly between the two species.

Functional Effects of the Mouse weaver Mutation on G Protein–Gated Inwardly Rectifying K+ Channels

The weaver mutation corresponds to a substitution of glycine to serine in the H5 region of a G protein-gated inwardly rectifying K+ channel gene (GIRK2). By studying mutant GIRK2 weaver homomultimeric channels and heteromultimeric channels comprised of GIRK2 weaver and GIRK1 in Xenopus oocytes, we found that GIRK2 weaver homomultimeric channels lose their selectivity for K+ ions, giving rise to inappropriate receptor-activated and basally active Na+ currents, whereas heteromultimers of GIRK2 weaver and GIRK1 appeared to have reduced current. Immunohistochemical localization indicates that GIRK2 and GIRK1 proteins are expressed in the cerebellar neurons of mice at postnatal day 4, at a time when these neurons normally undergo differentiation. Thus, the aberrant behavior of mutant GIRK2 weaver channels could affect the development of weaver mice in at least two distinct ways.

Empirical characterization of the expression ratio noise structure in high-density oligonucleotide arrays

BackgroundHigh-density oligonucleotide arrays (HDONAs) are a powerful tool for assessing differential mRNA expression levels. To establish the statistical significance of an observed change in expression, one must take into account the noise introduced by the enzymatic and hybridization steps, called type I noise. We undertake an empirical characterization of the experimental repeatability of results by carrying out statistical analysis of a large number of duplicate HDONA experiments.ResultsWe assign scoring functions for expression ratios and associated quality measures. Both the perfect-match (PM) probes and the differentials between PM and single-mismatch (MM) probes are considered as raw intensities. We then calculate the log-ratio of the noise structure using robust estimates of their intensity-dependent variance. The noise structure in the log-ratios follows a local log-normal distribution in both the PM and PM-MM cases. Significance relative to the type I noise can therefore be quantified reliably using the local standard deviation (SD). We discuss the intensity dependence of the SD and show that ratio scores greater than 1.25 are significant in the mid- to high-intensity range.ConclusionsThe noise inherent in HDONAs is characteristically dependent on intensity and can be well described in terms of local normalization of log-ratio distributions. Therefore, robust estimates of the local SD of these distributions provide a simple and powerful way to assess significance (relative to type I noise) in differential gene expression, and will be helpful in practice for improving the reliability of predictions from hybridization experiments.

Matching Strategies for Genetic Association Studies in Structured Populations

Association studies in populations that are genetically heterogeneous can yield large numbers of spurious associations if population subgroups are unequally represented among cases and controls. This problem is particularly acute for studies involving pooled genotyping of very large numbers of single-nucleotide-polymorphism (SNP) markers, because most methods for analysis of association in structured populations require individual genotyping data. In this study, we present several strategies for matching case and control pools to have similar genetic compositions, based on ancestry information inferred from genotype data for approximately 300 SNPs tiled on an oligonucleotide-based genotyping array. We also discuss methods for measuring the impact of population stratification on an association study. Results for an admixed population and a phenotype strongly confounded with ancestry show that these simple matching strategies can effectively mitigate the impact of population stratification.

In vivo transcriptional profile analysis reveals RNA splicing and chromatin remodeling as prominent processes for adult neurogenesis

Neural stem cells and neurogenesis persist in the adult mammalian brain subventricular zone (SVZ). Cells born in the rodent SVZ migrate to the olfactory bulb (Ob) where they differentiate into interneurons. To determine the gene expression and functional profile of SVZ neurogenesis, we performed three complementary sets of transcriptional analysis experiments using Affymetrix GeneChips: (1) comparison of adult mouse SVZ and Ob gene expression profiles with those of the striatum, cerebral cortex, and hippocampus; (2) profiling of SVZ stem cells and ependyma isolated by fluorescent-activated cell sorting (FACS); and (3) analysis of gene expression changes during in vivo SVZ regeneration after anti-mitotic treatment. Gene Ontology (GO) analysis of data from these three separate approaches showed that in adult SVZ neurogenesis, RNA splicing and chromatin remodeling are biological processes as statistically significant as cell proliferation, transcription, and neurogenesis. In non-neurogenic brain regions, RNA splicing and chromatin remodeling were not prominent processes. Fourteen mRNA splicing factors including Sf3b1, Sfrs2, Lsm4, and Khdrbs1/Sam68 were detected along with 9 chromatin remodeling genes including Mll, Bmi1, Smarcad1, Baf53a, and Hat1. We validated the transcriptional profile data with Northern blot analysis and in situ hybridization. The data greatly expand the catalogue of cell cycle components, transcription factors, and migration genes for adult SVZ neurogenesis and reveal RNA splicing and chromatin remodeling as prominent biological processes for these germinal cells.

Curating Genetic Association Literature for Common Diseases

Papers describing genetic associations with common diseases are currently being published at a rapid rate. These new papers add to an already large body of literature which includes candidate gene studies, genome wide association studies, review papers, and meta-analyses. Related papers describe the basic epidemiology of these common diseases, gene-environment interactions, gene-gene interactions, and pharmacogenomics (gene-drug interactions), all of which may affect disease predisposition and management.