Publications by Year: 2013

Tucker G*, Loh P-R*, Berger B. A sampling framework for incorporating quantitative mass spectrometry data in protein interaction analysis. BMC Bioinformatics 2013;14:299.Abstract
BACKGROUND: Comprehensive protein-protein interaction (PPI) maps are a powerful resource for uncovering the molecular basis of genetic interactions and providing mechanistic insights. Over the past decade, high-throughput experimental techniques have been developed to generate PPI maps at proteome scale, first using yeast two-hybrid approaches and more recently via affinity purification combined with mass spectrometry (AP-MS). Unfortunately, data from both protocols are prone to both high false positive and false negative rates. To address these issues, many methods have been developed to post-process raw PPI data. However, with few exceptions, these methods only analyze binary experimental data (in which each potential interaction tested is deemed either observed or unobserved), neglecting quantitative information available from AP-MS such as spectral counts. RESULTS: We propose a novel method for incorporating quantitative information from AP-MS data into existing PPI inference methods that analyze binary interaction data. Our approach introduces a probabilistic framework that models the statistical noise inherent in observations of co-purifications. Using a sampling-based approach, we model the uncertainty of interactions with low spectral counts by generating an ensemble of possible alternative experimental outcomes. We then apply the existing method of choice to each alternative outcome and aggregate results over the ensemble. We validate our approach on three recent AP-MS data sets and demonstrate performance comparable to or better than state-of-the-art methods. Additionally, we provide an in-depth discussion comparing the theoretical bases of existing approaches and identify common aspects that may be key to their performance. CONCLUSIONS: Our sampling framework extends the existing body of work on PPI analysis using binary interaction data to apply to the richer quantitative data now commonly available through AP-MS assays. This framework is quite general, and many enhancements are likely possible. Fruitful future directions may include investigating more sophisticated schemes for converting spectral counts to probabilities and applying the framework to direct protein complex prediction methods.
Moorjani P, Thangaraj K, Patterson N, Lipson M, Loh P-R, Govindaraj P, Berger B, Reich D, Singh L. Genetic evidence for recent population mixture in India. Am J Hum Genet 2013;93(3):422-38.Abstract
Most Indian groups descend from a mixture of two genetically divergent populations: Ancestral North Indians (ANI) related to Central Asians, Middle Easterners, Caucasians, and Europeans; and Ancestral South Indians (ASI) not closely related to groups outside the subcontinent. The date of mixture is unknown but has implications for understanding Indian history. We report genome-wide data from 73 groups from the Indian subcontinent and analyze linkage disequilibrium to estimate ANI-ASI mixture dates ranging from about 1,900 to 4,200 years ago. In a subset of groups, 100% of the mixture is consistent with having occurred during this period. These results show that India experienced a demographic transformation several thousand years ago, from a region in which major population mixture was common to one in which mixture even between closely related groups became rare because of a shift to endogamy.
Lipson M*, Loh P-R*, Levin A, Reich D, Patterson N, Berger B. Efficient moment-based inference of admixture parameters and sources of gene flow. Mol Biol Evol 2013;30(8):1788-802.Abstract
The recent explosion in available genetic data has led to significant advances in understanding the demographic histories of and relationships among human populations. It is still a challenge, however, to infer reliable parameter values for complicated models involving many populations. Here, we present MixMapper, an efficient, interactive method for constructing phylogenetic trees including admixture events using single nucleotide polymorphism (SNP) genotype data. MixMapper implements a novel two-phase approach to admixture inference using moment statistics, first building an unadmixed scaffold tree and then adding admixed populations by solving systems of equations that express allele frequency divergences in terms of mixture parameters. Importantly, all features of the model, including topology, sources of gene flow, branch lengths, and mixture proportions, are optimized automatically from the data and include estimates of statistical uncertainty. MixMapper also uses a new method to express branch lengths in easily interpretable drift units. We apply MixMapper to recently published data for Human Genome Diversity Cell Line Panel individuals genotyped on a SNP array designed especially for use in population genetics studies, obtaining confident results for 30 populations, 20 of them admixed. Notably, we confirm a signal of ancient admixture in European populations-including previously undetected admixture in Sardinians and Basques-involving a proportion of 20-40% ancient northern Eurasian ancestry.
Loh P-R*, Lipson M*, Patterson N, Moorjani P, Pickrell JK, Reich D, Berger B. Inferring admixture histories of human populations using linkage disequilibrium. Genetics 2013;193(4):1233-54.Abstract
Long-range migrations and the resulting admixtures between populations have been important forces shaping human genetic diversity. Most existing methods for detecting and reconstructing historical admixture events are based on allele frequency divergences or patterns of ancestry segments in chromosomes of admixed individuals. An emerging new approach harnesses the exponential decay of admixture-induced linkage disequilibrium (LD) as a function of genetic distance. Here, we comprehensively develop LD-based inference into a versatile tool for investigating admixture. We present a new weighted LD statistic that can be used to infer mixture proportions as well as dates with fewer constraints on reference populations than previous methods. We define an LD-based three-population test for admixture and identify scenarios in which it can detect admixture events that previous formal tests cannot. We further show that we can uncover phylogenetic relationships among populations by comparing weighted LD curves obtained using a suite of references. Finally, we describe several improvements to the computation and fitting of weighted LD curves that greatly increase the robustness and speed of the calculations. We implement all of these advances in a software package, ALDER, which we validate in simulations and apply to test for admixture among all populations from the Human Genome Diversity Project (HGDP), highlighting insights into the admixture history of Central African Pygmies, Sardinians, and Japanese.
Moorjani P, Patterson N, Loh P-R, Lipson M, Kisfali P, Melegh BI, Bonin M, Kádaši L, Rieß O, Berger B, Reich D, Melegh B. Reconstructing Roma history from genome-wide data. PLoS One 2013;8(3):e58633.Abstract
The Roma people, living throughout Europe and West Asia, are a diverse population linked by the Romani language and culture. Previous linguistic and genetic studies have suggested that the Roma migrated into Europe from South Asia about 1,000-1,500 years ago. Genetic inferences about Roma history have mostly focused on the Y chromosome and mitochondrial DNA. To explore what additional information can be learned from genome-wide data, we analyzed data from six Roma groups that we genotyped at hundreds of thousands of single nucleotide polymorphisms (SNPs). We estimate that the Roma harbor about 80% West Eurasian ancestry-derived from a combination of European and South Asian sources-and that the date of admixture of South Asian and European ancestry was about 850 years before present. We provide evidence for Eastern Europe being a major source of European ancestry, and North-west India being a major source of the South Asian ancestry in the Roma. By computing allele sharing as a measure of linkage disequilibrium, we estimate that the migration of Roma out of the Indian subcontinent was accompanied by a severe founder event, which appears to have been followed by a major demographic expansion after the arrival in Europe.
Lakhani KR, Boudreau KJ, Loh P-R, Backstrom L, Baldwin C, Lonstein E, Lydon M, MacCormack A, Arnaout RA, Guinan EC. Prize-based contests can provide solutions to computational biology problems. Nat Biotechnol 2013;31(2):108-11.