Academic Appointments

Honors & Awards

  • Stanford Professorship in Population Genetics & Society, Stanford University School of Humanitites & Sciences (2014)
  • Dean's Basic Science Research Award, University of Michigan Medical School (2010)
  • Sloan Fellow in Computational and Evolutionary Molecular Biology, Alfred P. Sloan Foundation (2006)
  • Career Award in the Biomedical Sciences, Burroughs Wellcome Fund (2004)

Boards, Advisory Committees, Professional Organizations

  • Associate Editor, Evolution, Medicine, and Public Health (2014 - Present)
  • Editor-in-Chief, Theoretical Population Biology (2013 - Present)
  • Associate Editor, Genetics (2010 - Present)
  • Associate Editor, Human Biology (2010 - Present)
  • Associate Editor, Molecular Biology and Evolution (2011 - 2014)
  • Associate Editor, BMC Bioinformatics (2010 - 2014)
  • Associate Editor, American Journal of Human Genetics (2008 - 2010)

Professional Education

  • BA, Rice University, Mathematics (1997)
  • MS, Stanford University, Mathematics (1999)
  • PhD, Stanford University, Biology (2001)
  • Postdoc, University of Southern California, Molecular/Computational Biology (2005)

Current Research and Scholarly Interests

Research in the lab addresses problems in evolutionary biology and human
genetics through a combination of mathematical modeling, computer
simulations, development of statistical methods, and inference from
population-genetic data. Our current work covers topics such as human
genetic variation, inference of human evolutionary history, the role of
population genetics in the search for disease-susceptibility genes, the
relationship of gene trees and species trees, and mathematical properties
of statistics used for analyzing genetic variability.

2014-15 Courses

Graduate and Fellowship Programs

  • Biology (School of Humanities and Sciences) (Phd Program)

Journal Articles

  • Upper bounds on F-ST in terms of the frequency of the most frequent allele and total homozygosity: The case of a specified number of alleles THEORETICAL POPULATION BIOLOGY Edge, M. D., Rosenberg, N. A. 2014; 97: 20-34
  • Autosomal Admixture Levels Are Informative About Sex Bias in Admixed Populations GENETICS Goldberg, A., Verdu, P., Rosenberg, N. A. 2014; 198 (3): 1209-1229
  • Theory and applications of a deterministic approximation to the coalescent model THEORETICAL POPULATION BIOLOGY Jewett, E. M., Rosenberg, N. A. 2014; 93: 14-29


    Under the coalescent model, the random number nt of lineages ancestral to a sample is nearly deterministic as a function of time when nt is moderate to large in value, and it is well approximated by its expectation E[nt]. In turn, this expectation is well approximated by simple deterministic functions that are easy to compute. Such deterministic functions have been applied to estimate allele age, effective population size, and genetic diversity, and they have been used to study properties of models of infectious disease dynamics. Although a number of simple approximations of E[nt] have been derived and applied to problems of population-genetic inference, the theoretical accuracy of the resulting approximate formulas and the inferences obtained using these approximations is not known, and the range of problems to which they can be applied is not well understood. Here, we demonstrate general procedures by which the approximation nt≈E[nt] can be used to reduce the computational complexity of coalescent formulas, and we show that the resulting approximations converge to their true values under simple assumptions. Such approximations provide alternatives to exact formulas that are computationally intractable or numerically unstable when the number of sampled lineages is moderate or large. We also extend an existing class of approximations of E[nt] to the case of multiple populations of time-varying size with migration among them. Our results facilitate the use of the deterministic approximation nt≈E[nt] for deriving functionally simple, computationally efficient, and numerically stable approximations of coalescent formulas under complicated demographic scenarios.

    View details for DOI 10.1016/j.tpb.2013.12.007

    View details for Web of Science ID 000333727800002

  • An empirical evaluation of two-stage species tree inference strategies using a multilocus dataset from North American pines BMC EVOLUTIONARY BIOLOGY DeGiorgio, M., Syring, J., Eckert, A. J., Liston, A., Cronn, R., Neale, D. B., Rosenberg, N. A. 2014; 14
  • Discordance of Species Trees with Their Most Likely Gene Trees: A Unifying Principle MOLECULAR BIOLOGY AND EVOLUTION Rosenberg, N. A. 2013; 30 (12): 2709-2713


    A labeled gene tree topology that disagrees with a labeled species tree topology is said to be anomalous if it is more probable under a coalescent model for gene lineage evolution than the labeled gene tree topology that matches the species tree. It has previously been shown that as a consequence of short internal branches of the species tree, for every labeled species tree topology with five or more taxa, and for asymmetric four-taxon species tree topologies, an assignment of species tree branch lengths can be made which gives rise to anomalous gene trees (AGTs). Here, I offer an alternative characterization of this result--a labeled species tree topology produces AGTs if and only if it contains two consecutive internal branches in an ancestor-descendant relationship--and I provide a proof that follows from the change in perspective. The reformulation and alternative proof of the existence result for AGTs provide the insight that it is not merely short internal branches that generate AGTs, but instead, short internal branches that are arranged consecutively.

    View details for DOI 10.1093/molbev/mst160

    View details for Web of Science ID 000327793000016

    View details for PubMedID 24030555

  • A population-genetic perspective on the similarities and differences among worldwide human populations. Human biology Rosenberg, N. A. 2011; 83 (6): 659-684


    Recent studies have produced a variety of advances in the investigation of genetic similarities and differences among human populations. Here, I pose a series of questions about human population-genetic similarities and differences, and I then answer these questions by numerical computation with a single shared population-genetic data set. The collection of answers obtained provides an introductory perspective for understanding key results on the features of worldwide human genetic variation.

    View details for DOI 10.3378/027.083.0601

    View details for PubMedID 22276967

  • Genotype, haplotype and copy-number variation in worldwide human populations NATURE Jakobsson, M., Scholz, S. W., Scheet, P., Gibbs, J. R., VanLiere, J. M., Fung, H., Szpiech, Z. A., Degnan, J. H., Wang, K., Guerreiro, R., Bras, J. M., Schymick, J. C., Hernandez, D. G., Traynor, B. J., Simon-Sanchez, J., Matarin, M., Britton, A., van de Leemput, J., Rafferty, I., Bucan, M., Cann, H. M., Hardy, J. A., Rosenberg, N. A., Singleton, A. B. 2008; 451 (7181): 998-1003


    Genome-wide patterns of variation across individuals provide a powerful source of data for uncovering the history of migration, range expansion, and adaptation of the human species. However, high-resolution surveys of variation in genotype, haplotype and copy number have generally focused on a small number of population groups. Here we report the analysis of high-quality genotypes at 525,910 single-nucleotide polymorphisms (SNPs) and 396 copy-number-variable loci in a worldwide sample of 29 populations. Analysis of SNP genotypes yields strongly supported fine-scale inferences about population structure. Increasing linkage disequilibrium is observed with increasing geographic distance from Africa, as expected under a serial founder effect for the out-of-Africa spread of human populations. New approaches for haplotype analysis produce inferences about population structure that complement results based on unphased SNPs. Despite a difference from SNPs in the frequency spectrum of the copy-number variants (CNVs) detected--including a comparatively large number of CNVs in previously unexamined populations from Oceania and the Americas--the global distribution of CNVs largely accords with population structure analyses for SNP data sets of similar size. Our results produce new inferences about inter-population variation, support the utility of CNVs in human population-genetic research, and serve as a genomic resource for human-genetic studies in diverse worldwide populations.

    View details for DOI 10.1038/nature06742

    View details for Web of Science ID 000253313100050

    View details for PubMedID 18288195

  • AABC: Approximate approximate Bayesian computation for inference in population-genetic models. Theoretical population biology Buzbas, E. O., Rosenberg, N. A. 2015; 99: 31-42


    Approximate Bayesian computation (ABC) methods perform inference on model-specific parameters of mechanistically motivated parametric models when evaluating likelihoods is difficult. Central to the success of ABC methods, which have been used frequently in biology, is computationally inexpensive simulation of data sets from the parametric model of interest. However, when simulating data sets from a model is so computationally expensive that the posterior distribution of parameters cannot be adequately sampled by ABC, inference is not straightforward. We present "approximate approximate Bayesian computation" (AABC), a class of computationally fast inference methods that extends ABC to models in which simulating data is expensive. In AABC, we first simulate a number of data sets small enough to be computationally feasible to simulate from the parametric model. Conditional on these data sets, we use a statistical model that approximates the correct parametric model and enables efficient simulation of a large number of data sets. We show that under mild assumptions, the posterior distribution obtained by AABC converges to the posterior distribution obtained by ABC, as the number of data sets simulated from the parametric model and the sample size of the observed data set increase. We demonstrate the performance of AABC on a population-genetic model of natural selection, as well as on a model of the admixture history of hybrid populations. This latter example illustrates how, in population genetics, AABC is of particular utility in scenarios that rely on conceptually straightforward but potentially slow forward-in-time simulations.

    View details for DOI 10.1016/j.tpb.2014.09.002

    View details for PubMedID 25261426

  • On the Number of Ranked Species Trees Producing Anomalous Ranked Gene Trees IEEE-ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS Disanto, F., Rosenberg, N. A. 2014; 11 (6): 1229-1238
  • Patterns of Admixture and Population Structure in Native Populations of Northwest North America PLOS GENETICS Verdu, P., Pemberton, T. J., Laurent, R., Kemp, B. M., Gonzalez-Oliver, A., Gorodezky, C., Hughes, C. E., Shattuck, M. R., Petzelt, B., Mitchell, J., Harry, H., William, T., Worl, R., Cybulski, J. S., Rosenberg, N. A., Malhi, R. S. 2014; 10 (8)


    The initial contact of European populations with indigenous populations of the Americas produced diverse admixture processes across North, Central, and South America. Recent studies have examined the genetic structure of indigenous populations of Latin America and the Caribbean and their admixed descendants, reporting on the genomic impact of the history of admixture with colonizing populations of European and African ancestry. However, relatively little genomic research has been conducted on admixture in indigenous North American populations. In this study, we analyze genomic data at 475,109 single-nucleotide polymorphisms sampled in indigenous peoples of the Pacific Northwest in British Columbia and Southeast Alaska, populations with a well-documented history of contact with European and Asian traders, fishermen, and contract laborers. We find that the indigenous populations of the Pacific Northwest have higher gene diversity than Latin American indigenous populations. Among the Pacific Northwest populations, interior groups provide more evidence for East Asian admixture, whereas coastal groups have higher levels of European admixture. In contrast with many Latin American indigenous populations, the variance of admixture is high in each of the Pacific Northwest indigenous populations, as expected for recent and ongoing admixture processes. The results reveal some similarities but notable differences between admixture patterns in the Pacific Northwest and those in Latin America, contributing to a more detailed understanding of the genomic consequences of European colonization events throughout the Americas.

    View details for DOI 10.1371/journal.pgen.1004530

    View details for Web of Science ID 000341577800027

    View details for PubMedID 25122539

  • Population-Genetic Influences on Genomic Estimates of the Inbreeding Coefficient: A Global Perspective HUMAN HEREDITY Pemberton, T. J., Rosenberg, N. A. 2014; 77 (1-4): 37-48


    Culturally driven marital practices provide a key instance of an interaction between social and genetic processes in shaping patterns of human genetic variation, producing, for example, increased identity by descent through consanguineous marriage. A commonly used measure to quantify identity by descent in an individual is the inbreeding coefficient, a quantity that reflects not only consanguinity, but also other aspects of kinship in the population to which the individual belongs. Here, in populations worldwide, we examine the relationship between genomic estimates of the inbreeding coefficient and population patterns in genetic variation.Using genotypes at 645 microsatellites, we compare inbreeding coefficients from 5,043 individuals representing 237 populations worldwide to demographic consanguinity frequency estimates available for 26 populations as well as to other quantities that can illuminate population-genetic influences on inbreeding coefficients.We observe higher inbreeding coefficient estimates in populations and geographic regions with known high levels of consanguinity or genetic isolation and in populations with an increased effect of genetic drift and decreased genetic diversity with increasing distance from Africa. For the small number of populations with specific consanguinity estimates, we find a correlation between inbreeding coefficients and consanguinity frequency (r = 0.349, p = 0.040).The results emphasize the importance of both consanguinity and population-genetic factors in influencing variation in inbreeding coefficients, and they provide insight into factors useful for assessing the effect of consanguinity on genomic patterns in different populations. © 2014 S. Karger AG, Basel.

    View details for DOI 10.1159/000362878

    View details for Web of Science ID 000339321800006

    View details for PubMedID 25060268

  • From generation to generation: the genetics of jewish populations. Human biology Rosenberg, N. A., Weitzman, S. P. 2013; 85 (6): 817-824

    View details for PubMedID 25079121

  • Genetics and the History of the Samaritans: Y-Chromosomal Microsatellites and Genetic Affinity between Samaritans and Cohanim HUMAN BIOLOGY Oefner, P. J., Hoelzl, G., Shen, P., Shpirer, I., Gefel, D., Lavi, T., Woolf, E., Cohen, J., Cinnioglu, C., Underhill, P. A., Rosenberg, N. A., Hochrein, J., Granka, J. M., Hillel, J., Feldman, M. W. 2013; 85 (6): 825-857
  • Genotype Imputation Reference Panel Selection Using Maximal Phylogenetic Diversity GENETICS Zhang, P., Zhan, X., Rosenberg, N. A., Zoellner, S. 2013; 195 (2): 319-330
  • Coalescent Histories for Caterpillar-Like Families IEEE-ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS Rosenberg, N. A. 2013; 10 (5): 1253-1262


    A coalescent history is an assignment of branches of a gene tree to branches of a species tree on which coalescences in the gene tree occur. The number of coalescent histories for a pair consisting of a labeled gene tree topology and a labeled species tree topology is important in gene tree probability computations, and more generally, in studying evolutionary possibilities for gene trees on species trees. Defining the Tr-caterpillar-like family as a sequence of n-taxon trees constructed by replacing the r-taxon subtree of n-taxon caterpillars by a specific r-taxon labeled topology Tr, we examine the number of coalescent histories for caterpillar-like families with matching gene tree and species tree labeled topologies. For each Tr with size r≤8, we compute the number of coalescent histories for n-taxon trees in the Tr-caterpillar-like family. Next, as n→∞, we find that the limiting ratio of the numbers of coalescent histories for the Tr family and caterpillars themselves is correlated with the number of labeled histories for Tr. The results support a view that large numbers of coalescent histories occur when a tree has both a relatively balanced subtree and a high tree depth, contributing to deeper understanding of the combinatorics of gene trees and species trees.

    View details for DOI 10.1109/TCBB.2013.123

    View details for Web of Science ID 000331461400017

    View details for PubMedID 24524157

  • Genotype imputation in a coalescent model with infinitely-many-sites mutation THEORETICAL POPULATION BIOLOGY Huang, L., Buzbas, E. O., Rosenberg, N. A. 2013; 87: 62-74


    Empirical studies have identified population-genetic factors as important determinants of the properties of genotype-imputation accuracy in imputation-based disease association studies. Here, we develop a simple coalescent model of three sequences that we use to explore the theoretical basis for the influence of these factors on genotype-imputation accuracy, under the assumption of infinitely-many-sites mutation. Employing a demographic model in which two populations diverged at a given time in the past, we derive the approximate expectation and variance of imputation accuracy in a study sequence sampled from one of the two populations, choosing between two reference sequences, one sampled from the same population as the study sequence and the other sampled from the other population. We show that, under this model, imputation accuracy-as measured by the proportion of polymorphic sites that are imputed correctly in the study sequence-increases in expectation with the mutation rate, the proportion of the markers in a chromosomal region that are genotyped, and the time to divergence between the study and reference populations. Each of these effects derives largely from an increase in information available for determining the reference sequence that is genetically most similar to the sequence targeted for imputation. We analyze as a function of divergence time the expected gain in imputation accuracy in the target using a reference sequence from the same population as the target rather than from the other population. Together with a growing body of empirical investigations of genotype imputation in diverse human populations, our modeling framework lays a foundation for extending imputation techniques to novel populations that have not yet been extensively examined.

    View details for DOI 10.1016/j.tpb.2012.09.006

    View details for Web of Science ID 000322688800007

    View details for PubMedID 23079542

  • Long Runs of Homozygosity Are Enriched for Deleterious Variation AMERICAN JOURNAL OF HUMAN GENETICS Szpiech, Z. A., Xu, J., Pemberton, T. J., Peng, W., Zoellner, S., Rosenberg, N. A., Li, J. Z. 2013; 93 (1): 90-102


    Exome sequencing offers the potential to study the population-genomic variables that underlie patterns of deleterious variation. Runs of homozygosity (ROH) are long stretches of consecutive homozygous genotypes probably reflecting segments shared identically by descent as the result of processes such as consanguinity, population size reduction, and natural selection. The relationship between ROH and patterns of predicted deleterious variation can provide insight into the way in which these processes contribute to the maintenance of deleterious variants. Here, we use exome sequencing to examine ROH in relation to the distribution of deleterious variation in 27 individuals of varying levels of apparent inbreeding from 6 human populations. A significantly greater fraction of all genome-wide predicted damaging homozygotes fall in ROH than would be expected from the corresponding fraction of nondamaging homozygotes in ROH (p < 0.001). This pattern is strongest for long ROH (p < 0.05). ROH, and especially long ROH, harbor disproportionately more deleterious homozygotes than would be expected on the basis of the total ROH coverage of the genome and the genomic distribution of nondamaging homozygotes. The results accord with a hypothesis that recent inbreeding, which generates long ROH, enables rare deleterious variants to exist in homozygous form. Thus, just as inbreeding can elevate the occurrence of rare recessive diseases that represent homozygotes for strongly deleterious mutations, inbreeding magnifies the occurrence of mildly deleterious variants as well.

    View details for DOI 10.1016/j.ajhg.2013.05.003

    View details for Web of Science ID 000321804500008

    View details for PubMedID 23746547

  • Population Structure in a Comprehensive Genomic Data Set on Human Microsatellite Variation G3-GENES GENOMES GENETICS Pemberton, T. J., DeGiorgio, M., Rosenberg, N. A. 2013; 3 (5): 891-907


    Over the past two decades, microsatellite genotypes have provided the data for landmark studies of human population-genetic variation. However, the various microsatellite data sets have been prepared with different procedures and sets of markers, so that it has been difficult to synthesize available data for a comprehensive analysis. Here, we combine eight human population-genetic data sets at the 645 microsatellite loci they share in common, accounting for procedural differences in the production of the different data sets, to assemble a single data set containing 5795 individuals from 267 worldwide populations. We perform a systematic analysis of genetic relatedness, detecting 240 intra-population and 92 inter-population pairs of previously unidentified close relatives and proposing standardized subsets of unrelated individuals for use in future studies. We then augment the human data with a data set of 84 chimpanzees at the 246 loci they share in common with the human samples. Multidimensional scaling and neighbor-joining analyses of these data sets offer new insights into the structure of human populations and enable a comparison of genetic variation patterns in chimpanzees with those in humans. Our combined data sets are the largest of their kind reported to date and provide a resource for use in human population-genetic studies.

    View details for DOI 10.1534/g3.113.005728

    View details for Web of Science ID 000319438700010

    View details for PubMedID 23550135

  • The Relationship Between F-ST and the Frequency of the Most Frequent Allele GENETICS Jakobsson, M., Edge, M. D., Rosenberg, N. A. 2013; 193 (2): 515-528


    F(ST) is frequently used as a summary of genetic differentiation among groups. It has been suggested that F(ST) depends on the allele frequencies at a locus, as it exhibits a variety of peculiar properties related to genetic diversity: higher values for biallelic single-nucleotide polymorphisms (SNPs) than for multiallelic microsatellites, low values among high-diversity populations viewed as substantially distinct, and low values for populations that differ primarily in their profiles of rare alleles. A full mathematical understanding of the dependence of F(ST) on allele frequencies, however, has been elusive. Here, we examine the relationship between F(ST) and the frequency of the most frequent allele, demonstrating that the range of values that F(ST) can take is restricted considerably by the allele-frequency distribution. For a two-population model, we derive strict bounds on F(ST) as a function of the frequency M of the allele with highest mean frequency between the pair of populations. Using these bounds, we show that for a value of M chosen uniformly between 0 and 1 at a multiallelic locus whose number of alleles is left unspecified, the mean maximum F(ST) is ∼0.3585. Further, F(ST) is restricted to values much less than 1 when M is low or high, and the contribution to the maximum F(ST) made by the most frequent allele is on average ∼0.4485. Using bounds on homozygosity that we have previously derived as functions of M, we describe strict bounds on F(ST) in terms of the homozygosity of the total population, finding that the mean maximum F(ST) given this homozygosity is 1 - ln 2 ≈ 0.3069. Our results provide a conceptual basis for understanding the dependence of F(ST) on allele frequencies and genetic diversity and for interpreting the roles of these quantities in computations of F(ST) from population-genetic data. Further, our analysis suggests that many unusual observations of F(ST), including the relatively low F(ST) values in high-diversity human populations from Africa and the relatively low estimates of F(ST) for microsatellites compared to SNPs, can be understood not as biological phenomena associated with different groups of populations or classes of markers but rather as consequences of the intrinsic mathematical dependence of F(ST) on the properties of allele-frequency distributions.

    View details for DOI 10.1534/genetics.112.144758

    View details for Web of Science ID 000314821300015

    View details for PubMedID 23172852

  • Geographic Sampling Scheme as a Determinant of the Major Axis of Genetic Variation in Principal Components Analysis MOLECULAR BIOLOGY AND EVOLUTION DeGiorgio, M., Rosenberg, N. A. 2013; 30 (2): 480-488


    Principal component (PC) maps, which plot the values of a given PC estimated on the basis of allele frequency variation at the geographic sampling locations of a set of populations, are often used to investigate the properties of past range expansions. Some studies have argued that in a range expansion, the axis of greatest variation (i.e., the first PC) is parallel to the axis of expansion. In contrast, others have identified a pattern in which the axis of greatest variation is perpendicular to the axis of expansion. Here, we seek to understand this difference in outcomes by investigating the effect of the geographic sampling scheme on the direction of the axis of greatest variation under a two-dimensional range expansion model. From datasets simulated using each of two different schemes for the geographic sampling of populations under the model, we create PC maps for the first PC. We find that depending on the geographic sampling scheme, the axis of greatest variation can be either parallel or perpendicular to the axis of expansion. We provide an explanation for this result in terms of intra- and interpopulation coalescence times.

    View details for DOI 10.1093/molbev/mss233

    View details for Web of Science ID 000314122000023

    View details for PubMedID 23051843

  • Mathematical properties of the deep coalescence cost. IEEE/ACM transactions on computational biology and bioinformatics / IEEE, ACM Than, C. V., Rosenberg, N. A. 2013; 10 (1): 61-72


    In the minimizing-deep-coalescences (MDC) approach for species tree inference, a tree that has the minimal deep coalescence cost for reconciling a collection of gene trees is taken as an estimate of the species tree topology. The MDC method possesses the desirable Pareto property, and in practice it is quite accurate and computationally efficient. Here, in order to better understand the MDC method, we investigate some properties of the deep coalescence cost. We prove that the unit neighborhood of either a rooted species tree or a rooted gene tree under the deep coalescence cost is exactly the same as the tree's unit neighborhood under the rooted nearest-neighbor interchange (NNI) distance. Next, for a fixed species tree, we obtain the maximum deep coalescence cost across all gene trees as well as the number of gene trees that achieve the maximum cost. We also study corresponding problems for a fixed gene tree.

    View details for DOI 10.1109/TCBB.2012.133

    View details for PubMedID 23702544

  • A Characterization of the Set of Species Trees that Produce Anomalous Ranked Gene Trees IEEE-ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS Degnan, J. H., Rosenberg, N. A., Stadler, T. 2012; 9 (6): 1558-1568


    Ranked gene trees, which consider both the gene tree topology and the sequence in which gene lineages separate, can potentially provide a new source of information for use in modeling genealogies and performing inference of species trees. Recently,we have calculated the probability distribution of ranked gene trees under the standard multispecies coalescent model for the evolution of gene lineages along the branches of a fixed species tree, demonstrating the existence of anomalous ranked gene trees (ARGTs), in which a ranked gene tree that does not match the ranked species tree can have greater probability under the model than the matching ranked gene tree. Here, we fully characterize the set of unranked species tree topologies that give rise to ARGTs, showing that this set contains all species tree topologies with five or more taxa, with the exceptions of caterpillars and pseudocaterpillars. The results have implications for the use of ranked gene trees in phylogenetic inference.

    View details for DOI 10.1109/TCBB.2012.110

    View details for Web of Science ID 000312558400002

    View details for PubMedID 22868677

  • Genomic Patterns of Homozygosity in Worldwide Human Populations AMERICAN JOURNAL OF HUMAN GENETICS Pemberton, T. J., Absher, D., Feldman, M. W., Myers, R. M., Rosenberg, N. A., Li, J. Z. 2012; 91 (2): 275-292


    Genome-wide patterns of homozygosity runs and their variation across individuals provide a valuable and often untapped resource for studying human genetic diversity and evolutionary history. Using genotype data at 577,489 autosomal SNPs, we employed a likelihood-based approach to identify runs of homozygosity (ROH) in 1,839 individuals representing 64 worldwide populations, classifying them by length into three classes-short, intermediate, and long-with a model-based clustering algorithm. For each class, the number and total length of ROH per individual show considerable variation across individuals and populations. The total lengths of short and intermediate ROH per individual increase with the distance of a population from East Africa, in agreement with similar patterns previously observed for locus-wise homozygosity and linkage disequilibrium. By contrast, total lengths of long ROH show large interindividual variations that probably reflect recent inbreeding patterns, with higher values occurring more often in populations with known high frequencies of consanguineous unions. Across the genome, distributions of ROH are not uniform, and they have distinctive continental patterns. ROH frequencies across the genome are correlated with local genomic variables such as recombination rate, as well as with signals of recent positive selection. In addition, long ROH are more frequent in genomic regions harboring genes associated with autosomal-dominant diseases than in regions not implicated in Mendelian diseases. These results provide insight into the way in which homozygosity patterns are produced, and they generate baseline homozygosity patterns that can be used to aid homozygosity mapping of genes associated with recessive diseases.

    View details for DOI 10.1016/j.ajhg.2012.06.014

    View details for Web of Science ID 000307608700006

    View details for PubMedID 22883143

  • Inferring Species Trees Directly from Biallelic Genetic Markers: Bypassing Gene Trees in a Full Coalescent Analysis MOLECULAR BIOLOGY AND EVOLUTION Bryant, D., Bouckaert, R., Felsenstein, J., Rosenberg, N. A., RoyChoudhury, A. 2012; 29 (8): 1917-1932


    The multispecies coalescent provides an elegant theoretical framework for estimating species trees and species demographics from genetic markers. However, practical applications of the multispecies coalescent model are limited by the need to integrate or sample over all gene trees possible for each genetic marker. Here we describe a polynomial-time algorithm that computes the likelihood of a species tree directly from the markers under a finite-sites model of mutation effectively integrating over all possible gene trees. The method applies to independent (unlinked) biallelic markers such as well-spaced single nucleotide polymorphisms, and we have implemented it in SNAPP, a Markov chain Monte Carlo sampler for inferring species trees, divergence dates, and population sizes. We report results from simulation experiments and from an analysis of 1997 amplified fragment length polymorphism loci in 69 individuals sampled from six species of Ourisia (New Zealand native foxglove).

    View details for DOI 10.1093/molbev/mss086

    View details for Web of Science ID 000307171300004

    View details for PubMedID 22422763

  • A Quantitative Comparison of the Similarity between Genes and Geography in Worldwide Human Populations PLOS GENETICS Wang, C., Zoellner, S., Rosenberg, N. A. 2012; 8 (8)


    Multivariate statistical techniques such as principal components analysis (PCA) and multidimensional scaling (MDS) have been widely used to summarize the structure of human genetic variation, often in easily visualized two-dimensional maps. Many recent studies have reported similarity between geographic maps of population locations and MDS or PCA maps of genetic variation inferred from single-nucleotide polymorphisms (SNPs). However, this similarity has been evident primarily in a qualitative sense; and, because different multivariate techniques and marker sets have been used in different studies, it has not been possible to formally compare genetic variation datasets in terms of their levels of similarity with geography. In this study, using genome-wide SNP data from 128 populations worldwide, we perform a systematic analysis to quantitatively evaluate the similarity of genes and geography in different geographic regions. For each of a series of regions, we apply a Procrustes analysis approach to find an optimal transformation that maximizes the similarity between PCA maps of genetic variation and geographic maps of population locations. We consider examples in Europe, Sub-Saharan Africa, Asia, East Asia, and Central/South Asia, as well as in a worldwide sample, finding that significant similarity between genes and geography exists in general at different geographic levels. The similarity is highest in our examples for Asia and, once highly distinctive populations have been removed, Sub-Saharan Africa. Our results provide a quantitative assessment of the geographic structure of human genetic variation worldwide, supporting the view that geography plays a strong role in giving rise to human population structure.

    View details for DOI 10.1371/journal.pgen.1002886

    View details for Web of Science ID 000308529300044

    View details for PubMedID 22927824

  • Improvements to a Class of Distance Matrix Methods for Inferring Species Trees from Gene Trees JOURNAL OF COMPUTATIONAL BIOLOGY Helmkamp, L. J., Jewett, E. M., Rosenberg, N. A. 2012; 19 (6): 632-649


    Among the methods currently available for inferring species trees from gene trees, the GLASS method of Mossel and Roch (2010), the Shallowest Divergence (SD) method of Maddison and Knowles (2006), the STEAC method of Liu et al. (2009), and a related method that we call Minimum Average Coalescence (MAC) are computationally efficient and provide branch length estimates. Further, GLASS and STEAC have been shown to be consistent estimators of tree topology under a multispecies coalescent model. However, divergence time estimates obtained with these methods are all systematically biased under the model because the pairwise interspecific gene divergence times on which they rely must be more ancient than the species divergence time. Jewett and Rosenberg (2012) derived an expression for the bias of GLASS and used it to propose an improved method that they termed iGLASS. Here, we derive the biases of SD, STEAC, and MAC, and we propose improved analogues of these methods that we call iSD, iSTEAC, and iMAC. We conduct simulations to compare the performance of these methods with their original counterparts and with GLASS and iGLASS, finding that each of them decreases the bias and mean squared error of pairwise divergence time estimates. The new methods can therefore contribute to improvements in the estimation of species trees from information on gene trees.

    View details for DOI 10.1089/cmb.2012.0042

    View details for Web of Science ID 000305335100006

    View details for PubMedID 22697239

  • iGLASS: An Improvement to the GLASS Method for Estimating Species Trees from Gene Trees JOURNAL OF COMPUTATIONAL BIOLOGY Jewett, E. M., Rosenberg, N. A. 2012; 19 (3): 293-315


    Several methods have been designed to infer species trees from gene trees while taking into account gene tree/species tree discordance. Although some of these methods provide consistent species tree topology estimates under a standard model, most either do not estimate branch lengths or are computationally slow. An exception, the GLASS method of Mossel and Roch, is consistent for the species tree topology, estimates branch lengths, and is computationally fast. However, GLASS systematically overestimates divergence times, leading to biased estimates of species tree branch lengths. By assuming a multispecies coalescent model in which multiple lineages are sampled from each of two taxa at L independent loci, we derive the distribution of the waiting time until the first interspecific coalescence occurs between the two taxa, considering all loci and measuring from the divergence time. We then use the mean of this distribution to derive a correction to the GLASS estimator of pairwise divergence times. We show that our improved estimator, which we call iGLASS, consistently estimates the divergence time between a pair of taxa as the number of loci approaches infinity, and that it is an unbiased estimator of divergence times when one lineage is sampled per taxon. We also show that many commonly used clustering methods can be combined with the iGLASS estimator of pairwise divergence times to produce a consistent estimator of the species tree topology. Through simulations, we show that iGLASS can greatly reduce the bias and mean squared error in obtaining estimates of divergence times in a species tree.

    View details for DOI 10.1089/cmb.2011.0231

    View details for Web of Science ID 000301355100005

    View details for PubMedID 22216756

  • Refining the relationship between homozygosity and the frequency of the most frequent allele JOURNAL OF MATHEMATICAL BIOLOGY Reddy, S. B., Rosenberg, N. A. 2012; 64 (1-2): 87-108


    Recent work has established that for an arbitrary genetic locus with its number of alleles unspecified, the homozygosity of the locus confines the frequency of the most frequent allele within a narrow range, and vice versa. Here we extend beyond this limiting case by investigating the relationship between homozygosity and the frequency of the most frequent allele when the number of alleles at the locus is treated as known. Given the homozygosity of a locus with at most K alleles, we find that by taking into account the value of K, the width of the allowed range for the frequency of the most frequent allele decreases from 2/3 - ?(2)/18 ? 0.1184 to 1/3 - 1/(3K) - {K/[3(K - 1)]} ?(K)(k = 2) 1/k(2). We further show that properties of the relationship between homozygosity and the frequency of the most frequent allele in the unspecified-K case can be obtained from the specified-K case by taking limits as K ? ?. The results contribute to a greater understanding of the mathematical properties of fundamental statistics employed in population-genetic analysis.

    View details for DOI 10.1007/s00285-011-0406-8

    View details for Web of Science ID 000298652400004

    View details for PubMedID 21305294

  • The probability distribution of ranked gene trees on a species tree MATHEMATICAL BIOSCIENCES Degnan, J. H., Rosenberg, N. A., Stadler, T. 2012; 235 (1): 45-55


    The properties of random gene tree topologies have recently been studied under a coalescent model that treats a species tree as a fixed parameter. Here we develop the analogous theory for random ranked gene tree topologies, in which both the topology and the sequence of coalescences for a random gene tree are considered. We derive the probability distribution of ranked gene tree topologies conditional on a fixed species tree. We then show that similar to the unranked case, ranked gene trees that do not match either the ranking or the topology of the species tree can have greater probability than the matching ranked gene tree.

    View details for DOI 10.1016/j.mbs.2011.10.006

    View details for Web of Science ID 000299761300005

    View details for PubMedID 22075548

  • Haploscope: A Tool for the Graphical Display of Haplotype Structure in Populations GENETIC EPIDEMIOLOGY San Lucas, F. A., Rosenberg, N. A., Scheet, P. 2012; 36 (1): 17-21


    Patterns of linkage disequilibrium are often depicted pictorially by using tools that rely on visualizations of raw data or pairwise correlations among individual markers. Such approaches can fail to highlight some of the more interesting and complex features of haplotype structure. To enable natural visual comparisons of haplotype structure across subgroups of a population (e.g. isolated subpopulations or cases and controls), we propose an alternative visualization that provides a novel graphical representation of haplotype frequencies. We introduce Haploscope, a tool for visualizing the haplotype cluster frequencies that are produced by statistical models for population haplotype variation. We demonstrate the utility of our technique by examining haplotypes around the LCT gene, an example of recent positive selection, in samples from the Human Genome Diversity Panel. Haploscope, which has flexible options for annotation and inspection of haplotypes, is available for download at

    View details for DOI 10.1002/gepi.20640

    View details for Web of Science ID 000302244400003

    View details for PubMedID 22147662

  • A General Mechanistic Model for Admixture Histories of Hybrid Populations GENETICS Verdu, P., Rosenberg, N. A. 2011; 189 (4): 1413-?


    Admixed populations have been used for inferring migrations, detecting natural selection, and finding disease genes. These applications often use a simple statistical model of admixture rather than a modeling perspective that incorporates a more realistic history of the admixture process. Here, we develop a general model of admixture that mechanistically accounts for complex historical admixture processes. We consider two source populations contributing to the ancestry of a hybrid population, potentially with variable contributions across generations. For a random individual in the hybrid population at a given point in time, we study the fraction of genetic admixture originating from a specific one of the source populations by computing its moments as functions of time and of introgression parameters. We show that very different admixture processes can produce identical mean admixture proportions, but that such processes produce different values for the variance of the admixture proportion. When introgression parameters from each source population are constant over time, the long-term limit of the expectation of the admixture proportion depends only on the ratio of the introgression parameters. The variance of admixture decreases quickly over time after the source populations stop contributing to the hybrid population, but remains substantial when the contributions are ongoing. Our approach will facilitate the understanding of admixture mechanisms, illustrating how the moments of the distribution of admixture proportions can be informative about the historical admixture processes contributing to the genetic diversity of hybrid populations.

    View details for DOI 10.1534/genetics.111.132787

    View details for Web of Science ID 000298412100023

    View details for PubMedID 21968194

  • Haplotype variation and genotype imputation in African populations GENETIC EPIDEMIOLOGY Huang, L., Jakobsson, M., Pemberton, T. J., Ibrahim, M., Nyambo, T., Omar, S., Pritchard, J. K., Tishkoff, S. A., Rosenberg, N. A. 2011; 35 (8): 766-780


    Sub-Saharan Africa has been identified as the part of the world with the greatest human genetic diversity. This high level of diversity causes difficulties for genome-wide association (GWA) studies in African populations-for example, by reducing the accuracy of genotype imputation in African populations compared to non-African populations. Here, we investigate haplotype variation and imputation in Africa, using 253 unrelated individuals from 15 Sub-Saharan African populations. We identify the populations that provide the greatest potential for serving as reference panels for imputing genotypes in the remaining groups. Considering reference panels comprising samples of recent African descent in Phase 3 of the HapMap Project, we identify mixtures of reference groups that produce the maximal imputation accuracy in each of the sampled populations. We find that optimal HapMap mixtures and maximal imputation accuracies identified in detailed tests of imputation procedures can instead be predicted by using simple summary statistics that measure relationships between the pattern of genetic variation in a target population and the patterns in potential reference panels. Our results provide an empirical basis for facilitating the selection of reference panels in GWA studies of diverse human populations, especially those of African ancestry.

    View details for DOI 10.1002/gepi.20626

    View details for Web of Science ID 000297468600003

    View details for PubMedID 22125220

  • Coalescence-Time Distributions in a Serial Founder Model of Human Evolutionary History GENETICS DeGiorgio, M., Degnan, J. H., Rosenberg, N. A. 2011; 189 (2): 579-593


    Simulation studies have demonstrated that a variety of patterns in worldwide genetic variation are compatible with the trends predicted by a serial founder model, in which populations expand outward from an initial source via a process in which new populations contain only subsets of the genetic diversity present in their parental populations. Here, we provide analytical results for key quantities under the serial founder model, deriving distributions of coalescence times for pairs of lineages sampled either from the same population or from different populations. We use these distributions to obtain expectations for coalescence times and for homozygosity and heterozygosity values. A predicted approximate linear decline in expected heterozygosity with increasing distance from the source population reproduces a pattern that has been observed both in human genetic data and in simulations. Our formulas predict that populations close to the source location have lower between-population gene identity than populations far from the source, also mirroring results obtained from data and simulations. We show that different models that produce similar declining patterns in heterozygosity generate quite distinct patterns in coalescence-time distributions and gene identity measures, thereby providing a basis for distinguishing these models. We interpret the theoretical results in relation to their implications for human population genetics.

    View details for DOI 10.1534/genetics.111.129296

    View details for Web of Science ID 000296158500014

    View details for PubMedID 21775469

  • On the size distribution of private microsatellite alleles THEORETICAL POPULATION BIOLOGY Szpiech, Z. A., Rosenberg, N. A. 2011; 80 (2): 100-113


    Private microsatellite alleles tend to be found in the tails rather than in the interior of the allele size distribution. To explain this phenomenon, we have investigated the size distribution of private alleles in a coalescent model of two populations, assuming the symmetric stepwise mutation model as the mode of microsatellite mutation. For the case in which four alleles are sampled, two from each population, we condition on the configuration in which three distinct allele sizes are present, one of which is common to both populations, one of which is private to one population, and the third of which is private to the other population. Conditional on this configuration, we calculate the probability that the two private alleles occupy the two tails of the size distribution. This probability, which increases as a function of mutation rate and divergence time between the two populations, is seen to be greater than the value that would be predicted if there was no relationship between privacy and location in the allele size distribution. In accordance with the prediction of the model, we find that in pairs of human populations, the frequency with which private microsatellite alleles occur in the tails of the allele size distribution increases as a function of genetic differentiation between populations.

    View details for DOI 10.1016/j.tpb.2011.03.006

    View details for Web of Science ID 000293765500003

    View details for PubMedID 21514313

  • Consistency Properties of Species Tree Inference by Minimizing Deep Coalescences JOURNAL OF COMPUTATIONAL BIOLOGY Than, C. V., Rosenberg, N. A. 2011; 18 (1): 1-15


    Methods for inferring species trees from sets of gene trees need to account for the possibility of discordance among the gene trees. Assuming that discordance is caused by incomplete lineage sorting, species tree estimates can be obtained by finding those species trees that minimize the number of "deep" coalescence events required for a given collection of gene trees. Efficient algorithms now exist for applying the minimizing-deep-coalescence (MDC) criterion, and simulation experiments have demonstrated its promising performance. However, it has also been noted from simulation results that the MDC criterion is not always guaranteed to infer the correct species tree estimate. In this article, we investigate the consistency of the MDC criterion. Using the multispecies coalescent model, we show that there are indeed anomaly zones for the MDC criterion for asymmetric four-taxon species tree topologies, and for all species tree topologies with five or more taxa.

    View details for DOI 10.1089/cmb.2010.0102

    View details for Web of Science ID 000285965600001

    View details for PubMedID 21210728

  • Coalescent histories for discordant gene trees and species trees THEORETICAL POPULATION BIOLOGY Rosenberg, N. A., Degnan, J. H. 2010; 77 (3): 145-151


    Given a gene tree and a species tree, a coalescent history is a list of the branches of the species tree on which coalescences in the gene tree take place. Each pair consisting of a gene tree topology and a species tree topology has some number of possible coalescent histories. Here we show that, for each n>or=7, there exist a species tree topology S and a gene tree topology G not equalS, both with n leaves, for which the number of coalescent histories exceeds the corresponding number of coalescent histories when the species tree topology is S and the gene tree topology is also S. This result has the interpretation that the gene tree topology G discordant with the species tree topology S can be produced by the evolutionary process in more ways than can the gene tree topology that matches the species tree topology, providing further insight into the surprising combinatorial properties of gene trees that arise from their joint consideration with species trees.

    View details for DOI 10.1016/j.tpb.2009.12.004

    View details for Web of Science ID 000276751300001

    View details for PubMedID 20064540

  • Lack of Population Diversity in Commonly Used Human Embryonic Stem-Cell Lines NEW ENGLAND JOURNAL OF MEDICINE Mosher, J. T., Pemberton, T. J., Harter, K., Wang, C., Buzbas, E. O., Dvorak, P., Simon, C., Morrison, S. J., Rosenberg, N. A. 2010; 362 (2): 183-185

    View details for DOI 10.1056/NEJMc0910371

    View details for Web of Science ID 000273558500033

    View details for PubMedID 20018958

  • Genomic microsatellites identify shared Jewish ancestry intermediate between Middle Eastern and European populations BMC GENETICS Kopelman, N. M., Stone, L., Wang, C., Gefel, D., Feldman, M. W., Hillel, J., Rosenberg, N. A. 2009; 10


    Genetic studies have often produced conflicting results on the question of whether distant Jewish populations in different geographic locations share greater genetic similarity to each other or instead, to nearby non-Jewish populations. We perform a genome-wide population-genetic study of Jewish populations, analyzing 678 autosomal microsatellite loci in 78 individuals from four Jewish groups together with similar data on 321 individuals from 12 non-Jewish Middle Eastern and European populations.We find that the Jewish populations show a high level of genetic similarity to each other, clustering together in several types of analysis of population structure. Further, Bayesian clustering, neighbor-joining trees, and multidimensional scaling place the Jewish populations as intermediate between the non-Jewish Middle Eastern and European populations.These results support the view that the Jewish populations largely share a common Middle Eastern ancestry and that over their history they have undergone varying degrees of admixture with non-Jewish populations of European descent.

    View details for DOI 10.1186/1471-2156-10-80

    View details for Web of Science ID 000273553900001

    View details for PubMedID 19995433

  • Out of Africa: modern human origins special feature: explaining worldwide patterns of human genetic variation using a coalescent-based serial founder model of migration outward from Africa. Proceedings of the National Academy of Sciences of the United States of America DeGiorgio, M., Jakobsson, M., Rosenberg, N. A. 2009; 106 (38): 16057-16062


    Studies of worldwide human variation have discovered three trends in summary statistics as a function of increasing geographic distance from East Africa: a decrease in heterozygosity, an increase in linkage disequilibrium (LD), and a decrease in the slope of the ancestral allele frequency spectrum. Forward simulations of unlinked loci have shown that the decline in heterozygosity can be described by a serial founder model, in which populations migrate outward from Africa through a process where each of a series of populations is formed from a subset of the previous population in the outward expansion. Here, we extend this approach by developing a retrospective coalescent-based serial founder model that incorporates linked loci. Our model both recovers the observed decline in heterozygosity with increasing distance from Africa and produces the patterns observed in LD and the ancestral allele frequency spectrum. Surprisingly, although migration between neighboring populations and limited admixture between modern and archaic humans can be accommodated in the model while continuing to explain the three trends, a competing model in which a wave of outward modern human migration expands into a series of preexisting archaic populations produces nearly opposite patterns to those observed in the data. We conclude by developing a simpler model to illustrate that the feature that permits the serial founder model but not the archaic persistence model to explain the three trends observed with increasing distance from Africa is its incorporation of a cumulative effect of genetic drift as humans colonized the world.

    View details for DOI 10.1073/pnas.0903341106

    View details for PubMedID 19706453

  • Replication of Genetic Associations as Pseudoreplication due to Shared Genealogy GENETIC EPIDEMIOLOGY Rosenberg, N. A., VanLiere, J. M. 2009; 33 (6): 479-487


    The genotypes of individuals in replicate genetic association studies have some level of correlation due to shared descent in the complete pedigree of all living humans. As a result of this genealogical sharing, replicate studies that search for genotype-phenotype associations using linkage disequilibrium between marker loci and disease-susceptibility loci can be considered as "pseudoreplicates" rather than true replicates. We examine the size of the pseudoreplication effect in association studies simulated from evolutionary models of the history of a population, evaluating the excess probability that both of a pair of studies detect a disease association compared to the probability expected under the assumption that the two studies are independent. Each of nine combinations of a demographic model and a penetrance model leads to a detectable pseudoreplication effect, suggesting that the degree of support that can be attributed to a replicated genetic association result is less than that which can be attributed to a replicated result in a context of true independence.

    View details for DOI 10.1002/gepi.20400

    View details for Web of Science ID 000269432400002

    View details for PubMedID 19191270

  • Population differentiation and migration: Coalescence times in a two-sex island model for autosomal and X-linked loci THEORETICAL POPULATION BIOLOGY Ramachandran, S., Rosenberg, N. A., Feldman, M. W., Wakeley, J. 2008; 74 (4): 291-301


    Evolutionists have debated whether population-genetic parameters, such as effective population size and migration rate, differ between males and females. In humans, most analyses of this problem have focused on the Y chromosome and the mitochondrial genome, while the X chromosome has largely been omitted from the discussion. Past studies have compared F(ST) values for the Y chromosome and mitochondrion under a model with migration rates that differ between the sexes but with equal male and female population sizes. In this study we investigate rates of coalescence for X-linked and autosomal lineages in an island model with different population sizes and migration rates for males and females, obtaining the mean time to coalescence for pairs of lineages from the same deme and for pairs of lineages from different demes. We apply our results to microsatellite data from the Human Genome Diversity Panel, and we examine the male and female migration rates implied by observed F(ST) values.

    View details for DOI 10.1016/j.tpb.2008.08.003

    View details for Web of Science ID 000261533200002

    View details for PubMedID 18817799

  • ADZE: a rarefaction approach for counting alleles private to combinations of populations BIOINFORMATICS Szpiech, Z. A., Jakobsson, M., Rosenberg, N. A. 2008; 24 (21): 2498-2504


    Analysis of the distribution of alleles across populations is a useful tool for examining population diversity and relationships. However, sample sizes often differ across populations, sometimes making it difficult to assess allelic distributions across groups.We introduce a generalized rarefaction approach for counting alleles private to combinations of populations. Our method evaluates the number of alleles found in each of a set of populations but absent in all remaining populations, considering equal-sized subsamples from each population. Applying this method to a worldwide human microsatellite dataset, we observe a high number of alleles private to the combination of African and Oceanian populations. This result supports the possibility of a migration out of Africa into Oceania separate from the migrations responsible for the majority of the ancestry of the modern populations of Asia, and it highlights the utility of our approach to sample size correction in evaluating hypotheses about population history.We have implemented our method in the computer pro-gram ADZE, which is available for download at

    View details for DOI 10.1093/bioinformatics/btn478

    View details for Web of Science ID 000260381200012

    View details for PubMedID 18779233