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Biomedical subjects

Noah A Rosenberg

Publications and source records attributed to Noah A Rosenberg.

At least 19 recordsLinked to original sources
PubMed2006

A worldwide survey of haplotype variation and linkage disequilibrium in the human genome.

Recent genomic surveys have produced high-resolution haplotype information, but only in a small number of human populations. We report haplotype structure across 12 Mb of DNA sequence in 927 individuals representing 52 populations. The geographic distribution of haplotypes reflects human history, with a loss of haplotype diversity as distance increases from Africa. Although the extent of linkage disequilibrium (LD) varies markedly across populations, considerable sharing of haplotype structure exists, and inferred recombination hotspot locations generally match across groups. The four samples in the International HapMap Project contain the majority of common haplotypes found in most populations: averaging across populations, 83% of common 20-kb haplotypes in a population are also common in the most similar HapMap sample. Consequently, although the portability of tag SNPs based on the HapMap is reduced in low-LD Africans, the HapMap will be helpful for the design of genome-wide association mapping studies in nearly all human populations.

Chromosome Mapping↗
PubMed2006

Sampling properties of homozygosity-based statistics for linkage disequilibrium.

Homozygosity-based statistics such as Ohta's identity-in-state (IIS) excess offer the potential to measure linkage disequilibrium for multiallelic loci in small samples. However, previous observations have suggested that for independent loci, in small samples these statistics might produce values that more frequently lie on one side rather than on the other side of zero. Here we investigate the sampling properties of the IIS excess. We find that for any pair of independent polymorphic loci, as sample size n approaches infinity, the sampling distribution of the IIS excess approaches a normal distribution. For large samples, the IIS excess tends towards symmetry around zero, and the probabilities of positive and of negative IIS excess both approach 1/2. Surprisingly, however, we also find that for sufficiently large n, independent loci can be chosen so that the probability of a sample having positive IIS excess is arbitrarily close to either 0 or 1. The results are applied to interpretation of data from human populations, and we conclude that before employing homozygosity-based statistics to measure LD in a particular sample, especially for loci with either very small or very large homozygosities, it is useful to verify that loci with the observed homozygosity values are not likely to produce a large bias in IIS excess in samples of the given size.

Algorithms↗
PubMed2006

Discordance of species trees with their most likely gene trees.

Because of the stochastic way in which lineages sort during speciation, gene trees may differ in topology from each other and from species trees. Surprisingly, assuming that genetic lineages follow a coalescent model of within-species evolution, we find that for any species tree topology with five or more species, there exist branch lengths for which gene tree discordance is so common that the most likely gene tree topology to evolve along the branches of a species tree differs from the species phylogeny. This counterintuitive result implies that in combining data on multiple loci, the straightforward procedure of using the most frequently observed gene tree topology as an estimate of the species tree topology can be asymptotically guaranteed to produce an incorrect estimate. We conclude with suggestions that can aid in overcoming this new obstacle to accurate genomic inference of species phylogenies.

Algorithms↗
PubMed2006

A general population-genetic model for the production by population structure of spurious genotype-phenotype associations in discrete, admixed or spatially distributed populations.

In linkage disequilibrium mapping of genetic variants causally associated with phenotypes, spurious associations can potentially be generated by any of a variety of types of population structure. However, mathematical theory of the production of spurious associations has largely been restricted to population structure models that involve the sampling of individuals from a collection of discrete subpopulations. Here, we introduce a general model of spurious association in structured populations, appropriate whether the population structure involves discrete groups, admixture among such groups, or continuous variation across space. Under the assumptions of the model, we find that a single common principle--applicable to both the discrete and admixed settings as well as to spatial populations--gives a necessary and sufficient condition for the occurrence of spurious associations. Using a mathematical connection between the discrete and admixed cases, we show that in admixed populations, spurious associations are less severe than in corresponding mixtures of discrete subpopulations, especially when the variance of admixture across individuals is small. This observation, together with the results of simulations that examine the relative influences of various model parameters, has important implications for the design and analysis of genetic association studies in structured populations.

Computer Simulation↗
PubMed2006

Standardized subsets of the HGDP-CEPH Human Genome Diversity Cell Line Panel, accounting for atypical and duplicated samples and pairs of close relatives.

The HGDP-CEPH Human Genome Diversity Cell Line Panel is a widely-used resource for studies of human genetic variation. Here, pairs of close relatives that have been included in the panel are identified. Together with information on atypical and duplicated samples, the inferred relative pairs suggest standardized subsets of the panel for use in future population-genetic studies.

Alleles↗
PubMed2006

Low levels of genetic divergence across geographically and linguistically diverse populations from India.

Ongoing modernization in India has elevated the prevalence of many complex genetic diseases associated with a western lifestyle and diet to near-epidemic proportions. However, although India comprises more than one sixth of the world's human population, it has largely been omitted from genomic surveys that provide the backdrop for association studies of genetic disease. Here, by genotyping India-born individuals sampled in the United States, we carry out an extensive study of Indian genetic variation. We analyze 1,200 genome-wide polymorphisms in 432 individuals from 15 Indian populations. We find that populations from India, and populations from South Asia more generally, constitute one of the major human subgroups with increased similarity of genetic ancestry. However, only a relatively small amount of genetic differentiation exists among the Indian populations. Although caution is warranted due to the fact that United States-sampled Indian populations do not represent a random sample from India, these results suggest that the frequencies of many genetic variants are distinctive in India compared to other parts of the world and that the effects of population heterogeneity on the production of false positives in association studies may be smaller in Indians (and particularly in Indian-Americans) than might be expected for such a geographically and linguistically diverse subset of the human population.

Alleles↗
PubMed2005

Clines, clusters, and the effect of study design on the inference of human population structure.

Previously, we observed that without using prior information about individual sampling locations, a clustering algorithm applied to multilocus genotypes from worldwide human populations produced genetic clusters largely coincident with major geographic regions. It has been argued, however, that the degree of clustering is diminished by use of samples with greater uniformity in geographic distribution, and that the clusters we identified were a consequence of uneven sampling along genetic clines. Expanding our earlier dataset from 377 to 993 markers, we systematically examine the influence of several study design variables--sample size, number of loci, number of clusters, assumptions about correlations in allele frequencies across populations, and the geographic dispersion of the sample--on the "clusteredness" of individuals. With all other variables held constant, geographic dispersion is seen to have comparatively little effect on the degree of clustering. Examination of the relationship between genetic and geographic distance supports a view in which the clusters arise not as an artifact of the sampling scheme, but from small discontinuous jumps in genetic distance for most population pairs on opposite sides of geographic barriers, in comparison with genetic distance for pairs on the same side. Thus, analysis of the 993-locus dataset corroborates our earlier results: if enough markers are used with a sufficiently large worldwide sample, individuals can be partitioned into genetic clusters that match major geographic subdivisions of the globe, with some individuals from intermediate geographic locations having mixed membership in the clusters that correspond to neighboring regions.

Alleles↗
PubMed2005

A sharp minimum on the mean number of steps taken in adaptive walks.

It was recently conjectured by H.A. Orr that from a random initial point on a random fitness landscape of alphabetic sequences with one-mutation adjacency, chosen from a larger class of landscapes, no adaptive algorithm can arrive at a local optimum in fewer than on average e-1 steps. Here, using an example in which the mean number of steps to a local optimum equals (A-1)/A, where A is the number of distinct "letters" in the "alphabet" from which sequences are constructed, it is shown that as originally stated, the conjecture does not hold. It is also demonstrated that (A-1)/A is a sharp minimum on the mean number of steps taken in adaptive walks on fitness landscapes of alphabetic sequences with one-mutation adjacency. As the example that achieves the new lower bound has properties that are not often considered as potential attributes for fitness landscapes-non-identically distributed fitnesses and negative fitness correlations for adjacent points-a weaker set of conditions characteristic of more commonly studied fitness landscapes is proposed under which the lower bound on the mean length of adaptive walks is conjectured to equal e-1.

Adaptation, Physiological↗
PubMed2005

Support from the relationship of genetic and geographic distance in human populations for a serial founder effect originating in Africa.

Equilibrium models of isolation by distance predict an increase in genetic differentiation with geographic distance. Here we find a linear relationship between genetic and geographic distance in a worldwide sample of human populations, with major deviations from the fitted line explicable by admixture or extreme isolation. A close relationship is shown to exist between the correlation of geographic distance and genetic differentiation (as measured by F(ST)) and the geographic pattern of heterozygosity across populations. Considering a worldwide set of geographic locations as possible sources of the human expansion, we find that heterozygosities in the globally distributed populations of the data set are best explained by an expansion originating in Africa and that no geographic origin outside of Africa accounts as well for the observed patterns of genetic diversity. Although the relationship between F(ST) and geographic distance has been interpreted in the past as the result of an equilibrium model of drift and dispersal, simulation shows that the geographic pattern of heterozygosities in this data set is consistent with a model of a serial founder effect starting at a single origin. Given this serial-founder scenario, the relationship between genetic and geographic distance allows us to derive bounds for the effects of drift and natural selection on human genetic variation.

Africa↗
PubMed2005

The pattern of polymorphism in Arabidopsis thaliana.

We resequenced 876 short fragments in a sample of 96 individuals of Arabidopsis thaliana that included stock center accessions as well as a hierarchical sample from natural populations. Although A. thaliana is a selfing weed, the pattern of polymorphism in general agrees with what is expected for a widely distributed, sexually reproducing species. Linkage disequilibrium decays rapidly, within 50 kb. Variation is shared worldwide, although population structure and isolation by distance are evident. The data fail to fit standard neutral models in several ways. There is a genome-wide excess of rare alleles, at least partially due to selection. There is too much variation between genomic regions in the level of polymorphism. The local level of polymorphism is negatively correlated with gene density and positively correlated with segmental duplications. Because the data do not fit theoretical null distributions, attempts to infer natural selection from polymorphism data will require genome-wide surveys of polymorphism in order to identify anomalous regions. Despite this, our data support the utility of A. thaliana as a model for evolutionary functional genomics.

Arabidopsis↗
PubMed2005

Statistical tests of the coalescent model based on the haplotype frequency distribution and the number of segregating sites.

Several tests of neutral evolution employ the observed number of segregating sites and properties of the haplotype frequency distribution as summary statistics and use simulations to obtain rejection probabilities. Here we develop a "haplotype configuration test" of neutrality (HCT) based on the full haplotype frequency distribution. To enable exact computation of rejection probabilities for small samples, we derive a recursion under the standard coalescent model for the joint distribution of the haplotype frequencies and the number of segregating sites. For larger samples, we consider simulation-based approaches. The utility of the HCT is demonstrated in simulations of alternative models and in application to data from Drosophila melanogaster.

Chromosome Segregation↗
PubMed2005

Algorithms for selecting informative marker panels for population assignment.

Given a set of potential source populations, genotypes of an individual of unknown origin at a collection of markers can be used to predict the correct source population of the individual. For improved efficiency, informative markers can be chosen from a larger set of markers to maximize the accuracy of this prediction. However, selecting the loci that are individually most informative does not necessarily produce the optimal panel. Here, using genotypes from eight species--carp, cat, chicken, dog, fly, grayling, human, and maize--this univariate accumulation procedure is compared to new multivariate "greedy" and "maximin" algorithms for choosing marker panels. The procedures generally suggest similar panels, although the greedy method often recommends inclusion of loci that are not chosen by the other algorithms. In seven of the eight species, when applied to five or more markers, all methods achieve at least 94% assignment accuracy on simulated individuals, with one species--dog--producing this level of accuracy with only three markers, and the eighth species--human--requiring approximately 13-16 markers. The new algorithms produce substantial improvements over use of randomly selected markers; where differences among the methods are noticeable, the greedy algorithm leads to slightly higher probabilities of correct assignment. Although none of the approaches necessarily chooses the panel with optimal performance, the algorithms all likely select panels with performance near enough to the maximum that they all are suitable for practical use.

Algorithms↗
PubMed2004

The control of copy number of IS6110 in Mycobacterium tuberculosis.

Insertion sequence (IS) elements are bacterial genes that are able to transpose to different locations in the genome. These elements are often used in molecular epidemiology as genetic markers that track the spread of pathogens. Transposable elements have frequently been described as "selfish DNA" because they facilitate their own transposition, causing damage when they insert into coding regions, while contributing little if anything to the bacterial host. According to this hypothesis, the expansion of copy number of insertion sequences is opposed by negative selection against high copy numbers. From an alternative point of view, we might expect IS elements to intrinsically regulate transposition within cells, thereby limiting damage to their bacterial host. Here, we report evidence that the copy number of IS6110 in Mycobacterium tuberculosis is controlled by selection against the element. We first construct 12 different models of marker change resulting from a combination of possible transposition functions and selective regimes. We then compute the Akaike Information Criterion for each model to identify the models that best explain data consisting of serial isolates of M. tuberculosis genotyped with IS6110. We find that the best performing models all include selection against the accumulation of copies. Specifically, our analysis points to the interaction of separate copies of the element causing lethal effects. We discuss the implications of these findings for genome evolution and molecular epidemiology.

DNA Transposable Elements↗
PubMed2004

Polyploid and multilocus extensions of the Wahlund inequality.

Wahlund's inequality informally states that if a structured and an unstructured population have the same allele frequencies at a locus, the structured population contains more homozygotes. We show that this inequality holds generally for ploidy level P, that is, the structured population has more P-polyhomozygotes. Further, for M randomly chosen loci (M >or= 2), the structured population is also expected to contain more M-multihomozygotes than an unstructured population with the same single-locus homozygosities. The extended inequalities suggest multilocus identity coefficients analogous to F(ST). Using microsatellite genotypes from human populations, we demonstrate that the multilocus Wahlund inequality can explain a positive bias in "identity-in-state excess".

Chromosome Mapping↗
PubMed2004

Robustness of the inference of human population structure: a comparison of X-chromosomal and autosomal microsatellites.

In this paper, data on 20 X-chromosomal microsatellite polymorphisms from the HGDP-CEPH cell line panel are used to infer human population structure. Inferences from these data are compared to those obtained from autosomal microsatellites. Some of the major features of the structure seen with 377 autosomal markers are generally visible with the X-linked markers, although the latter provide less resolution. Differences between the X-chromosomal and autosomal results can be explained without requiring major differences in demographic parameters between males and females. The dependence of the partitioning on the number of individuals sampled from each region and on the number of markers used is discussed.

Analysis of Variance↗
PubMed2003

Informativeness of genetic markers for inference of ancestry.

Inference of individual ancestry is useful in various applications, such as admixture mapping and structured-association mapping. Using information-theoretic principles, we introduce a general measure, the informativeness for assignment (I(n)), applicable to any number of potential source populations, for determining the amount of information that multiallelic markers provide about individual ancestry. In a worldwide human microsatellite data set, we identify markers of highest informativeness for inference of regional ancestry and for inference of population ancestry within regions; these markers, which are listed in online-only tables in our article, can be useful both in testing for and in controlling the influence of ancestry on case-control genetic association studies. Markers that are informative in one collection of source populations are generally informative in others. Informativeness of random dinucleotides, the most informative class of microsatellites, is five to eight times that of random single-nucleotide polymorphisms (SNPs), but 2%-12% of SNPs have higher informativeness than the median for dinucleotides. Our results can aid in decisions about the type, quantity, and specific choice of markers for use in studies of ancestry.

Algorithms↗
PubMed2003

Features of evolution and expansion of modern humans, inferred from genomewide microsatellite markers.

We study data on variation in 52 worldwide populations at 377 autosomal short tandem repeat loci, to infer a demographic history of human populations. Variation at di-, tri-, and tetranucleotide repeat loci is distributed differently, although each class of markers exhibits a decrease of within-population genetic variation in the following order: sub-Saharan Africa, Eurasia, East Asia, Oceania, and America. There is a similar decrease in the frequency of private alleles. With multidimensional scaling, populations belonging to the same major geographic region cluster together, and some regions permit a finer resolution of populations. When a stepwise mutation model is used, a population tree based on TD estimates of divergence time suggests that the branches leading to the present sub-Saharan African populations of hunter-gatherers were the first to diverge from a common ancestral population (approximately 71-142 thousand years ago). The branches corresponding to sub-Saharan African farming populations and those that left Africa diverge next, with subsequent splits of branches for Eurasia, Oceania, East Asia, and America. African hunter-gatherer populations and populations of Oceania and America exhibit no statistically significant signature of growth. The features of population subdivision and growth are discussed in the context of the ancient expansion of modern humans.

Africa↗