Doctor of Philosophy, Stanford University, Physics
Bachelor of Arts, Columbia University, Physics and Mathematics
Noah Rosenberg, Postdoctoral Faculty Sponsor
Designing gene drives to limit spillover to non-target populations.
2021; 17 (2): e1009278
The prospect of utilizing CRISPR-based gene-drive technology for controlling populations has generated much excitement. However, the potential for spillovers of gene-drive alleles from the target population to non-target populations has raised concerns. Here, using mathematical models, we investigate the possibility of limiting spillovers to non-target populations by designing differential-targeting gene drives, in which the expected equilibrium gene-drive allele frequencies are high in the target population but low in the non-target population. We find that achieving differential targeting is possible with certain configurations of gene drive parameters, but, in most cases, only under relatively low migration rates between populations. Under high migration, differential targeting is possible only in a narrow region of the parameter space. Because fixation of the gene drive in the non-target population could severely disrupt ecosystems, we outline possible ways to avoid this outcome. We apply our model to two potential applications of gene drives-field trials for malaria-vector gene drives and control of invasive species on islands. We discuss theoretical predictions of key requirements for differential targeting and their practical implications.
View details for DOI 10.1371/journal.pgen.1009278
View details for PubMedID 33630838
Skin deep: The decoupling of genetic admixture levels from phenotypes that differed between source populations.
American journal of physical anthropology
In genetic admixture processes, source groups for an admixed population possess distinct patterns of genotype and phenotype at the onset of admixture. Particularly in the context of recent and ongoing admixture, such differences are sometimes taken to serve as markers of ancestry for individuals-that is, phenotypes initially associated with the ancestral background in one source population are assumed to continue to reflect ancestry in that population. Such phenotypes might possess ongoing significance in social categorizations of individuals, owing in part to perceived continuing correlations with ancestry. However, genotypes or phenotypes initially associated with ancestry in one specific source population have been seen to decouple from overall admixture levels, so that they no longer serve as proxies for genetic ancestry. Here, we aim to develop an understanding of the joint dynamics of admixture levels and phenotype distributions in an admixed population.We devise a mechanistic model, consisting of an admixture model, a quantitative trait model, and a mating model. We analyze the behavior of the mechanistic model in relation to the model parameters.We find that it is possible for the decoupling of genetic ancestry and phenotype to proceed quickly, and that it occurs faster if the phenotype is driven by fewer loci. Positive assortative mating attenuates the process of dissociation relative to a scenario in which mating is random with respect to genetic admixture and with respect to phenotype.The mechanistic framework suggests that in an admixed population, a trait that initially differed between source populations might serve as a reliable proxy for ancestry for only a short time, especially if the trait is determined by few loci. It follows that a social categorization based on such a trait is increasingly uninformative about genetic ancestry and about other traits that differed between source populations at the onset of admixture.
View details for DOI 10.1002/ajpa.24261
View details for PubMedID 33772750
Distance metrics for ranked evolutionary trees.
Proceedings of the National Academy of Sciences of the United States of America
Genealogical tree modeling is essential for estimating evolutionary parameters in population genetics and phylogenetics. Recent mathematical results concerning ranked genealogies without leaf labels unlock opportunities in the analysis of evolutionary trees. In particular, comparisons between ranked genealogies facilitate the study of evolutionary processes of different organisms sampled at multiple time periods. We propose metrics on ranked tree shapes and ranked genealogies for lineages isochronously and heterochronously sampled. Our proposed tree metrics make it possible to conduct statistical analyses of ranked tree shapes and timed ranked tree shapes or ranked genealogies. Such analyses allow us to assess differences in tree distributions, quantify estimation uncertainty, and summarize tree distributions. We show the utility of our metrics via simulations and an application in infectious diseases.
View details for DOI 10.1073/pnas.1922851117
View details for PubMedID 33139566
Human-Genetic Ancestry Inference and False Positives in Forensic Familial Searching.
G3 (Bethesda, Md.)
In forensic familial search methods, a query DNA profile is tested against a database to determine if the query profile represents a close relative of a database entrant. One challenge for familial search is that the calculations may require specification of allele frequencies for the unknown population from which the query profile has originated. Allele-frequency misspecification can substantially inflate false-positive rates compared to use of allele frequencies drawn from the same population as the query profile. Here, we use ancestry inference on the query profile to circumvent the high false-positive rates that result from highly misspecified allele frequencies. In particular, we perform ancestry inference on the query profile and make use of allele frequencies based on its inferred genetic ancestry. In a test for sibling matches on profiles that represent unrelated individuals, we demonstrate that false-positive rates for familial search with use of ancestry inference to specify the allele frequencies are similar to those seen when allele frequencies align with the population of origin of a profile. Because ancestry inference is possible to perform on query profiles, the extreme allele-frequency misspecifications that produce the highest false-positive rates can be avoided. We discuss the implications of the results in the context of concerns about the forensic use of familial searching.
View details for DOI 10.1534/g3.120.401473
View details for PubMedID 32586848
Statistical Detection of Relatives Typed with Disjoint Forensic and Biomedical Loci.
In familial searching in forensic genetics, a query DNA profile is tested against a database to determine whether it represents a relative of a database entrant. We examine the potential for using linkage disequilibrium to identify pairs of profiles as belonging torelatives when the query and database rely on nonoverlapping genetic markers. Considering data on individuals genotyped with both microsatellites used in forensic applications and genome-wide SNPs, we find that 30%-32% of parent-offspring pairs and 35%-36% of sib pairs can be identified from the SNPs of one member of the pair and the microsatellites of the other. The method suggests the possibility of performing familial searches of microsatellite databases using query SNP profiles, or vice versa. It also reveals that privacy concerns arising from computations across multiple databases that share no genetic markers in common entail risks, not only for database entrants, but for their close relatives as well.
View details for PubMedID 30318150
Mathematical and Simulation-Based Analysis of the Behavior of Admixed Taxa in the Neighbor-Joining Algorithm.
Bulletin of mathematical biology
The neighbor-joining algorithm for phylogenetic inference (NJ) has been seen to have three specific properties when applied to distance matrices that contain an admixed taxon: (1) antecedence of clustering, in which the admixed taxon agglomerates with one of its source taxa before the two source taxa agglomerate with each other; (2) intermediacy of distances, in which the distance on an inferred NJ tree between an admixed taxon and either of its source taxa is smaller than the distance between the two source taxa; and (3) intermediacy of path lengths, in which the number of edges separating the admixed taxon and either of its source taxa is less than or equal to the number of edges between the source taxa. We examine the behavior of neighbor-joining on distance matrices containing an admixed group, investigating the occurrence of antecedence of clustering, intermediacy of distances, and intermediacy of path lengths. We first mathematically predict the frequency with which the properties are satisfied for a labeled unrooted binary tree selected uniformly at random in the absence of admixture. We then introduce a taxon constructed by a linear admixture of distances from two source taxa, examining three admixture scenarios by simulation: a model in which distance matrices are chosen at random, a model in which an admixed taxon is added to a set of taxa that reflect treelike evolution, and a model that introduces a perturbation of the treelike scenario. In contrast to previous conjectures, we observe that the three properties are sometimes violated by distance matrices that include an admixed taxon. However, we also find that they are satisfied more often than is expected by chance when the distance matrix contains an admixed taxon, especially when evolution among the non-admixed taxa is treelike. The results contribute to a deeper understanding of the nature of evolutionary trees constructed from data that do not necessarily reflect a treelike evolutionary process.
View details for PubMedID 29876842
Matching CODIS genotypes to SNP genotypes using linkage disequilibrium
WILEY. 2018: 75–76
View details for Web of Science ID 000430656801020
Individual Identifiability Predicts Population Identifiability in Forensic Microsatellite Markers.
2016; 26 (7): 935-942
Highly polymorphic genetic markers with significant potential for distinguishing individual identity are used as a standard tool in forensic testing [1, 2]. At the same time, population-genetic studies have suggested that genetically diverse markers with high individual identifiability also confer information about genetic ancestry [3-6]. The dual influence of polymorphism levels on ancestry inference and forensic desirability suggests that forensically useful marker sets with high levels of individual identifiability might also possess substantial ancestry information. We study a standard forensic marker set-the 13 CODIS loci used in the United States and elsewhere [2, 7-9]-together with 779 additional microsatellites , using direct population structure inference to test whether markers with substantial individual identifiability also produce considerable information about ancestry. Despite having been selected for individual identification and not for ancestry inference , the CODIS markers generate nontrivial model-based clustering patterns similar to those of other sets of 13 tetranucleotide microsatellites. Although the CODIS markers have relatively low values of the FST divergence statistic, their high heterozygosities produce greater ancestry inference potential than is possessed by less heterozygous marker sets. More generally, we observe that marker sets with greater individual identifiability also tend toward greater population identifiability. We conclude that population identifiability regularly follows as a byproduct of the use of highly polymorphic forensic markers. Our findings have implications for the design of new forensic marker sets and for evaluations of the extent to which individual characteristics beyond identification might be predicted from current and future forensic data.
View details for DOI 10.1016/j.cub.2016.01.065
View details for PubMedID 26996508
- Ab initio multiple spawning on laser-dressed states: a study of 1,3-cyclohexadiene photoisomerization via light-induced conical intersections JOURNAL OF PHYSICS B-ATOMIC MOLECULAR AND OPTICAL PHYSICS 2015; 48 (16)
Enhancement of strong-field multiple ionization in the vicinity of the conical intersection in 1,3-cyclohexadiene ring opening
JOURNAL OF CHEMICAL PHYSICS
2013; 139 (18)
Nonradiative energy dissipation in electronically excited polyatomic molecules proceeds through conical intersections, loci of degeneracy between electronic states. We observe a marked enhancement of laser-induced double ionization in the vicinity of a conical intersection during a non-radiative transition. We measured double ionization by detecting the kinetic energy of ions released by laser-induced strong-field fragmentation during the ring-opening transition between 1,3-cyclohexadiene and 1,3,5-hexatriene. The enhancement of the double ionization correlates with the conical intersection between the HOMO and LUMO orbitals.
View details for DOI 10.1063/1.4829766
View details for Web of Science ID 000327712800032
View details for PubMedID 24320276
Enhanced strong-field multiple ionization in the vicinity of S-1/S-0 conical intersection in 1,3-cyclohexadiene
AMER CHEMICAL SOC. 2013
View details for Web of Science ID 000329618406281
Transient X-Ray Fragmentation: Probing a Prototypical Photoinduced Ring Opening
PHYSICAL REVIEW LETTERS
2012; 108 (25)
We report the first study of UV-induced photoisomerization probed via core ionization by an x-ray laser. We investigated x-ray ionization and fragmentation of the cyclohexadiene-hexatriene system at 850 eV during the ring opening. We find that the ion-fragmentation patterns evolve over a picosecond, reflecting a change in the state of excitation and the molecular geometry: the average kinetic energy per ion fragment and H(+)-ion count increase as the ring opens and the molecule elongates. We discuss new opportunities for molecular photophysics created by optical pump x-ray probe experiments.
View details for DOI 10.1103/PhysRevLett.108.253006
View details for Web of Science ID 000305569100005
View details for PubMedID 23004597
Control of 1,3-Cyclohexadiene Photoisomerization Using Light-Induced Conical Intersections
JOURNAL OF PHYSICAL CHEMISTRY A
2012; 116 (11): 2758-2763
We have studied the photoinduced isomerization from 1,3-cyclohexadiene to 1,3,5-hexatriene in the presence of an intense ultrafast laser pulse. We find that the laser field maximally suppresses isomerization if it is both polarized parallel to the excitation dipole and present 50 fs after the initial photoabsorption, at the time when the system is expected to be in the vicinity of a conical intersection that mediates this structural transition. A modified ab initio multiple spawning (AIMS) method shows that the laser induces a resonant coupling between the excited state and the ground state, i.e., a light-induced conical intersection. The theory accounts for the timing and direction of the effect.
View details for DOI 10.1021/jp208384b
View details for Web of Science ID 000301766500022
View details for PubMedID 22082319
Ultrafast ring opening in 1,3-cyclohexadiene investigated by simplex-based spectral unmixing
JOURNAL OF CHEMICAL PHYSICS
2012; 136 (5)
We use spectral unmixing to determine the number of transient photoproducts and to track their evolution following the photo-excitation of 1,3-cyclohexadiene (CHD) to form 1,3,5-hexatriene (HT) in the gas phase. The ring opening is initiated with a 266 nm ultraviolet laser pulse and probed via fragmentation with a delayed intense infrared 800 nm laser pulse. The ion time-of-flight (TOF) spectra are analyzed with a simplex-based spectral unmixing technique. We find that at least three independent spectra are needed to model the transient TOF spectra. Guided by mathematical and physical constraints, we decompose the transient TOF spectra into three spectra associated with the presence of CHD, CHD(+), and HT, and show how these three species appear at different times during the ring opening.
View details for DOI 10.1063/1.3681258
View details for Web of Science ID 000300547200020
View details for PubMedID 22320738
Shining new light on 1,3-cyclohexadiene isomerization
AMER CHEMICAL SOC. 2010
View details for Web of Science ID 000208189304246
Interactions between individual carbon nanotubes studied by Rayleigh scattering spectroscopy
PHYSICAL REVIEW LETTERS
2006; 96 (16)
The electronic properties of single-walled carbon nanotubes (SWNTs) are altered by intertube coupling whenever bundles are formed. These effects are examined experimentally by applying Rayleigh scattering spectroscopy to probe the optical transitions of given individual SWNTs in their isolated and bundled forms. The transition energies of SWNTs are observed to undergo redshifts of tens of meVs upon bundling with other SWNTs. These intertube coupling effects can be understood as arising from the mutual dielectric screening of SWNTs in a bundle.
View details for DOI 10.1103/PhysRevLett.96.167401
View details for Web of Science ID 000237156700068
View details for PubMedID 16712273