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1.  Sequencing Y Chromosomes Resolves Discrepancy in Time to Common Ancestor of Males versus Females 
Science (New York, N.Y.)  2013;341(6145):562-565.
The Y chromosome and the mitochondrial genome (mtDNA) have been used to estimate when the common patrilineal and matrilineal ancestors of humans lived. We sequenced the genomes of 69 males from nine populations, including two in which we find basal branches of the Y chromosome tree. We identify ancient phylogenetic structure within African haplogroups and resolve a long-standing ambiguity deep within the tree. Applying equivalent methodologies to the Y and mtDNA, we estimate the time to the most recent common ancestor (TMRCA) of the Y chromosome to be 120–156 thousand years and the mtDNA TMRCA to be 99–148 ky. Our findings suggest that, contrary to prior claims, male lineages do not coalesce significantly more recently than female lineages.
PMCID: PMC4032117  PMID: 23908239
2.  Distinguishing the co-ancestries of haplogroup G Y-chromosomes in the populations of Europe and the Caucasus 
European Journal of Human Genetics  2012;20(12):1275-1282.
Haplogroup G, together with J2 clades, has been associated with the spread of agriculture, especially in the European context. However, interpretations based on simple haplogroup frequency clines do not recognize underlying patterns of genetic diversification. Although progress has been recently made in resolving the haplogroup G phylogeny, a comprehensive survey of the geographic distribution patterns of the significant sub-clades of this haplogroup has not been conducted yet. Here we present the haplogroup frequency distribution and STR variation of 16 informative G sub-clades by evaluating 1472 haplogroup G chromosomes belonging to 98 populations ranging from Europe to Pakistan. Although no basal G-M201* chromosomes were detected in our data set, the homeland of this haplogroup has been estimated to be somewhere nearby eastern Anatolia, Armenia or western Iran, the only areas characterized by the co-presence of deep basal branches as well as the occurrence of high sub-haplogroup diversity. The P303 SNP defines the most frequent and widespread G sub-haplogroup. However, its sub-clades have more localized distribution with the U1-defined branch largely restricted to Near/Middle Eastern and the Caucasus, whereas L497 lineages essentially occur in Europe where they likely originated. In contrast, the only U1 representative in Europe is the G-M527 lineage whose distribution pattern is consistent with regions of Greek colonization. No clinal patterns were detected suggesting that the distributions are rather indicative of isolation by distance and demographic complexities.
PMCID: PMC3499744  PMID: 22588667
Y-chromosome; haplogroup G; human evolution; population genetics
3.  Afghan Hindu Kush: Where Eurasian Sub-Continent Gene Flows Converge 
PLoS ONE  2013;8(10):e76748.
Despite being located at the crossroads of Asia, genetics of the Afghanistan populations have been largely overlooked. It is currently inhabited by five major ethnic populations: Pashtun, Tajik, Hazara, Uzbek and Turkmen. Here we present autosomal from a subset of our samples, mitochondrial and Y- chromosome data from over 500 Afghan samples among these 5 ethnic groups. This Afghan data was supplemented with the same Y-chromosome analyses of samples from Iran, Kyrgyzstan, Mongolia and updated Pakistani samples (HGDP-CEPH). The data presented here was integrated into existing knowledge of pan-Eurasian genetic diversity. The pattern of genetic variation, revealed by structure-like and Principal Component analyses and Analysis of Molecular Variance indicates that the people of Afghanistan are made up of a mosaic of components representing various geographic regions of Eurasian ancestry. The absence of a major Central Asian-specific component indicates that the Hindu Kush, like the gene pool of Central Asian populations in general, is a confluence of gene flows rather than a source of distinctly autochthonous populations that have arisen in situ: a conclusion that is reinforced by the phylogeography of both haploid loci.
PMCID: PMC3799995  PMID: 24204668
4.  Novel Epitopes Identified by Anti-PrP Monoclonal Antibodies Produced Following Immunization of Prnp0/0 Balb/cJ Mice with Purified Scrapie Prions 
Hybridoma  2012;31(5):314-324.
Prions, or infectious proteins, cause a class of uniformly fatal neurodegenerative diseases. Prions are composed solely of an aberrantly folded isoform (PrPSc) of a normal cellular protein (PrPC). Shared sequence identity of PrPSc with PrPC has limited the detection sensitivity of immunochemical assays, as antibodies specific for the disease-causing PrPSc isoform have not been developed. Here we report the generation of three new monoclonal antibodies (MAbs) to PrP, which were isolated following immunization of Prnp0/0 Balb/cJ mice with highly purified PrPSc isolated from brain lipid rafts. Epitope mapping using synthetic PrP peptides revealed that the three MAbs bind different epitopes of PrP. The DRM1-31 MAb has a conformational epitope at the proposed binding site for the putative prion conversion co-factor “protein X.” The DRM1-60 MAb binds a single linear epitope localized to the β2–α2 loop region of PrP, whereas DRM2-118 binds an epitope that includes sequences within the octarepeat region and near the site of N-terminal truncation of PrPSc by proteinase K. Our novel anti-PrP MAbs with defined PrP epitopes may be useful in deciphering the conformational conversion of PrPC into PrPSc.
PMCID: PMC3482378  PMID: 23098297
5.  Influence of Parental Health Literacy and Dosing Responsibility on Pediatric Glaucoma Medication Adherence 
Archives of ophthalmology  2012;130(3):306-311.
To assess glaucoma medication adherence in children, hypothesizing that poor parental health literacy and eye drop instillation by the child are associated with worse adherence.
This prospective, observational study enrolled pediatric patients with glaucoma who were prescribed eye drops. Parent(s) reported who was responsible for eye drop instillation (parent vs child), took the Rapid Estimate of Adult Literacy in Medicine, and were instructed on the use and purpose of the Medication Event Monitoring System. Calculations included average adherence (proportion of prescribed doses taken), dosing errors (number of overdosing or underdosing events in 24 hours), and proportion of doses taken on schedule (doses taken within 2 hours of prescribed dosing interval). Results are reported as mean (SD) or median.
The study included 46 of the 50 enrolled children who used the Medication Event Monitoring System for 30 days or more. Adherence ranged from 43% to 107% (93%[12%]) and was not associated with age (slope, 0.09 [0.52]; P = .86) but decreased with the parent’s lower health literacy (slope, 0.62 [0.24]; P = .01).The mean number of dosing errors for medications prescribed daily vs twice daily was similar (3.3 vs 2.9; P = .66). The proportion of doses taken on schedule (within 2 hours of prescribed dosing interval) ranged from 3% to 97% (median, 34%; mean, 41% [24%]) and was better when the parent vs the child instilled eye drops (46% [26%] vs 23% [19%]; P < .001).
Time-dependent glaucoma medication adherence was better when the parent was responsible for eye drop instillation. Overall decreased adherence was associated with decreased parental health literacy. Children of parents with poor health literacy are vulnerable to poor medication adherence; efforts to address poor health literacy may improve outcomes.
PMCID: PMC3715130  PMID: 22411659
6.  Molecular Profiling of Individual Tumor Cells by Hyperspectral Microscopic Imaging 
Translational Research  2011;159(5):366-375.
We have developed a hyperspectral microscopic imaging (HMI) platform that can precisely identify and quantify 10 molecular markers in individual cancer cells in a single pass. Exploitation of an improved separation of circulating tumor cells and the application of HMI has provided an opportunity to identify molecular changes in these cells, the recognition of co-expression of these markers, and poses an important opportunity for non-invasive diagnosis, and the use of targeted therapy. We have balanced the intensity of 10 fluorochromes bound to 10 different antibodies, each specific to a particular tumor marker, so that the intensity of each fluorochrome can be discerned from overlapping emissions. Using 2 touch preps from each primary breast cancer, the average molecular marker-intensities of 25 tumor cells gave a representative molecular signature for the tumor despite some cellular heterogeneity. The intensities determined by the HMI correlate well with the conventional 0-3+ analysis by experts in cellular pathology. Since additional multiplexes can be developed using the same fluorochromes but different antibodies, this analysis allows quantification of a large number of molecular markers on individual tumor cells. HMI can be completely automated and, eventually, could allow standardization of protein biomarkers and improve reproducibility among clinical pathology laboratories.
PMCID: PMC3337082  PMID: 22500509
7.  Social and monetary reward learning engage overlapping neural substrates 
Learning to make choices that yield rewarding outcomes requires the computation of three distinct signals: stimulus values that are used to guide choices at the time of decision making, experienced utility signals that are used to evaluate the outcomes of those decisions and prediction errors that are used to update the values assigned to stimuli during reward learning. Here we investigated whether monetary and social rewards involve overlapping neural substrates during these computations. Subjects engaged in two probabilistic reward learning tasks that were identical except that rewards were either social (pictures of smiling or angry people) or monetary (gaining or losing money). We found substantial overlap between the two types of rewards for all components of the learning process: a common area of ventromedial prefrontal cortex (vmPFC) correlated with stimulus value at the time of choice and another common area of vmPFC correlated with reward magnitude and common areas in the striatum correlated with prediction errors. Taken together, the findings support the hypothesis that shared anatomical substrates are involved in the computation of both monetary and social rewards.
PMCID: PMC3304477  PMID: 21427193
social reward; monetary reward; ventromedial prefrontal cortex; ventral striatum
8.  A major Y-chromosome haplogroup R1b Holocene era founder effect in Central and Western Europe 
The phylogenetic relationships of numerous branches within the core Y-chromosome haplogroup R-M207 support a West Asian origin of haplogroup R1b, its initial differentiation there followed by a rapid spread of one of its sub-clades carrying the M269 mutation to Europe. Here, we present phylogeographically resolved data for 2043 M269-derived Y-chromosomes from 118 West Asian and European populations assessed for the M412 SNP that largely separates the majority of Central and West European R1b lineages from those observed in Eastern Europe, the Circum-Uralic region, the Near East, the Caucasus and Pakistan. Within the M412 dichotomy, the major S116 sub-clade shows a frequency peak in the upper Danube basin and Paris area with declining frequency toward Italy, Iberia, Southern France and British Isles. Although this frequency pattern closely approximates the spread of the Linearbandkeramik (LBK), Neolithic culture, an advent leading to a number of pre-historic cultural developments during the past ≤10 thousand years, more complex pre-Neolithic scenarios remain possible for the L23(xM412) components in Southeast Europe and elsewhere.
PMCID: PMC3039512  PMID: 20736979
Y-chromosome; haplogroup R1b; human evolution; population genetics
9.  Reduced social preferences in autism: evidence from charitable donations 
People with autism have abnormal preferences, ranging from an apparent lack of preference for social stimuli to unusually strong preferences for restricted sets of highly idiosyncratic stimuli. Yet the profile of preferences across social and nonsocial domains has not been mapped out in detail, and the processes responsible remain poorly understood.
To assess preferences across a range of stimuli, we measured real monetary donations to 50 charities spanning categories pertaining to people, mental health, animals, or the environment. We compared the donations made by 16 high-functioning adults with autism to those made by neurotypical controls matched on age, gender and education. We additionally collected ratings of how people evaluated the different charities.
Compared with controls, high-functioning adults with autism donated less overall and also showed a significantly disproportionate reduction in donations to people charities compared with donations to the other charities. Furthermore, whereas controls discriminated strongly between different people charities, choosing to donate a lot of money to some and very little to others, much less discrimination was seen in the autism group. Ratings that probed how participants constructed their preferences did not differ between groups, except for a difference in the perceived impact of pictures and text information about people charities. Strikingly, there were some charities related to mental health, and autism in particular, to which the autism group donated considerably more than did the controls.
People with autism were found to have reduced preference and sensitivity towards charities benefiting other people. The findings provide evidence for a domain-specific impairment in social cognition in autism spectrum disorder, and in particular in linking otherwise intact social knowledge to the construction of value signals on which preferences regarding other people are based.
PMCID: PMC3436698  PMID: 22958506
10.  Impaired Learning of Social Compared to Monetary Rewards in Autism 
A leading hypothesis to explain the social dysfunction in people with autism spectrum disorders (ASD) is that they exhibit a deficit in reward processing and motivation specific to social stimuli. However, there have been few direct tests of this hypothesis to date. Here we used an instrumental reward learning task that contrasted learning with social rewards (pictures of positive and negative faces) against learning with monetary reward (winning and losing money). The two tasks were structurally identical except for the type of reward, permitting direct comparisons. We tested 10 high-functioning people with ASD (7M, 3F) and 10 healthy controls who were matched on gender, age, and education. We found no significant differences between the two groups in terms of overall ability behaviorally to discriminate positive from negative slot machines, reaction-times, and valence ratings, However, there was a specific impairment in the ASD group in learning to choose social rewards, compared to monetary rewards: they had a significantly lower cumulative number of choices of the most rewarding social slot machine, and had a significantly slower initial learning rate for the socially rewarding slot machine, compared to the controls. The findings show a deficit in reward learning in ASD that is greater for social rewards than for monetary rewards, and support the hypothesis of a disproportionate impairment in social reward processing in ASD.
PMCID: PMC3461406  PMID: 23060743
social reward; monetary reward; autism
11.  Functional roles for the GerE-family carboxyl-terminal domains of nitrate response regulators NarL and NarP of Escherichia coli K-12 
Microbiology  2010;156(Pt 10):2933-2943.
NarL and NarP are paralogous response regulators that control anaerobic gene expression in response to the favoured electron acceptors nitrate and nitrite. Their DNA-binding carboxyl termini are in the widespread GerE–LuxR–FixJ subfamily of tetrahelical helix–turn–helix domains. Previous biochemical and crystallographic studies with NarL suggest that dimerization and DNA binding by the carboxyl-terminal domain (CTD) is inhibited by the unphosphorylated amino-terminal receiver domain. We report here that NarL-CTD and NarP-CTD, liberated from their receiver domains, activated transcription in vivo from the class II napF and yeaR operon control regions, but failed to activate from the class I narG and fdnG operon control regions. Alanine substitutions were made to examine requirements for residues in the NarL DNA recognition helix. Substitutions for Val-189 and Arg-192 blocked DNA binding as assayed both in vivo and in vitro, whereas substitution for Arg-188 had a strong effect only in vivo. Similar results were obtained with the corresponding residues in NarP. Finally, Ala substitutions identified residues within the NarL CTD as important for transcription activation. Overall, results are congruent with those obtained for other GerE-family members, including GerE, TraR, LuxR and FixJ.
PMCID: PMC3068693  PMID: 20634237
13.  Separating the post-Glacial coancestry of European and Asian Y chromosomes within haplogroup R1a 
Human Y-chromosome haplogroup structure is largely circumscribed by continental boundaries. One notable exception to this general pattern is the young haplogroup R1a that exhibits post-Glacial coalescent times and relates the paternal ancestry of more than 10% of men in a wide geographic area extending from South Asia to Central East Europe and South Siberia. Its origin and dispersal patterns are poorly understood as no marker has yet been described that would distinguish European R1a chromosomes from Asian. Here we present frequency and haplotype diversity estimates for more than 2000 R1a chromosomes assessed for several newly discovered SNP markers that introduce the onset of informative R1a subdivisions by geography. Marker M434 has a low frequency and a late origin in West Asia bearing witness to recent gene flow over the Arabian Sea. Conversely, marker M458 has a significant frequency in Europe, exceeding 30% in its core area in Eastern Europe and comprising up to 70% of all M17 chromosomes present there. The diversity and frequency profiles of M458 suggest its origin during the early Holocene and a subsequent expansion likely related to a number of prehistoric cultural developments in the region. Its primary frequency and diversity distribution correlates well with some of the major Central and East European river basins where settled farming was established before its spread further eastward. Importantly, the virtual absence of M458 chromosomes outside Europe speaks against substantial patrilineal gene flow from East Europe to Asia, including to India, at least since the mid-Holocene.
PMCID: PMC2987245  PMID: 19888303
Y chromosome; haplogroup R1a; human evolution; population genetics
14.  The coming of the Greeks to Provence and Corsica: Y-chromosome models of archaic Greek colonization of the western Mediterranean 
The process of Greek colonization of the central and western Mediterranean during the Archaic and Classical Eras has been understudied from the perspective of population genetics. To investigate the Y chromosomal demography of Greek colonization in the western Mediterranean, Y-chromosome data consisting of 29 YSNPs and 37 YSTRs were compared from 51 subjects from Provence, 58 subjects from Smyrna and 31 subjects whose paternal ancestry derives from Asia Minor Phokaia, the ancestral embarkation port to the 6th century BCE Greek colonies of Massalia (Marseilles) and Alalie (Aleria, Corsica).
19% of the Phokaian and 12% of the Smyrnian representatives were derived for haplogroup E-V13, characteristic of the Greek and Balkan mainland, while 4% of the Provencal, 4.6% of East Corsican and 1.6% of West Corsican samples were derived for E-V13. An admixture analysis estimated that 17% of the Y-chromosomes of Provence may be attributed to Greek colonization. Using the following putative Neolithic Anatolian lineages: J2a-DYS445 = 6, G2a-M406 and J2a1b1-M92, the data predict a 0% Neolithic contribution to Provence from Anatolia. Estimates of colonial Greek vs. indigenous Celto-Ligurian demography predict a maximum of a 10% Greek contribution, suggesting a Greek male elite-dominant input into the Iron Age Provence population.
Given the origin of viniculture in Provence is ascribed to Massalia, these results suggest that E-V13 may trace the demographic and socio-cultural impact of Greek colonization in Mediterranean Europe, a contribution that appears to be considerably larger than that of a Neolithic pioneer colonization.
PMCID: PMC3068964  PMID: 21401952
15.  The emergence of Y-chromosome haplogroup J1e among Arabic-speaking populations 
Haplogroup J1 is a prevalent Y-chromosome lineage within the Near East. We report the frequency and YSTR diversity data for its major sub-clade (J1e). The overall expansion time estimated from 453 chromosomes is 10 000 years. Moreover, the previously described J1 (DYS388=13) chromosomes, frequently found in the Caucasus and eastern Anatolian populations, were ancestral to J1e and displayed an expansion time of 9000 years. For J1e, the Zagros/Taurus mountain region displays the highest haplotype diversity, although the J1e frequency increases toward the peripheral Arabian Peninsula. The southerly pattern of decreasing expansion time estimates is consistent with the serial drift and founder effect processes. The first such migration is predicted to have occurred at the onset of the Neolithic, and accordingly J1e parallels the establishment of rain-fed agriculture and semi-nomadic herders throughout the Fertile Crescent. Subsequently, J1e lineages might have been involved in episodes of the expansion of pastoralists into arid habitats coinciding with the spread of Arabic and other Semitic-speaking populations.
PMCID: PMC2987219  PMID: 19826455
Y-chromosome haplogroup J1e; Neolithic; Arabic languages; pastoralism
16.  Y-chromosome Short Tandem Repeat Intermediate Variant Alleles DYS392.2, DYS449.2, and DYS385.2 Delineate New Phylogenetic Substructure in Human Y-chromosome Haplogroup Tree 
Croatian Medical Journal  2009;50(3):239-249.
To determine the human Y-chromosome haplogroup backgrounds of intermediate-sized variant alleles displayed by short tandem repeat (STR) loci DYS392, DYS449, and DYS385, and to evaluate the potential of each intermediate variant to elucidate new phylogenetic substructure within the human Y-chromosome haplogroup tree.
Molecular characterization of lineages was achieved using a combination of Y-chromosome haplogroup defining binary polymorphisms and up to 37 short tandem repeat loci. DNA sequencing and median-joining network analyses were used to evaluate Y-chromosome lineages displaying intermediate variant alleles.
We show that DYS392.2 occurs on a single haplogroup background, specifically I1*-M253, and likely represents a new phylogenetic subdivision in this European haplogroup. Intermediate variants DYS449.2 and DYS385.2 both occur on multiple haplogroup backgrounds, and when evaluated within specific haplogroup contexts, delineate new phylogenetic substructure, with DYS449.2 being informative within haplogroup A-P97 and DYS385.2 in haplogroups D-M145, E1b1a-M2, and R1b*-M343. Sequence analysis of variant alleles observed within the various haplogroup backgrounds showed that the nature of the intermediate variant differed, confirming the mutations arose independently.
Y-chromosome short tandem repeat intermediate variant alleles, while relatively rare, typically occur on multiple haplogroup backgrounds. This distribution indicates that such mutations arise at a rate generally intermediate to those of binary markers and Y-STR loci. As a result, intermediate-sized Y-STR variants can reveal phylogenetic substructure within the Y-chromosome phylogeny not currently detected by either binary or Y-STR markers alone, but only when such variants are evaluated within a haplogroup context.
PMCID: PMC2702739  PMID: 19480020
17.  Y-chromosome Short Tandem Repeat DYS458.2 Non-consensus Alleles Occur Independently in Both Binary Haplogroups J1-M267 and R1b3-M405 
Croatian Medical Journal  2007;48(4):450-459.
To determine the human Y-chromosome haplogroup backgrounds of non-consensus DYS458.2 short tandem repeat alleles and evaluate their phylogenetic substructure and frequency in representative samples from the Middle East, Europe, and Pakistan.
Molecular characterization of lineages was achieved using a combination of Y-chromosome haplogroup defining binary polymorphisms and up to 37 short tandem repeat loci, including DYS388 to construct haplotypes. DNA sequencing of the DYS458 locus and median-joining network analyses were used to evaluate Y-chromosome lineages displaying the DYS458.2 motif.
We showed that the DYS458.2 allelic innovation arose independently on at least two distinctive binary haplogroup backgrounds and possibly a third as well. The partial allele length pattern was fixed in all haplogroup J1 chromosomes examined, including its known rare sub-haplogroups. Within the alternative R1b3 associated M405 defined sub-haplogroup, both DYS458.0 and DYS458.2 allele classes occurred. A single chromosome also allocated to the R1b3-M269*(xM405) classification. The physical position of the partial insertion/deletion occurrence within the normal tetramer tract differed distinctly in each haplogroup context.
While unusual DYS458.2 alleles are informative, additional information for other linked polymorphic loci is required when using such non-conforming alleles to infer haplogroup background and common ancestry.
PMCID: PMC2080563  PMID: 17696299
18.  Phylogenetic applications of whole Y-chromosome sequences and the Near Eastern origin of Ashkenazi Levites 
Nature Communications  2013;4:2928.
Previous Y-chromosome studies have demonstrated that Ashkenazi Levites, members of a paternally inherited Jewish priestly caste, display a distinctive founder event within R1a, the most prevalent Y-chromosome haplogroup in Eastern Europe. Here we report the analysis of 16 whole R1 sequences and show that a set of 19 unique nucleotide substitutions defines the Ashkenazi R1a lineage. While our survey of one of these, M582, in 2,834 R1a samples reveals its absence in 922 Eastern Europeans, we show it is present in all sampled R1a Ashkenazi Levites, as well as in 33.8% of other R1a Ashkenazi Jewish males and 5.9% of 303 R1a Near Eastern males, where it shows considerably higher diversity. Moreover, the M582 lineage also occurs at low frequencies in non-Ashkenazi Jewish populations. In contrast to the previously suggested Eastern European origin for Ashkenazi Levites, the current data are indicative of a geographic source of the Levite founder lineage in the Near East and its likely presence among pre-Diaspora Hebrews.
Population genetics studies continue to debate whether Ashkenazi Levites originated in Europe or the Near East. Here, Rootsi et al. use whole Y-chromosome DNA sequences to unravel the phylogenetic origin of the Ashkenazi Levite and suggest an origin for the Levite founder lineage in the Near East.
PMCID: PMC3905698  PMID: 24346185

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