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Peidong Shen

Publications and source records attributed to Peidong Shen.

15 recordsLinked to original sources
PubMed2005

The role of selection in the evolution of human mitochondrial genomes.

High mutation rate in mammalian mitochondrial DNA generates a highly divergent pool of alleles even within species that have dispersed and expanded in size recently. Phylogenetic analysis of 277 human mitochondrial genomes revealed a significant (P < 0.01) excess of rRNA and nonsynonymous base substitutions among hotspots of recurrent mutation. Most hotspots involved transitions from guanine to adenine that, with thymine-to-cytosine transitions, illustrate the asymmetric bias in codon usage at synonymous sites on the heavy-strand DNA. The mitochondrion-encoded tRNAThr varied significantly more than any other tRNA gene. Threonine and valine codons were involved in 259 of the 414 amino acid replacements observed. The ratio of nonsynonymous changes from and to threonine and valine differed significantly (P = 0.003) between populations with neutral (22/58) and populations with significantly negative Tajima's D values (70/76), independent of their geographic location. In contrast to a recent suggestion that the excess of nonsilent mutations is characteristic of Arctic populations, implying their role in cold adaptation, we demonstrate that the surplus of nonsynonymous mutations is a general feature of the young branches of the phylogenetic tree, affecting also those that are found only in Africa. We introduce a new calibration method of the mutation rate of synonymous transitions to estimate the coalescent times of mtDNA haplogroups.

Amino Acid Substitution↗
PubMed2005

Conservation of the RB1 gene in human and primates.

Mutations in the RB1 gene are associated with retinoblastoma, which has served as an important model for understanding hereditary predisposition to cancer. Despite the great scrutiny that RB1 has enjoyed as the prototypical tumor suppressor gene, it has never been the object of a comprehensive survey of sequence variation in diverse human populations and primates. Therefore, we analyzed the coding (2,787 bp) and adjacent intronic and untranslated (7,313 bp) sequences of RB1 in 137 individuals from a wide range of ethnicities, including 19 Asian Indian hereditary retinoblastoma cases, and five primate species. Aside from nine apparently disease-associated mutations, 52 variants were identified. They included six singleton, coding variants that comprised five amino acid replacements and one silent site. Nucleotide diversity of the coding region (pi=0.0763+/-1.35 x 10(-4)) was 52 times lower than that of the noncoding regions (pi=3.93+/-5.26 x 10(-4)), indicative of significant sequence conservation. The occurrence of purifying selection was corroborated by phylogeny-based maximum likelihood analysis of the RB1 sequences of human and five primates, which yielded an estimated ratio of replacement to silent substitutions (omega) of 0.095 across all lineages. RB1 displayed extensive linkage disequilibrium over 174 kb, and only four unique recombination events, two in Africa and one each in Europe and Southwest Asia, were observed. Using a parsimony approach, 15 haplotypes could be inferred. Ten were found in Africa, though only 12.4% of the 274 chromosomes screened were of African origin. In non-Africans, a single haplotype accounted for from 63 to 84% of all chromosomes, most likely the consequence of natural selection and a significant bottleneck in effective population size during the colonization of the non-African continents.

Animals↗
PubMed2005

FEM1A is a candidate gene for polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age, and is characterized by infertility, hyperandrogenism and insulin resistance in skeletal muscle. There is evidence for a PCOS gene localized to chromosome 19p13.3. The FEMIA gene maps to chromosome 19p13.3 and is highly expressed in skeletal muscle. FEMIA is a homolog of fem-1, a sex-determination gene of Caenorhabditis elegans that controls masculinization. In a pilot study of Caucasian PCOS patients from our local clinic, we found that one of these five patients exhibited a heterozygous germline missense mutation in FEM1A, designated FEM1A*H500Y. This mutation alters an amino acid conserved from human to C. elegans, and was not found in any of 198 control chromosomes. This missense allele was not found in any of a separate group of 30 PCOS patients from a different regional/ethnic background. Immunostaining of mouse ovary demonstrated that the mouse homolog of FEM1A is expressed in androgen-producing secondary interstitial cells, with a marked increase in expression after puberty, consistent with a key feature of PCOS -- ovarian hyperandrogenism. In conclusion, FEM1A should be considered a candidate gene for PCOS, and more extensive analysis of FEM1A, both coding and regulatory sequences, is warranted in patients and families with PCOS.

Cell Cycle Proteins↗
PubMed2004

Phylogeography of Y-chromosome haplogroup I reveals distinct domains of prehistoric gene flow in europe.

To investigate which aspects of contemporary human Y-chromosome variation in Europe are characteristic of primary colonization, late-glacial expansions from refuge areas, Neolithic dispersals, or more recent events of gene flow, we have analyzed, in detail, haplogroup I (Hg I), the only major clade of the Y phylogeny that is widespread over Europe but virtually absent elsewhere. The analysis of 1,104 Hg I Y chromosomes, which were identified in the survey of 7,574 males from 60 population samples, revealed several subclades with distinct geographic distributions. Subclade I1a accounts for most of Hg I in Scandinavia, with a rapidly decreasing frequency toward both the East European Plain and the Atlantic fringe, but microsatellite diversity reveals that France could be the source region of the early spread of both I1a and the less common I1c. Also, I1b*, which extends from the eastern Adriatic to eastern Europe and declines noticeably toward the southern Balkans and abruptly toward the periphery of northern Italy, probably diffused after the Last Glacial Maximum from a homeland in eastern Europe or the Balkans. In contrast, I1b2 most likely arose in southern France/Iberia. Similarly to the other subclades, it underwent a postglacial expansion and marked the human colonization of Sardinia approximately 9,000 years ago.

Africa, Northern↗
PubMed2004

Origin, diffusion, and differentiation of Y-chromosome haplogroups E and J: inferences on the neolithization of Europe and later migratory events in the Mediterranean area.

The phylogeography of Y-chromosome haplogroups E (Hg E) and J (Hg J) was investigated in >2400 subjects from 29 populations, mainly from Europe and the Mediterranean area but also from Africa and Asia. The observed 501 Hg E and 445 Hg J samples were subtyped using 36 binary markers and eight microsatellite loci. Spatial patterns reveal that (1). the two sister clades, J-M267 and J-M172, are distributed differentially within the Near East, North Africa, and Europe; (2). J-M267 was spread by two temporally distinct migratory episodes, the most recent one probably associated with the diffusion of Arab people; (3). E-M81 is typical of Berbers, and its presence in Iberia and Sicily is due to recent gene flow from North Africa; (4). J-M172(xM12) distribution is consistent with a Levantine/Anatolian dispersal route to southeastern Europe and may reflect the spread of Anatolian farmers; and (5). E-M78 (for which microsatellite data suggest an eastern African origin) and, to a lesser extent, J-M12(M102) lineages would trace the subsequent diffusion of people from the southern Balkans to the west. A 7%-22% contribution of Y chromosomes from Greece to southern Italy was estimated by admixture analysis.

Africa, Northern↗
PubMed2004

Reconstruction of patrilineages and matrilineages of Samaritans and other Israeli populations from Y-chromosome and mitochondrial DNA sequence variation.

The Samaritan community, which numbered more than a million in late Roman times and only 146 in 1917, numbers today about 640 people representing four large families. They are culturally different from both Jewish and non-Jewish populations in the Middle East and their origin remains a question of great interest. Genetic differences between the Samaritans and neighboring Jewish and non-Jewish populations are corroborated in the present study of 7,280 bp of nonrecombining Y-chromosome and 5,622 bp of coding and hypervariable segment I (HVS-I) mitochondrial DNA (mtDNA) sequences. Comparative sequence analysis was carried out on 12 Samaritan Y-chromosome, and mtDNA samples from nine male and seven female Samaritans separated by at least two generations. In addition, 18-20 male individuals were analyzed, each representing Ethiopian, Ashkenazi, Iraqi, Libyan, Moroccan, and Yemenite Jews, as well as Druze and Palestinians, all currently living in Israel. The four Samaritan families clustered to four distinct Y-chromosome haplogroups according to their patrilineal identity. Of the 16 Samaritan mtDNA samples, 14 carry either of two mitochondrial haplotypes that are rare or absent among other worldwide ethnic groups. Principal component analysis suggests a common ancestry of Samaritan and Jewish patrilineages. Most of the former may be traced back to a common ancestor in the paternally-inherited Jewish high priesthood (Cohanim) at the time of the Assyrian conquest of the kingdom of Israel.

Africa↗
PubMed2004

Reduced genetic structure of the Iberian peninsula revealed by Y-chromosome analysis: implications for population demography.

Europe has been influenced by both intra- and intercontinental migrations. Since the Iberian peninsula was a refuge during the Last Glacial Maximum, demographic factors associated with contraction, isolation, subsequent expansion and gene flow episodes have contributed complexity to its population history. In this work, we analysed 26 Y-chromosome biallelic markers in 568 chromosomes from 11 different Iberian population groups and compared them to published data on the Basques and Catalans to gain insight into the paternal gene pool of these populations and find out to what extent major demographic processes account for their genetic structure. Our results reveal a reduced, although geographically correlated, Y-chromosomal interpopulation variance (1.2%), which points to a limited heterogeneity in the region. Coincidentally, spatial analysis of genetic distances points to a focal distribution of Y-chromosome haplogroups in this area. These results indicate that neither old or recent Levantine expansions nor North African contacts have influenced the current Iberian Y-chromosome diversity so that geographical patterns can be identified.

Chromosomes, Human, Y↗
PubMed2003

Excavating Y-chromosome haplotype strata in Anatolia.

Analysis of 89 biallelic polymorphisms in 523 Turkish Y chromosomes revealed 52 distinct haplotypes with considerable haplogroup substructure, as exemplified by their respective levels of accumulated diversity at ten short tandem repeat (STR) loci. The major components (haplogroups E3b, G, J, I, L, N, K2, and R1; 94.1%) are shared with European and neighboring Near Eastern populations and contrast with only a minor share of haplogroups related to Central Asian (C, Q and O; 3.4%), Indian (H, R2; 1.5%) and African (A, E3*, E3a; 1%) affinity. The expansion times for 20 haplogroup assemblages was estimated from associated STR diversity. This comprehensive characterization of Y-chromosome heritage addresses many multifaceted aspects of Anatolian prehistory, including: (1) the most frequent haplogroup, J, splits into two sub-clades, one of which (J2) shows decreasing variances with increasing latitude, compatible with a northward expansion; (2) haplogroups G1 and L show affinities with south Caucasus populations in their geographic distribution as well as STR motifs; (3) frequency of haplogroup I, which originated in Europe, declines with increasing longitude, indicating gene flow arriving from Europe; (4) conversely, haplogroup G2 radiates towards Europe; (5) haplogroup E3b3 displays a latitudinal correlation with decreasing frequency northward; (6) haplogroup R1b3 emanates from Turkey towards Southeast Europe and Caucasia and; (7) high resolution SNP analysis provides evidence of a detectable yet weak signal (<9%) of recent paternal gene flow from Central Asia. The variety of Turkish haplotypes is witness to Turkey being both an important source and recipient of gene flow.

Africa, Northern↗
PubMed2003

Experimental test of a method for determining causal connectivities of species in reactions.

Theoretical analysis has shown the possibility of determining causal connectivities of reacting species and the reaction mechanism in complex chemical and biochemical reaction systems by applying pulse changes of concentrations of one or more species, of arbitrary magnitude, and measuring the temporal response of as many species as possible. This method, limited to measured and pulsed species, is given here an experimental test on a part of glycolysis including the sequence of reactions from glucose to fructose 1,6-biphosphate, followed by the bifurcation of that sequence into two branches, one ending in glycerol 3-phosphate, the other in glyceraldehyde 3-phosphate. Pulses of concentrations of one species at a time are applied to the open system in a non-equilibrium stationary state, and the temporal responses in concentrations of six metabolites are measured by capillary zone electrophoresis. From the results of these measurements and the use of the theory for their interpretation, we establish the causal connectivities of the metabolites and thus the reaction mechanism, including the bifurcation of one chain of reactions into two. In this test case of the pulse method, no prior knowledge was assumed of the biochemistry of this system. We conclude that the pulse method is relatively simple and effective in determining reaction mechanisms in complex systems, including reactants, products, intermediates, and catalysts and their effectors. The method is likely to be useful for substantially more complex systems.

Electrophoresis, Capillary↗
PubMed2002

A back migration from Asia to sub-Saharan Africa is supported by high-resolution analysis of human Y-chromosome haplotypes.

The variation of 77 biallelic sites located in the nonrecombining portion of the Y chromosome was examined in 608 male subjects from 22 African populations. This survey revealed a total of 37 binary haplotypes, which were combined with microsatellite polymorphism data to evaluate internal diversities and to estimate coalescence ages of the binary haplotypes. The majority of binary haplotypes showed a nonuniform distribution across the continent. Analysis of molecular variance detected a high level of interpopulation diversity (PhiST=0.342), which appears to be partially related to the geography (PhiCT=0.230). In sub-Saharan Africa, the recent spread of a set of haplotypes partially erased pre-existing diversity, but a high level of population (PhiST=0.332) and geographic (PhiCT=0.179) structuring persists. Correspondence analysis shows that three main clusters of populations can be identified: northern, eastern, and sub-Saharan Africans. Among the latter, the Khoisan, the Pygmies, and the northern Cameroonians are clearly distinct from a tight cluster formed by the Niger-Congo-speaking populations from western, central western, and southern Africa. Phylogeographic analyses suggest that a large component of the present Khoisan gene pool is eastern African in origin and that Asia was the source of a back migration to sub-Saharan Africa. Haplogroup IX Y chromosomes appear to have been involved in such a migration, the traces of which can now be observed mostly in northern Cameroon.

Africa↗
PubMed2002

Reduced Y-chromosome, but not mitochondrial DNA, diversity in human populations from West New Guinea.

To investigate the paternal population history of New Guinea, 183 individuals from 11 regional populations of West New Guinea (WNG) and 131 individuals from Papua New Guinea (PNG) were analyzed at 26 binary markers and seven short-tandem-repeat loci from the nonrecombining part of the human Y chromosome and were compared with 14 populations of eastern and southeastern Asia, Polynesia, and Australia. Y-chromosomal diversity was low in WNG compared with PNG and with most other populations from Asia/Oceania; a single haplogroup (M-M4) accounts for 75% of WNG Y chromosomes, and many WNG populations have just one Y haplogroup. Four Y-chromosomal lineages (haplogroups M-M4, C-M208, C-M38, and K-M230) account for 94% of WNG Y chromosomes and 78% of all Melanesian Y chromosomes and were identified to have most likely arisen in Melanesia. Haplogroup C-M208, which in WNG is restricted to the Dani and Lani, two linguistically closely related populations from the central and western highlands of WNG, was identified as the major Polynesian Y-chromosome lineage. A network analysis of associated Y-chromosomal short-tandem-repeat haplotypes suggests two distinct population expansions involving C-M208--one in New Guinea and one in Polynesia. The observed low levels of Y-chromosome diversity in WNG contrast with high levels of mtDNA diversity reported for the same populations. This most likely reflects extreme patrilocality and/or biased male reproductive success (polygyny). Our data further provide evidence for primarily female-mediated gene flow within the highlands of New Guinea but primarily male-mediated gene flow between highland and lowland/coastal regions.

Chromosomes, Human, Y↗
PubMed2002

Population genetic implications from DNA polymorphism in random human genomic sequences.

Denaturing high performance liquid chromatography (DHPLC) in combination with dye-terminator sequencing was used to survey 516 random genomic sequence tagged sites (STSs) for biallelic polymorphisms in 24 representatives of the major ethnic groups residing in the United States. Of the 301 polymorphic STSs (58.3%), 172 contained a single simple sequence polymorphism (SSP), while 78, 35, and 16 contained 2, 3, and 4-6 SSPs, respectively. Of the 541 SSPs identified, 342 (63%), 152 (28%), and 47 (9%) were transitions, transversions, and insertions or deletions, respectively. Only 21% of the STSs contained SSPs with a minor-allele frequency >20%. The nucleotide diversity estimate for random genomic sequences theta = 8.23 x 10(-4) was on average 50% higher than that for intragenic non-coding regions of the human genome ( theta = 5.52 x 10(-4). The discrepancy in Tajima's D statistic between 22 autosomal genes (D=-1.304+/-0.622, mean+/-SD) and random STSs (D=-0.27) suggests that, in the absence of significant mutation rate heterogeneity, the more negative values for genes are a consequence of directional selection rather than population growth.

Base Sequence↗
PubMed2002

Frequentist estimation of coalescence times from nucleotide sequence data using a tree-based partition.

This article proposes a method of estimating the time to the most recent common ancestor (TMRCA) of a sample of DNA sequences. The method is based on the molecular clock hypothesis, but avoids assumptions about population structure. Simulations show that in a wide range of situations, the point estimate has small bias and the confidence interval has at least the nominal coverage probability. We discuss conditions that can lead to biased estimates. Performance of this estimator is compared with existing methods based on the coalescence theory. The method is applied to sequences of Y chromosomes and mtDNAs to estimate the coalescent times of human male and female populations.

Algorithms↗
PubMed2002

Conservation of the class I beta-tubulin gene in human populations and lack of mutations in lung cancers and paclitaxel-resistant ovarian cancers.

The goal of this study was to determine the prevalence of sequence variants in the class I beta-tubulin (clone m40) gene and their occurrence in human tumors and cancer cell lines. DNA was isolated from 93 control individuals representing a wide variety of ethnicities, 49 paclitaxel-naive specimens (16 ovarian cancers, 17 non-small cell lung cancers, and 16 ovarian cancer cell lines), and 30 paclitaxel-resistant specimens (9 ovarian cancers, 9 ovarian cancer cell lines, and 12 ovarian cancer xenografts in nude mice). Denaturing high-performance liquid chromatography and direct sequence analysis detected two silent polymorphisms in exon 4, Leu217Leu (CTG/CTA) and Gly400Gly (GGC/GGT), with minor allele frequencies of 17 and 0.5%, respectively. Five nucleotide substitutions and one single-base deletion were detected in introns 1, 2, and 3 and in the 3' untranslated region. Analysis of 49 paclitaxel-naive and 30 paclitaxel-resistant specimens revealed no additional polymorphisms in the coding region. In addition, no amino acid replacements were found in chimpanzee, gorilla, and orangutan in comparison to human. Our data demonstrate a very high degree of sequence conservation in class I beta-tubulin, suggesting that all residues are important in tubulin structure and function. Individual variation in response to treatment with paclitaxel is not likely to be caused by genetic variations in the beta-tubulin drug target. Moreover, acquired mutations in class I beta-tubulin are unlikely to be a clinically relevant cause of drug resistance.

Animals↗