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PubMed1991

Spontaneous germinal activation of quiescent Uq transposable elements in Zea mays L.

The spontaneous germinal activation of quiescent Uq transposable elements is reported. Thirty-nine spotted exceptions were observed at a rate of about 2 x 10(-4) from 687 otherwise colorless ears produced from the cross of a-ruq/a-ruq (colorless or occasionally sectored) X an a-ruq tester (colorless). All exceptions had spotting patterns distinct from the pattern of our original standard Uq (Uq1)-a-ruq spotting. From these spotted exceptions five new Uq elements (Uq2, Uq3, Uq4, Uq5 and Uq6) have been isolated. Genetic evidence for the Uq nature of the five germinal isolates is presented. First, each of the five spotted exceptions was homozygous for the a-ruq reporter allele. Second, four new Uq isolates (Uq2, Uq3, Uq4 and Uq5), after being reconstituted into a alpha degrees sh2/alpha degrees sh2 (no Uq) line, could transactivate the standard a-ruq allele and continue to produce their distinct spotting phenotypes. Third, these five new Uqs are also capable of transactivating the c-ruq65 and c-ruq67 alleles. However, the transactivation of c-ruq is generally weaker than that of a-ruq.

DNA Transposable Elements↗
PubMed2000

Sequence variation at two eosinophil-associated ribonuclease loci in humans.

Host defense against invading pathogens is of great importance to the survival of higher organisms. We have been studying the evolution of mammalian eosinophil-associated ribonucleases (EARs), which are members of the ribonuclease A superfamily with known antipathogen activities. Earlier studies showed that positive selection promoted rapid diversification of paralogous EAR genes in both primates and rodents. Intraspecifically, however, it is unknown whether these genes also have divergent alleles. The recent discovery that the gene repertoire of the EAR family is much larger in rodents than in primates has led us to consider the possibility that primates maintain a large number of polymorphic alleles to compensate for a smaller gene repertoire. Here we present sequences of 2417 nucleotides at the two EAR loci, the eosinophil-derived neurotoxin (EDN, RNase 2) and eosinophil cationic protein (ECP, RNase 3), from >50 human individuals. Our data demonstrate that the nucleotide diversities (0.06-0.11%) at these loci are typical for human nuclear genes, thus permitting us to reject this polymorphism hypothesis. No significant departure from neutrality is noted and no signs of overdominant selection are observed. Similar patterns were observed in a preliminary study of chimpanzees. In summary, our results suggest that the antipathogen functions of the primate EARs are conserved after they are established and that these proteins are not currently undergoing rapid diversification in response to challenge from invading microorganisms.

Alleles↗
PubMed2002

Complex SNP-based haplotypes in three human helicases: implications for cancer association studies.

We have initiated a candidate gene approach to study variation and predisposition to cancer in the four major ethnic groups that constitute the U.S. population (African Americans, Caucasians, Hispanics, and Asians). We resequenced portions of three helicase genes (BLM, WRN, and RECQL) identifying a total of 37 noncoding single nucleotide polymorphisms (SNPs). Haplotype inference predicted 50 haplotypes in BLM, 56 in WRN, and 47 in RECQL in a sample of 600 chromosomes. Approximately 10% of the predicted haplotypes were shared among all ethnic groups. Linkage disequilibrium and recombination effects showed that each locus has taken a diverse evolutionary path. Primate DNA analysis of the same loci revealed one human haplotype per gene shared with the great apes, indicating that the observed diversity occurred since the divergence of humans from the last common ancestor. In BLM, we confirmed the presence of a founder haplotype among Ashkenazi Jews homozygous for the blm(Ash) mutation. The cosegregating haplotype was seen in all (6/6) samples of Ashkenazi descent, whereas in the general population it has a low frequency (0.02) and was not found in African Americans. In WRN, ethnic samples were studied for their haplotype content and the presence or absence of six previously described coding SNPs (cSNPs). Hispanic individuals carrying two of these cSNPs showed a 60% increase in the frequency of a common haplotype (haplotype No. 28). In the pooled sample, no association was found. Because (1) the majority of the haplotypes are population specific and (2) the patterns of linkage disequilibrium, recombination, and haplotype diversity are markedly different between gene regions, these data show the importance of either ethnically matched controls or within-family-based disease-gene association studies.

Alleles↗
PubMed2004

Genetic variants of the human H+/dipeptide transporter PEPT2: analysis of haplotype functions.

PEPT2 is a high-affinity H+/dipeptide transporter expressed in kidney, brain, lung, and mammary gland. The physiological role of PEPT2 in kidney is to reabsorb small peptides generated by luminal peptidases. PEPT2 is also a transporter for peptide-like drugs such as penicillins and cephalosporins. We have conducted a haplotype analysis of 27 single nucleotide polymorphisms located in or near exons of the human gene encoding hPEPT2 (SLC15A2), using genotyping data from 247 genomic DNA samples from the Coriell collection. Our analysis reveals that hPEPT2 has a >6-kilobase sequence block with at least 10 abundant polymorphisms in almost complete linkage disequilibrium. As a result, only two main hPEPT2 variants exist (hPEPT2*1 and *2) with several phased amino acid substitutions, present in substantial frequencies in all ethnic groups tested. When expressed in Chinese hamster ovary cells, hPEPT2*1 and *2 displayed similar Vmax values for glycyl-sarcosine (Gly-Sar), but they differed significantly in their Km values (83 +/- 16 and 233 +/- 38 microM, respectively). Moreover, hPEPT2*1 and *2 differed in their pH sensitivity for H+/Gly-Sar transport. In addition, hPEPT2*1 and *2 generated varying levels of mRNA in nine heterozygous kidney tissue samples, including one allele expressing no detectable mRNA, suggesting the presence of cis-acting polymorphisms affecting transcription or mRNA processing. The results indicate that polymorphisms in the gene encoding hPEPT2 can alter substrate transport and therefore could affect drug disposition in vivo.

Alleles↗
PubMed2003

Early origin and recent expansion of Plasmodium falciparum.

The emergence of virulent Plasmodium falciparum in Africa within the past 6000 years as a result of a cascade of changes in human behavior and mosquito transmission has recently been hypothesized. Here, we provide genetic evidence for a sudden increase in the African malaria parasite population about 10,000 years ago, followed by migration to other regions on the basis of variation in 100 worldwide mitochondrial DNA sequences. However, both the world and some regional populations appear to be older (50,000 to 100,000 years old), suggesting an earlier wave of migration out of Africa, perhaps during the Pleistocene migration of human beings.

Africa↗
PubMed2005

High frequency of the IVS2-2A>G DNA sequence variation in SLC26A5, encoding the cochlear motor protein prestin, precludes its involvement in hereditary hearing loss.

BACKGROUND: Cochlear outer hair cells change their length in response to variations in membrane potential. This capability, called electromotility, is believed to enable the sensitivity and frequency selectivity of the mammalian cochlea. Prestin is a transmembrane protein required for electromotility. Homozygous prestin knockout mice are profoundly hearing impaired. In humans, a single nucleotide change in SLC26A5, encoding prestin, has been reported in association with hearing loss. This DNA sequence variation, IVS2-2A>G, occurs in the exon 3 splice acceptor site and is expected to abolish splicing of exon 3. METHODS: To further explore the relationship between hearing loss and the IVS2-2A>G transition, and assess allele frequency, genomic DNA from hearing impaired and control subjects was analyzed by DNA sequencing. SLC26A5 genomic DNA sequences from human, chimp, rat, mouse, zebrafish and fruit fly were aligned and compared for evolutionary conservation of the exon 3 splice acceptor site. Alternative splice acceptor sites within intron 2 of human SLC26A5 were sought using a splice site prediction program from the Berkeley Drosophila Genome Project. RESULTS: The IVS2-2A>G variant was found in a heterozygous state in 4 of 74 hearing impaired subjects of Hispanic, Caucasian or uncertain ethnicity and 4 of 150 Hispanic or Caucasian controls (p = 0.45). The IVS2-2A>G variant was not found in 106 subjects of Asian or African American descent. No homozygous subjects were identified (n = 330). Sequence alignment of SLC26A5 orthologs demonstrated that the A nucleotide at position IVS2-2 is invariant among several eukaryotic species. Sequence analysis also revealed five potential alternative splice acceptor sites in intron 2 of human SLC26A5. CONCLUSION: These data suggest that the IVS2-2A>G variant may not occur more frequently in hearing impaired subjects than in controls. The identification of five potential alternative splice acceptor sites in intron 2 of human SLC26A5 suggests a potential mechanism by which expression of prestin might be maintained in cells carrying the SLC26A5 IVS2-2A>G DNA sequence variation. Additional studies are needed to evaluate the effect of the IVS2-2A>G transition on splicing of SLC26A5 transcripts and characterize the hearing status of individuals homozygous for the IVS2-2A>G variant.

Adenine↗
PubMed2005

Toward a neutral evolutionary model of gene expression.

We introduce a stochastic model that describes neutral changes of gene expression over evolutionary time as a compound Poisson process where evolutionary events cause changes of expression level according to a given probability distribution. The model produces simple estimators for model parameters and allows discrimination between symmetric and asymmetric distributions of evolutionary expression changes along an evolutionary lineage. Furthermore, we introduce two measures, the skewness of expression difference distributions and relative difference of evolutionary branch lengths, which are used to quantify deviation from clock-like behavior of gene expression distances. Model-based analyses of gene expression profiles in primate liver and brain samples yield the following results: (1) The majority of gene expression changes are consistent with a neutral model of evolution; (2) along evolutionary lineages, upward changes in expression are less frequent but of greater average magnitude than downward changes; and (3) the skewness measure and the relative branch length difference confirm that an acceleration of gene expression evolution occurred on the human lineage in brain but not in liver. We discuss the latter result with respect to a neutral model of transcriptome evolution and show that a small number of genes expressed in brain can account for the observed data.

Animals↗
PubMed2005

Comparative genomics and diversifying selection of the clustered vertebrate protocadherin genes.

To explain the mechanism for specifying diverse neuronal connections in the brain, Sperry proposed that individual cells carry chemoaffinity tags on their surfaces. The enormous complexity of these connections requires a tremendous diversity of cell-surface proteins. A large number of neural transmembrane protocadherin (Pcdh) proteins is encoded by three closely linked human and mouse gene clusters (alpha, beta, and gamma). To gain insight into Pcdh evolution, I performed comprehensive comparative cDNA and genomic DNA analyses for the three clusters in the chimpanzee, rat, and zebrafish genomes. I found that there are species-specific duplications in vertebrate Pcdh genes and that additional diversity is generated through alternative splicing within the zebrafish "variable" and "constant" regions. Moreover, different codons (sites) in the mammalian Pcdh ectodomains (ECs) are under diversifying selection, with some under diversity-enhancing positive Darwinian selection and others, including calcium-binding sites, under strong purifying selection. Interestingly, almost all positively selected codon positions are located on the surface of ECs 2 and 3. These diversified residues likely play an important role in combinatorial interactions of Pcdh proteins, which could provide the staggering diversity required for neuronal connections in the brain. These results also suggest that adaptive selection is an additional evolutionary factor for increasing Pcdh diversity.

Alternative Splicing↗
PubMed2005

Fixation of the human-specific CMP-N-acetylneuraminic acid hydroxylase pseudogene and implications of haplotype diversity for human evolution.

The human CMP-N-acetylneuraminic acid hydroxylase gene (CMAH) suffered deletion of an exon that encodes an active center for the enzyme approximately 3.2 million years ago (MYA). We analyzed a 7.3-kb intronic region of 132 CMAH genes to explore the fixation process of this pseudogene and the demographic implication of its haplotype diversity. Fifty-six variable sites were sorted into 18 different haplotypes with significant linkage disequilibrium. Despite the rather low nucleotide diversity, the most recent common ancestor at CMAH dates to 2.9 MYA. This deep genealogy follows shortly after the original exon deletion, indicating that the deletion has fixed in the population, although whether this fixation was facilitated by natural selection remains to be resolved. Remarkable features are exceptionally long persistence of two lineages and the confinement of one lineage in Africa, implying that some African local populations were in relative isolation while others were directly involved in multiple African exoduses of the genus Homo. Importantly, haplotypes found in Eurasia suggest interbreeding between then-contemporaneous human species. Although population structure within Africa complicates the interpretation of phylogeographic information of haplotypes, the data support a single origin of modern humans, but not with complete replacement of archaic inhabitants by modern humans.

Animals↗
PubMed1985

Flow cytometric characterization of normal and variant cells with monoclonal antibodies specific for glycophorin A.

Quantitative immunofluorescence measurements were performed on erythrocytes labeled with monoclonal antibodies to glycophorin A (GPA) to assess the level of binding of these antibodies to normal and variant cell types. The seven antibodies used in this study include two that bind preferentially to the M form of GPA, three that bind preferentially to the N form, and two that bind equally well to both. Flow cytometric analysis of mixtures of cells differing in M,N type showed binding specificities of greater than 100-fold for most of the antibodies, and showed that three antibodies bind cell-bound GPA with an affinity of approximately 10(9) M(-1). These data also showed that the level of expression of GPA varies by less than 10% from cell to cell and from individual to individual. Flow measurements were also done on human erythrocytes with the following variant forms of glycophorin: Mc, Mg, Mk, En(F), En(UK), Mi-I, Mi-II, Mi-III, S-s-U-, Tn+, and St(a+). Other cell types analyzed included erythrocytes from chimpanzee, rhesus, African green, and capuchin monkeys, and cells from the human erythroleukemia cell line, K562. Flow analysis with our seven antibodies showed these cell types have distinctive labeling patterns consistent with the known or inferred altered glycophorins presented on these cells. In most cases, variant alleles were expressed at normal levels. Our results support other observations that the variants En(UK) and St(a+) contain hybrid GPA-GPB proteins, and suggest that their level of expression is largely determined by the 3' end of the hybrid genes.

Animals↗
PubMed1993

Major histocompatibility complex class II polymorphisms in humans and chimpanzees.

Allelic variation at the MhcPatr-DR and -DQ loci was studied by molecular biological techniques and compared to available HLA data. With regard to the number of allelic lineages, the chimpanzee shows a condensation of its major histocompatibility complex (MHC) class II repertoire as compared to humans. This does not have an impact on the overall degree of MHC class II polymorphism in the chimpanzee since a few lineages that are oligomorphic in humans display an extensive degree of polymorphism in the chimpanzee.

Alleles↗
PubMed1982

Electrophoretic evidence that GLO2 is the ancestral allele at the glyoxalase-I locus in humans.

Glyoxalase-I (EC 4.4.1.5) is polymorphic in humans but not in the closely related hominoid species, Pan troglodytes (the common chimpanzee). The electrophoretic mobility of chimpanzee glyoxalase-I is identical to that of human GLO2, as is that of another Old World primate, Macaca fasicularis. These evidences suggest that GLO2 may be the ancestral allele at this locus in hominoids. The significance of the human GLO variation is discussed in the light of other recent findings showing balanced polymorphism at this locus.

Alleles↗
PubMed2004

A geometric morphometric assessment of hominoid crania: conservative African apes and their liberal implications.

This study examined the cranial affinities of all extant hominoids using 3D geometric morphometric analysis. A least squares Procrustean superimposition was used to eliminate differences due to location, orientation, and size. Because of a persistent correlation between centroid size and shape variation, an allometric size adjustment was also applied to these data. Phenetic affinities were then examined through a battery of multivariate statistical analyses. Results of this study indicate a strong affinity between Hylobates and Gorilla; Pan is also similar to these genera, while Pongo and Homo are each very different. The autapomorphic morphologies of orangutan and modern human crania have been well established from previous studies. The similarity between Hylobates and Gorilla, however, has important implications for studies of hominoid morphology. First, these results suggest that African ape crania--and particularly those of Gorilla--retain an overall morphology that is conservative among hominoids. Secondly, this similarity suggests that character coding of cranial features may tend to overestimate the degree of polymorphism among extant apes. This study concludes that allometry may play a greater role in the morphogenesis of hominoid cranial variation than has been previously thought. While this problem likely has negligible impact on systematic studies of extant hominoids, it seriously affects our ability to place fossil taxa within a phylogenetic framework.

Animals↗
PubMed2006

What do bonobos (Pan paniscus) understand about physical contact?

The present study aimed to test what bonobos (Pan paniscus) understand about contact. The task consisted of a clear horizontal tube containing a piece of food and a stick with a disk attached. The bonobos chose which side to push or pull the stick for the disk to contact the food and make it accessible. There were 9 variations in tube design, which differed in the positions of the stick, disk, and food. All 5 bonobos passed at least 1 configuration. A recent study (A. E. Helme, N. S. Clayton, & N. J. Emery, 2006) found that rooks could learn only tube configurations that provided an asymmetrical stick cue, whereas bonobos did not demonstrate an understanding of contact but showed more individual variation, attending to the positions of the food, disk, and stick.

Animals↗
PubMed1994

Levels of the genealogical hierarchy and the problem of hominoid phylogeny.

Molecular data are widely used to reconstruct phylogenetic relationships among species, and these phylogenies are often used as the basis for inferences about the history of evolutionary change in other nonmolecular characters. This approach is an appropriate and powerful one in many circumstances. But when several lineages diverge over a relatively short period of time, the assumption that a molecular (gene) tree will always be a valid basis for such inferences may not hold. Empirical evidence from humans, nonhuman primates, and other mammals indicates that the relationships among molecular divergence, morphological differentiation, and the origin of reproductive isolation between diverging lineages are complex. The simple dichotomously branching trees that result from molecular systematic studies of Homo, Gorilla, and Pan may be a misleading basis for reconstructions of evolutionary change in nonmolecular characters.

Animals↗
PubMed2003

Altered diurnal rhythm of intestinal peptide transporter by fasting and its effects on the pharmacokinetics of ceftibuten.

We previously demonstrated that H+/peptide cotransporter PEPT1 shows a diurnal rhythm in the rat small intestine. In the present study, we examined the effect of food intake on the diurnal rhythm of intestinal PEPT1 using fed and fasted rats and also determined whether such variation affected the pharmacokinetics of peptide-like drugs. In fed rats, PEPT1 protein level was significantly higher at 8:00 PM than at 8:00 AM. However, during fasting for 2 to 4 days, the differences of PEPT1 protein levels between 8:00 AM and 8:00 PM gradually disappeared. Intestinal absorption of an oral antibiotic ceftibuten (CETB), a pharmacological substrate for PEPT1, was also greater at 8:00 PM than at 8:00 AM in fed rats, but not different in 4-day fasted rats. In contrast to PEPT1 protein levels, PEPT1 mRNA levels retained a diurnal rhythm after 4 days of fasting. Pharmacokinetic analyses of CETB after intraintestinal administration demonstrated that both Cmax and area under the plasma concentration-time curve from 0 to 3 h were greater at 8:00 PM than at 8:00 AM in fed rats. In contrast, pharmacokinetic parameters showed no significant difference between 8:00 AM and 8:00 PM for intraintestinal administration in 4-day fasted rats and for intravenous administration in fed and 4-day fasted rats. These findings suggested that the diurnal rhythm of intestinal PEPT1 transport activity was disrupted by fasting and that diurnal variation of intestinal PEPT1 functionality could influence the pharmacokinetics of peptide-like drugs such as CETB.

Animals↗
PubMed2005

Joint effects between UDP-glucuronosyltransferase 1A7 genotype and dietary carcinogen exposure on risk of colon cancer.

The UDP-glucuronosyltransferase 1A7 (UGT1A7) gene is polymorphic and encodes an enzyme involved in the detoxification of heterocyclic amines (HCA) and polycyclic aromatic hydrocarbons (PAH). Consumption of pan-fried and well-done meat are surrogates for HCA and PAH exposure and are possibly associated with colon cancer. We have evaluated whether UGT1A7 allelic variations are associated with colon cancer and whether UGT1A7 genotype modified associations among meat intake, exposure to HCAs and PAHs, and colon cancer in a population-based case-control study of African Americans (197 cases and 202 controls) and whites (203 cases and 210 controls). As part of a 150-item food frequency questionnaire, meat intake was assessed by cooking method and doneness and used to estimate individual HCA and PAH exposure. UGT1A7 alleles (UGT1A7*1, UGT1A7*2, UGT1A7*3, and UGT1A7*4) were measured and genotypes were categorized into predicted activity groups (high: *1/*1, *1/*2, *2/*2; intermediate: *1/*3, *1/*4, *2/*3; low: *3/*3, *3/*4, *4/*4). There was no association with UGT1A7 low versus high/intermediate genotype [odds ratio (OR), 1.1; 95% confidence interval (95% CI), 0.7-1.8], regardless of race. Greater than additive joint effects were observed for UGT1A7 low genotype and HCA-related factors. For example, equal to or greater than the median daily intake of the HCA, 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx) and having UGT1A7 low genotype was positively associated with colon cancer (OR, 2.4; 95% CI, 1.2-4.8), compared with less than the median daily intake and UGT1A7 high/intermediate genotypes. These data suggest that the associations among cooked meat-derived compound exposure, and colon cancer are modified by the UGT1A7 genotype.

Aged↗
PubMed2026

Transposable elements as modulators of homoeologous gene expression in bread wheat: lessons from the pan-transcriptome era.

Bread wheat (Triticum aestivum L.) is an allohexaploid (AABBDD) whose three ancestral subgenomes generate complex patterns of gene regulation. Most genes exist as homoeologous triads, and the relative expression balance among copies, homoeolog expression bias, is central to polyploid evolution and adaptation. Recent high-quality assemblies, long-read transcriptomics, and pan-transcriptome resources have uncovered extensive cultivar-specific transcriptional diversity. Because transposable elements (TEs) compose over 80% of the wheat genome, they are prime candidates for shaping subgenome asymmetry. We synthesize recent pan-genomic and transcriptomic evidence, including genome-wide associations between TE insertions and genome-specific expression, and propose a unifying framework in which TEs modulate homoeolog expression by donating cis-regulatory sequences, altering chromatin states, producing small RNAs, and driving structural variation. We discuss experimental and computational challenges for establishing causality, and outline future functional and translational strategies to leverage TE-associated regulatory diversity in wheat breeding.

Triticum↗