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Biomedical subjects

J Hey

Publications and source records attributed to J Hey.

At least 19 recordsLinked to original sources
PubMed2001

The mind of the species problem.

The species problem is the long-standing failure of biologists to agree on how we should identify species and how we should define the word 'species'. The innumerable attacks on the problem have turned the often-repeated question 'what are species?' into a philosophical conundrum. Today, the preferred form of attack is the well-crafted argument, and debaters seem to have stopped inquiring about what new information is needed to solve the problem. However, our knowledge is not complete and we have overlooked something. The species problem can be overcome if we understand our own role, as conflicted investigators, in causing the problem.

Journal Article↗
PubMed2001

Human populations show reduced DNA sequence variation at the factor IX locus.

Levels and patterns of human DNA sequence variation vary widely among loci. However, some of this variation may be due to the different populations used in different studies. So far, few studies of diverse human populations have compared different genetic loci for the same samples of populations and individuals. Here, we present new polymorphism data from intron 4 of the Factor IX gene (FIX) sequenced in diverse Old World populations. An explicit comparison is made with another X-linked gene, PDHA1, for which the sampling of individuals was very similar. Despite having a similar amount of divergence from chimpanzees, as do other nuclear genes, FIX has comparatively much less DNA sequence variation among humans. Nucleotide diversity at FIX is the lowest among the existing non-Y chromosome nuclear gene datasets and is less than 10% of the diversity found at PDHA1. Estimates of effective population size based on FIX are 8,558, about half of the value obtained for PDHA1, and the time to the most recent common ancestry among human FIX gene copies (282,000 years) is one of the most recent estimates reported for human genes. Analyses presented here suggest a history for the FIX region that includes recent positive directional selection, or background, selection. The general conclusion emerging is that very large variations can exist between the histories of similar genomic regions, even when sampling differences are minimized.

Amino Acid Sequence↗
PubMed2000

The population genetics of the origin and divergence of the Drosophila simulans complex species.

The origins and divergence of Drosophila simulans and close relatives D. mauritiana and D. sechellia were examined using the patterns of DNA sequence variation found within and between species at 14 different genes. D. sechellia consistently revealed low levels of polymorphism, and genes from D. sechellia have accumulated mutations at a rate that is approximately 50% higher than the same genes from D. simulans. At synonymous sites, D. sechellia has experienced a significant excess of unpreferred codon substitutions. Together these observations suggest that D. sechellia has had a reduced effective population size for some time, and that it is accumulating slightly deleterious mutations as a result. D. simulans and D. mauritiana are both highly polymorphic and the two species share many polymorphisms, probably since the time of common ancestry. A simple isolation speciation model, with zero gene flow following incipient species separation, was fitted to both the simulans/mauritiana divergence and the simulans/sechellia divergence. In both cases the model fit the data quite well, and the analyses revealed little evidence of gene flow between the species. The exception is one gene copy at one locus in D. sechellia, which closely resembled other D. simulans sequences. The overall picture is of two allopatric speciation events that occurred quite near one another in time.

Animals↗
PubMed1999

The limits of selection during maize domestication.

The domestication of all major crop plants occurred during a brief period in human history about 10,000 years ago. During this time, ancient agriculturalists selected seed of preferred forms and culled out seed of undesirable types to produce each subsequent generation. Consequently, favoured alleles at genes controlling traits of interest increased in frequency, ultimately reaching fixation. When selection is strong, domestication has the potential to drastically reduce genetic diversity in a crop. To understand the impact of selection during maize domestication, we examined nucleotide polymorphism in teosinte branched1, a gene involved in maize evolution. Here we show that the effects of selection were limited to the gene's regulatory region and cannot be detected in the protein-coding region. Although selection was apparently strong, high rates of recombination and a prolonged domestication period probably limited its effects. Our results help to explain why maize is such a variable crop. They also suggest that maize domestication required hundreds of years, and confirm previous evidence that maize was domesticated from Balsas teosinte of southwestern Mexico.

Agriculture↗
PubMed1999

X chromosome evidence for ancient human histories.

Diverse African and non-African samples of the X-linked PDHA1 (pyruvate dehydrogenase E1 alpha subunit) locus revealed a fixed DNA sequence difference between the two sample groups. The age of onset of population subdivision appears to be about 200 thousand years ago. This predates the earliest modern human fossils, suggesting the transformation to modern humans occurred in a subdivided population. The base of the PDHA1 gene tree is relatively ancient, with an estimated age of 1.86 million years, a late Pliocene time associated with early species of Homo. PDHA1 revealed very low variation among non-Africans, but in other respects the data are consistent with reports from other X-linked and autosomal haplotype data sets. Like these other genes, but in conflict with microsatellite and mitochondrial data, PDHA1 does not show evidence of human population expansion.

Africa↗
PubMed1999

The neutralist, the fly and the selectionist.

The neutralist-selectionist debate was a staple of molecular evolution and population genetic discourse in the 1970s and 1980s. It waned thereafter, without resolution, as it has taken time to understand what DNA data can reveal about the subject. Recent developments using DNA data from Drosophila melanogaster show that natural selection is pervasive to an extent that is surprising to some former neutralists. It is now known that natural selection acts on synonymous variation, and that linkage effects between selected sites are shaping patterns of variation over large pieces of the genome.

Journal Article↗
PubMed1998

4-[(1H-imidazol-4-yl) methyl] benzamidines and benzylamidines: novel antagonists of the histamine H3 receptor.

A series of amidine substituted phenyl-, benzyl-, and phenethylimidazoles based on the known H3 agonist SK&F 91606 (4) has been synthesized and tested as ligands for the histamine H3 receptor. Insertion of a phenyl ring between the imidazole ring and the amidine moiety produces antagonists. The benzyl series was found to be the most potent and was further investigated. Compounds 9c and 18 (entries 5 and 12, Table 1) are potent ligands for the H3 receptor with K(i) values of 16 nM and 7.2 nM respectively. In vivo, both compounds were shown to be equipotent to thioperamide (2), the standard H3 antagonist.

Animals↗
PubMed1998

Selfish genes, pleiotropy and the origin of recombination.

If multiple linked polymorphisms are under natural selection, then conflicts arise and the efficiency of natural selection is hindered relative to the case of no linkage. This simple interaction between linkage and natural selection creates an opportunity for mutations that raise the level of recombination to increase in frequency and have an enhanced chance of fixation. This important finding by S. Otto and N. Barton means that mutations that raise the recombination rate, but are otherwise neutral, will be selectively favored under fairly general circumstances of multilocus selection and linkage. The effect described by Otto and Barton, which was limited to neutral modifiers, can also be extended to include all modifiers of recombination, both beneficial and deleterious. Computer simulations show that beneficial mutations that also increase recombination have an increased chance of fixation. Similarly, deleterious mutations that also decrease recombination have an increased chance of fixation. The results suggest that a simple model of recombination modifiers, including both neutral and pleiotropic modifiers, is a necessary explanation for the evolutionary origin of recombination.

Biological Evolution↗
PubMed1997

A coalescent estimator of the population recombination rate.

Population genetic models often use a population recombination parameter 4Nc, where N is the effective population size and c is the recombination rate per generation. In many ways 4Nc is comparable to 4Nu, the population mutation rate. Both combine genome level and population level processes, and together they describe the rate of production of genetic variation in a population. However, 4Nc is more difficult to estimate. For a population sample of DNA sequences, historical recombination can only be detected if polymorphisms exist, and even then most recombination events are not detectable. This paper describes an estimator of 4Nc, hereafter designated gamma (gamma), that was developed using a coalescent model for a sample of four DNA sequences with recombination. The reliability of gamma was assessed using multiple coalescent simulations. In general gamma has low to moderate bias, and the reliability of gamma is comparable, though less, than that for a widely used estimator of 4Nu. If there exists an independent estimate of the recombination rate (per generation, per base pair), gamma can be used to estimate the effective population size or the neutral mutation rate.

Genetics, Population↗
PubMed1997

Estimating ancestral population parameters.

The expected numbers of different categories of polymorphic sites are derived for two related models of population history the isolation model, in which an ancestral population splits into two descendents, and the size-change model, in which a single population undergoes an instantaneous change in size. For the isolation model, the observed numbers of shared, fixed, and exclusive polymorphic sites are used to estimate the relative sizes of the three populations, ancestral plus two descendent, as well as the time of the split. For the size change model, the numbers of sites segregating at particular frequencies in the sample are used to estimate the relative sizes of the ancestral and descendent populations plus the time the change took place. Parameters are estimated by choosing values that most closely equate expectations with observations. Computer simulations show that current and historical population parameters can be estimated accurately. The methods are applied to DNA data from two species of Drosophila and to some human mitochondrial DNA sequences.

Animals↗
PubMed1997

Gene flow and natural selection in the origin of Drosophila pseudoobscura and close relatives.

The divergence of Drosophila pseudoobscura and close relatives D. persimilis and D. pseudoobscura bogotana has been studied using comparative DNA sequence data from multiple nuclear loci. New data from the Hsp82 and Adh regions, in conjunction with existing data from Adh and the Period locus, are examined in the light of various models of speciation. The principal finding is that the three loci present very different histories, with Adh indicating large amounts of recent gene flow among the taxa, while little or no gene flow is apparent in the data from the other loci. The data were compared with predictions from several isolation models of divergence. These models include no gene flow, and they were found to be incompatible with the data. Instead the DNA data, taken together with other evidence, seem consistent with divergence models in which natural selection acts against gene flow at some loci more than at others. This family of models includes some sympatric and parapatric speciation models, as well as models of secondary contact and subsequent reinforcement of sexual isolation.

Alcohol Dehydrogenase↗
PubMed1997

Mitochondrial and nuclear genes present conflicting portraits of human origins.

Human mitochondrial DNA (mtDNA) sequences reveal an abundance of polymorphic sites in which the frequencies of the segregating bases are very different. A typical polymorphism involves one base at low frequency and the other base at high frequency. In contrast, nuclear gene data sets tend to show an excess of polymorphisms in which both segregating bases are at intermediate frequencies. A new statistical test of this difference finds significant differences between mtDNA and nuclear gene data sets reported in the literature. However, differences in the polymorphism patterns could be caused by different sample origins for the different data sets. To examine the mtDNA-nuclear difference more closely, DNA sequences were generated from a portion of the X-linked pyruvate dehydrogenase E1 alpha subunit (PDHA1) locus and from a portion of mitochondrial control region I (CRI) from each of eight individuals, four from sub-Saharan Africa. The two genes revealed a significant difference in the site frequency distribution of polymorphic sites. PDHA1 revealed an excess of intermediate-frequency polymorphisms, while CRI showed an excess of sites with the low-high frequency pattern. The discrepancy suggests that mitochondrial variation has been shaped by natural selection, and may not be ideal for some questions on human origins.

Cell Nucleus↗