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PubMed2003

Molecular population genetics of the beta-esterase gene cluster of Drosophila melanogaster.

We have investigated nucleotide polymorphism at the beta-esterase gene cluster including the Est-6 gene and psiEst-6 putative pseudogene in four samples of Drosophila melanogaster derived from natural populations of southern Africa (Zimbabwe), Europe (Spain), North America (USA: California), and South America (Venezuela). A complex haplotype structure is revealed in both Est-6 and psiEst-6. Total nucleotide diversity is twice in psiEst-6 as in Est-6; diversity is higher in the African sample than in the non-African ones. Strong linkage disequilibrium occurs within the beta-esterase gene cluster in non-African samples, but not in the African one. Intragenic gene conversion events are detected within Est-6 and, to a much greater extent, within psiEst-6; intergenic gene conversion events are rare. Tests of neutrality with recombination are significant for the beta-esterase gene cluster in the non-African samples but not significant in the African one. We suggest that the demographic history (bottleneck and admixture of genetically differentiated populations) is the major factor shaping the pattern of nucleotide polymorphism in the beta-esterase gene cluster. However there are some 'footprints' of directional and balancing selection shaping specific distribution of nucleotide polymorphism within the cluster. Intergenic epistatic selection between Est-6 and psiEst-6 may play an important role in the evolution of the beta-esterase gene cluster preserving the putative pseudogene from degenerative destruction and reflecting possible functional interaction between the functional gene and the putative pseudogene. Est-6 and psiEst-6 may represent an indivisible intergenic complex ('intergene') in which each single component (Est-6 or psiEst-6) cannot separately carry out the full functional role.

Animals↗

PubMed1999

Evolution of Mhc-DRB introns: implications for the origin of primates.

Introns are generally believed to evolve too rapidly and too erratically to be of much use in phylogenetic reconstructions. Few phylogenetically informative intron sequences are available, however, to ascertain the validity of this supposition. In the present study the supposition was tested on the example of the mammalian class II major histocompatibility complex (Mhc) genes of the DRB family. Since the Mhc genes evolve under balancing selection and are believed to recombine or rearrange frequently, the evolution of their introns could be expected to be particularly rapid and subject to scrambling. Sequences of intron 4 and 5 DRB genes were obtained from polymerase chain reaction-amplified fragments of genomic DNA from representatives of six eutherian orders-Primates, Scandentia, Chiroptera, Dermoptera, Lagomorpha, and Insectivora. Although short stretches of the introns have indeed proved to be unalignable, the bulk of the intron sequences from all six orders, spanning >85 million years (my) of evolution, could be aligned and used in a study of the tempo and mode of intron evolution. The analysis has revealed the Mhc introns to evolve at a rate similar to that of other genes and of synonymous sites of non-Mhc genes. No evidence of homogenization or large-scale scrambling of the intron sequences could be found. The Mhc introns apparently evolve largely by point mutations and insertions/deletions. The phylogenetic signals contained in the intron sequences could be used to identify Scandentia as the sister group of Primates, to support the existence of the Archonta superorder, and to confirm the monophyly of the Chiroptera.

Animals↗

PubMed2000

Ancient origin of the null allele se(428) of the human ABO-secretor locus (FUT2).

In human populations, a null allele having several nucleotide differences from the wild-type allele is segregating at the FUT2 locus (the ABO-Secretor locus) encoding alpha(1,2)fucosyltransferase. To estimate the age of the most recent common ancestor (MRCA) of these two alleles, we sequenced FUT2 homologues from chimpanzee, gorilla, orangutan, and green monkey. Since we did not detect acceleration or any heterogeneity in the substitution rate at this locus among these species, the age of the MRCA was estimated to be around 3 MYA, assuming the divergence time of human and chimpanzee to be 5 MYA. We developed a simple test to examine whether or not the old age of the MRCA of the FUT2 is consistent with that expected for two divergent neutral alleles sampled from a random mating population. An application of the test to the data at FUT2 indicated that the age of the MRCA is too old to be explained by the simple neutral assumptions, although our test depends on accurate estimation of the divergence time of human and chimpanzee in units of twice the human population size. Various possibilities including balancing selection are discussed to explain this old age of the MRCA.

ABO Blood-Group System↗

PubMed2001

Genome Evolution of the Cyanobacterium Nostoc linckia under Sharp Microclimatic Divergence at "Evolution Canyon," Israel.

We describe the genomic DNA diversity and divergence of the cyanobacterium Nostoc linckia from "Evolution Canyon," a microsite consisting of ecologically contrasting slopes, south-facing slope (SFS) and north-facing slope (NFS), at lower Nahal Oren, Mt. Carmel, Israel. The opposing slopes share their limestone lithology but vary greatly in their ecology, primarily because of different levels of solar radiation (which is six times higher on the SFS than on the NFS). The warm and xeric SFS displays a tropical African savanna, whereas the cool and mesic NFS displays a temperate South European Mediterranean live-oak maquis shrub forest. The cyanobacterium Nostoc linckia tested here is a sessile microorganism, growing as a carpet on rock surfaces and constantly exposed to environmental fluctuations of solar radiation, temperature, and desiccation. We demonstrate remarkable interslope and intraslope genetic divergence of the genome (including both coding and noncoding regions) of Nostoc linckia, by using 211 AFLP (amplified fragment length polymorphism) DNA molecular marker loci. Genetic polymorphism of N. linckia subpopulations on the ecologically harsher SFS was significantly (p <0.05) higher (p = 99.53%) than was that of the subpopulations on the climatically milder nfs (p = 85.78%). genetic polymorphism (p) and gene diversity (he) were significantly correlated with variables influencing aridity stress: solar radiation (sr) (rp = 0.956; p = 0.046), temperature (tm) (rp = 0.993; p = 0.0068), and day-night temperature difference (tdd) (rp = 0.975; p = 0.025). as in other tested organisms from "evolution canyon", but even more exceptionally because of its completely sedentary nature, we suggest that the climatically stressed sfs environment is responsible for this marked increase of genetic polymorphism, which is maintained by the combined evolutionary forces of diversifying and balancing selection. This could highlight the importance of ecological stress and selection in evolution and its remarkable effect on the genetic system across the prokaryotic genome.

Journal Article↗

PubMed2004

Gene duplication and gene conversion in class II MHC genes of New Zealand robins (Petroicidae).

In contrast to mammals, the evolution of MHC genes in birds appears to be characterized by high rates of gene duplication and concerted evolution. To further our understanding of the evolution of passerine MHC genes, we have isolated class II B sequences from two species of New Zealand robins, the South Island robin (Petroica australis australis), and the endangered Chatham Island black robin (Petroica traversi). Using an RT-PCR based approach we isolated four transcribed class II B MHC sequences from the black robin, and eight sequences from the South Island robin. RFLP analysis indicated that all class II B loci were contained within a single linkage group. Analysis of 3'-untranslated region sequences enabled putative orthologous loci to be identified in the two species, and indicated that multiple rounds of gene duplication have occurred within the MHC of New Zealand robins. The orthologous relationships are not retained within the coding region of the gene, instead the sequences group within species. A number of putative gene conversion events were identified across the length of our sequences that may account for this. Exon 2 sequences are highly diverse and appear to have diverged under balancing selection. It is also possible that gene conversion involving short stretches of sequence within exon 2 adds to this diversity. Our study is the first report of putative orthologous MHC loci in passerines, and provides further evidence for the importance of gene duplication and gene conversion in the evolution of the passerine MHC.

Amino Acid Sequence↗

PubMed2004

Recent duplication and inter-locus gene conversion in major histocompatibility class II genes in a teleost, the three-spined stickleback.

Using a bacterial artificial chromosome (BAC) library, we analysed a 99.5 kb genomic segment containing the major histocompatibility class II genes of a teleost, the three-spined stickleback Gasterosteus aculeatus. Experiments with G. aculeatus have provided direct evidence for balancing selection by pathogens and mate choice driving MH class II beta polymorphism. Two sets of paralogous class II alpha genes and beta genes in a tandem arrangement were identified, designated Gaac-DAA/DAB and Gaac-DBA/DBB. Expression analysis of the beta genes using single-strand conformation polymorphism revealed that both gene copies are expressed. Based on an analysis of pairwise nucleotide polymorphisms, we estimate that the duplication into two paralogous class II loci occurred only 1.2-2.4 million years ago, 1-2 orders of magnitude more recently than in other fish, bird or mammalian species. At the 3'-direction of the classical MH loci, we identified another seven genes or gene fragments, two of which (small inducible cytokine, complement regulatory factor) are related to immune function in other vertebrates. None of these genes were associated with MH class II genes in zebrafish, suggesting a markedly different organisation of the MH class II region in sticklebacks, and presumably, across bony fishes. When the nucleotide substitution pattern of the novel class II beta genes was analysed together with a representative sequence sample isolated from fish in northern Germany (n=27), we found that the peptide binding region of the Gaac-DAB and Gaac-DBB loci had undergone an inter-locus gene conversion (P=0.007). In accordance, we found a 10- to 20-fold higher frequency of CpG-islands on the MH class II segment compared to other species, a feature that may be conducive for inter-locus recombination.

Amino Acid Sequence↗

PubMed2006

High KIR diversity in Amerindians is maintained using few gene-content haplotypes.

Interaction between killer cell immunoglobulin-like receptors (KIR) and cognate HLA class I ligands influences the innate and adaptive immune response to infection. The KIR family varies in gene content and allelic polymorphism, thereby, distinguishing individuals and populations. KIR gene content was determined for 230 individuals from three Amerindian tribes from Venezuela: the Yucpa, Bari and Warao. Gene-content haplotypes could be assigned to 212 individuals (92%) because only five different haplotypes were present-group A and four group B. Six different haplotype combinations accounted for >80% of individuals. Each tribe has distinctive genotype frequencies. Despite few haplotypes, all 14 KIR genes are at high frequency in the three tribes, with the exception of 2DS3. Each population has an even frequency of group A and B haplotypes. Allele-level analysis of 3DL1/S1 distinguished five group A haplotypes and six group B haplotypes. The high frequency and divergence of the KIR haplotypes in the Amerindian tribes provide greater KIR diversity than is present in many larger populations. An extreme case being the Yucpa, for whom two gene-content haplotypes account for >90% of the population. These comprise the group A haplotype and a group B haplotype containing all the KIR genes, except 2DS3, that typify the group B haplotypes. Here is clear evidence for balancing selection on the KIR system and the biological importance of both A and B haplotypes for the survival of human populations.

Gene Frequency↗

PubMed2000

Mhc diversity in two passerine birds: no evidence for a minimal essential Mhc.

Humans express an array of Mhc genes, while the chicken has an Mhc that is relatively small and compact with fewer expressed genes. Here we ask whether the "minimal essential Mhc" of the chicken is representative for birds. We investigated the RFLP genotypes in 55 great reed warblers Acrocephalus arundinaceus and 10 willow warblers Phylloscopus trochilus to obtain an overview of the number of class II B genes. There were 13-17 bands per individual in the great reed warblers and 25-30 in the willow warblers, and every individual had a unique RFLP genotype. The high number of RFLP bands indicates that both species have a large number of class II B genes although some may be pseudogenes. Seven different class II B sequences were detected in a great reed warbler cDNA library. There was considerable sequence divergence between the cDNA sequences in exon 2 (peptide-binding region, PBR), whereas they were very similar in exon 3. The cDNA sequences were easily alignable to a classical chicken class II B sequence, and balancing selection was acting in the PBR. One of the cDNA sequences had two deletions and is likely nonfunctional. Finally, the polymorphic class I and class II B RFLP fragments seemed to be linked in the five studied great reed warbler families. These and previous results suggest that birds of the order Passeriformes in general have more Mhc class I and II B genes than birds of the order Galliformes. This difference could be caused by their phylogenetic past, and/or by variance in the selection pressure for maintaining a high number of Mhc genes.

Amino Acid Sequence↗

PubMed1997

Locus-specific conservation of the HLA class I introns by intra-locus homogenization.

The protein-coding sequences of the major histocompatibility complex (MHC) genes are characterized by extraordinarily high polymorphism, apparently maintained by balancing selection, which favors diversity in the peptide-binding domains of the MHC glycoproteins. Here we report that the introns flanking the polymorphic exons of the human MHC class I loci HLA-A, -B, and -C genes have been relatively conserved and have become locus-specific apparently as a result of recombination and subsequent genetic drift, leading to homogenization within loci over evolutionary time. Thus, HLA class I genes have been shaped by contrasting evolutionary forces maintaining polymorphism in the exons and leading to conservation in the introns. This study provides the first extensive analysis of the introns of a highly polymorphic gene family.

Alleles↗

PubMed2000

Characterization of hch, the Podospora anserina homolog of the het-c heterokaryon incompatibility gene of Neurospora crassa.

The het-c locus controls heterokaryon formation in Neurospora crassa. It is subject to balancing selection operating to maintain polymorphism at that locus in natural populations. We have isolated hch, the het-c homolog from the related species Podospora anserina (hch for het-c homolog), in order to determine if this gene also functions as a het gene in that species. The het-c and hch sequences are highly similar but differ in the region defining allele specificity in N. crassa het-c. Analysis of hch variability in 11 natural P. anserina isolates with different het genotypes revealed no polymorphism. This suggested that hch does not function as a het gene. However, heterologous expression of the N. crassa het-cPA allele in P. anserina triggers a growth defect reminiscent of the het-c incompatibility reaction.

Amino Acid Sequence↗

PubMed1997

High rates of polymorphism and recombination at the Opaque-2 locus in cultivated maize.

As a first step in the study of the functional consequences of molecular polymorphism at the Opaque-2 locus in maize, 1933 bp of the gene were sequenced in 21 inbred lines representative of the progenitors of cultivated varieties. High levels of polymorphism were found: 109 sites were variable in non-coding regions and 159 in protein-coding regions. Among the latter, 103 were nonsynonymous, resulting in 94 amino acid replacements in a 422-residue peptide. Moreover, 26 insertion/deletion polymorphisms were found, eight of them in coding regions. The high rate of polymorphism observed could indicate that the effective size of the ancestral population was very large, and/or that the O2 gene evolved under the influence of a high mutation rate or was subjected to some kind of balancing selection. The distribution of polymorphism within the sequence was not uniform. Silent polymorphisms were relatively frequent in exon 1 and rare in intron 5, whereas nonsynonymous polymorphisms were infrequent in the part of the sequence encoding the active domain of the transcription factor. The peptide sequence also showed a relatively higher level of resistance to amino acid replacements in this region. Sites in linkage disequilibrium were arranged mainly in three spatial patterns. This mosaic pattern can be related with an apparently large number of recombination events which might be a characteristic feature of this particular sample and/or imply that the O2 locus is a hot spot for recombination.

Base Sequence↗

PubMed2005

Human F7 sequence is split into three deep clades that are related to FVII plasma levels.

It is widely accepted that FVII levels are strongly, consistently, and independently related to cardiovascular risk. These levels are influenced by genetic and environmental factors. Among the genetic factors, only a limited number of polymorphisms in the F7 gene have been reported, and they explain only a small proportion of the genetic variability. Recently, we have accomplished the complete dissection of the F7 quantitative trait locus responsible for all of the genetic variability observed in FVII levels. Now, we present the thorough study of the haplotype organization of F7 DNA sequence variation among individuals and the evolutionary processes that produced this variation, by sequencing 15 kb of genomic DNA sequence from the F7 locus in 40 unrelated individual (80 chromosomes) from the genetic analysis of idiopathic thrombophilia (GAIT) project as well as four non-human primate species. Our study revealed 49 polymorphisms, of which 39 SNPs were further considered. Genotyping of these DNA variations in the whole family-based GAIT sample helped resolve linkage phases, and a total of 37 distinct haplotypes were identified.Tajima's D was significantly positive in this sample, suggesting balancing selection. This parameter was a reflection of the phylogenetic structure of F7 haplotype, which was deeply split into three well-supported clades or haplogroups, suggesting that functional differences among F7 variants do not depend on a few single-site variations. Moreover, haplogroup 2 was associated with high FVII levels and haplogroup 3 with low levels. In this study, we have for the first time established a clear relation between genotypic variability structure and phenotypic variability of a particular quantitative trait involved in a complex disease.

Animals↗

PubMed2001

Increased reproductive success of MHC class II heterozygous males among free-ranging rhesus macaques.

Gene conversion and balancing selection have been invoked to explain the ubiquitous diversity of the antigen-presenting proteins encoded in the vertebrate major histocompatibility complex (MHC). In the present study, direct evidence for over-dominant selection promoting MHC diversity in primates is provided by the observation that, in a large free-ranging population of rhesus macaques, males heterozygous at MHC class II locus Mamu-DQB1 sired significantly more offspring than homozygotes (the male-specific selection coefficient s equals 0.34). This heterozygote advantage appeared to be independent of the actual male Mamu-DQB1 genotype. No similar effect emerged for a captive group of monkeys of similar genetic background but under veterinary care.

Animals↗

PubMed2003

Variable continental distribution of polymorphisms in the coding regions of DNA-repair genes.

DNA-repair pathways are critical for maintaining the integrity of the genetic material by protecting against mutations due to exposure-induced damages or replication errors. Polymorphisms in the corresponding genes may be relevant in genetic epidemiology by modifying individual cancer susceptibility or therapeutic response. We report data on the population distribution of potentially functional variants in XRCC1, APEX1, ERCC2, ERCC4, hMLH1, and hMSH3 genes among groups representing individuals of European, Middle Eastern, African, Southeast Asian and North American descent. The data indicate little interpopulation differentiation in some of these polymorphisms and typical FST values ranging from 10 to 17% at others. Low FST was observed in APEX1 and hMSH3 exon 23 in spite of their relatively high minor allele frequencies, which could suggest the effect of balancing selection. In XRCC1, hMSH3 exon 21 and hMLH1 Africa clusters either with Middle East and Europe or with Southeast Asia, which could be related to the demographic history of human populations, whereby human migrations and genetic drift rather than selection would account for the observed differences.

Alleles↗

PubMed1988

Different peripheral vasodilator effects of isradipine in sodium-loaded and sodium-depleted rabbits.

1. The influence of acute changes in salt balance on the cardiovascular effects of the calcium antagonist isradipine were investigated in two groups of 6 rabbits pretreated 24 hr before an acute experiment, one by substituting 0.45% NaCl for drinking water, the other one with a subcutaneous injection of 20 mg kg-1 furosemide. 2. On the next day the animals were anaesthetized with barbiturates and 10 ml kg-1 0.9% NaCl or 5% glucose were infused into the salt loaded and salt depleted animals respectively. 3. Regional blood flows were then measured with microspheres before and after i.v. administration of 3 and 10 micrograms kg-1 isradipine (PN200-110). 4. Salt depleted animals had a lower cardiac output and lower flows to several regional vascular beds including the kidneys. 5. The isradipine effects on systemic haemodynamic variables were not different in the two groups. 6. However, the effects on regional blood flows were modified. In salt loaded animals skeletal muscle flow increased more, starting from a higher baseline, yet flow to the kidneys, pancrease and spleen was higher before and decreased significantly more after the calcium antagonist. 7. The results suggest that an alteration in the sodium balance selectively affects the mechanism responsible for vascular tone in a few vascular beds.

Animals↗

PubMed2006

Genetics of self/nonself recognition in Serpula lacrymans.

This study provides an analysis of the vegetative incompatibility system in Serpula lacrymans (Basidiomycota), a genetic system used to recognize nonself in fungi. Seventy-five worldwide isolates could be grouped into eight vegetative compatibility (VC) types, some of them distributed on different continents. Mating studies combined with vegetative incompatibility analyses revealed that the vegetative incompatibility response between isolates mainly could be explained by two biallelic vegetative incompatibility (vic) loci. The frequency distributions of the interpreted vic alleles do not seem to support the idea of frequency-dependent or balancing selection acting on the vic loci. We find little genetic variation at the vic loci and in one of the loci there was a significant heterozyote deficiency among strains in the overall material. The results may be explained by a recent worldwide dispersal of a few S. lacrymans isolates and, correspondingly, only a few vic alleles are being maintained in these populations.

Basidiomycota↗

PubMed2004

HLA DRB1* and DQB1* allelic diversity among Nadars: a primitive south Indian Dravidian caste group.

South India is one of the oldest geophysical regions occupied mainly by Dravidian language-speaking people. In the present study, 84 unrelated healthy Nadar individuals from Tamil Nadu State were analyzed for human leukocyte antigen (HLA) DRB1* and DQB1* allele frequencies and their haplotype frequencies were analyzed by high resolution polymerase chain reaction (PCR)-typing of genomic DNA. Results revealed that Nadars possessed >0.1 allele frequencies of HLA DRB1*15011, 03, 04, 1404, 0701, 1001, and DQB1*0201, 03, 0501, and 0503. The highest frequencies of DRB1*0317 (0.048), DRB1*1317 (0.012), and DRB1*1404 (0.107) in the world were found among the Nadar caste. The most frequent two-locus haplotypes identified among the Nadars were DRB1*0701-DQB1*0201 and DRB1*1000-DQB1*0501, and DRB1*1404-DQB1*0503 and DRB1*15011-DQB1*0601. When compared with world populations, HLA DRB1*1322, DRB1*1434, and DQB1*0614 were identified exclusively among Nadars. The heterozygosity and Watterson's homozygosity tests indicated that balancing selection still operates among the South Indian caste groups. The hierarchical cluster analysis for DRB1 data from the Indian caste and population groups showed that the Nadars cluster with Kashmir Brahmins and North Indians. The present study shows that the Nadar caste has several unique alleles and haplotypes at high frequency that are rare or absent in other populations of India and the world.

DNA Fingerprinting↗

PubMed2006

Atypical antipsychotics in bipolar depression: neurobiological basis and clinical implications.

The use of atypical antipsychotics is rapidly expanding in the management of bipolar disorder. This therapeutic class appears to have benefits across the spectrum of moods found in bipolar disorder, and a re-examination of the monoamine hypothesis is required. This paper reviews the evidence for the role of monoamines, and particularly dopamine, in bipolar depression and its implications in the treatment of patients, focusing upon the response to atypical antipsychotics. Relevant papers were identified undertaking a literature search using PubMed: preclinical and clinical studies that incriminate the dopaminergic system in bipolar depression, and recent controlled trials supporting the use of atypical antipsychotics, are reviewed. There is substantial evidence indicating that not only serotonin, but also dopamine may still play an important role as a mediator of antidepressant response in bipolar depression. A regionally selective balance between the dopamine and serotonin systems may account for the mood-stabilizing properties of these drugs, and in fact, a low D(2) occupancy might be more relevant to bipolar depression than greater 5-HT(2) action. This mechanism might correlate with the ability to induce neurogenetic effects. Hence, the greater the atypical profile, the more suitable for bipolar depression. Further studies are needed to confirm this hypothesis.

Antipsychotic Agents↗