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PubMed2004

Membrane lipids of symbiotic algae are diagnostic of sensitivity to thermal bleaching in corals.

Over the past three decades, massive bleaching events of zooxanthellate corals have been documented across the range of global distribution. Although the phenomenon is correlated with relatively small increases in sea-surface temperature and enhanced light intensity, the underlying physiological mechanism remains unknown. In this article we demonstrate that thylakoid membrane lipid composition is a key determinate of thermal-stress sensitivity in symbiotic algae of cnidarians. Analyses of thylakoid membranes reveal that the critical threshold temperature separating thermally tolerant from sensitive species of zooxanthellae is determined by the saturation of the lipids. The lipid composition is potentially diagnostic of the differential nature of thermally induced bleaching found in scleractinian corals. Measurements of variable chlorophyll fluorescence kinetic transients indicate that thermally damaged membranes are energetically uncoupled but remain capable of splitting water. Consequently, a fraction of the photosynthetically produced oxygen is reduced by photosystem I through the Mehler reaction to form reactive oxygen species, which rapidly accumulate at high irradiance levels and trigger death and expulsion of the endosymbiotic algae. Differential sensitivity to thermal stress among the various species of Symbiodinium seems to be distributed across all clades. A clocked molecular phylogenetic analysis suggests that the evolutionary history of symbiotic algae in cnidarians selected for a reduced tolerance to elevated temperatures in the latter portion of the Cenozoic.

Animals↗
PubMed2002

Analysis of a library of macaque nuclear mitochondrial sequences confirms macaque origin of divergent sequences from old oral polio vaccine samples.

Nuclear mtDNA sequences (numts) are a widespread family of paralogs evolving as pseudogenes in chromosomal DNA [Zhang, D. E. & Hewitt, G. M. (1996) TREE 11, 247-251 and Bensasson, D., Zhang, D., Hartl, D. L. & Hewitt, G. M. (2001) TREE 16, 314-321]. When trying to identify the species origin of an unknown DNA sample by way of an mtDNA locus, PCR may amplify both mtDNA and numts. Indeed, occasionally numts dominate confounding attempts at species identification [Bensasson, D., Zhang, D. X. & Hewitt, G. M. (2000) Mol. Biol. Evol. 17, 406-415; Wallace, D. C., et al. (1997) Proc. Natl. Acad. Sci. USA 94, 14900-14905]. Rhesus and cynomolgus macaque mtDNA haplotypes were identified in a study of oral polio vaccine samples dating from the late 1950s [Blancou, P., et al. (2001) Nature (London) 410, 1045-1046]. They were accompanied by a number of putative numts. To confirm that these putative numts were of macaque origin, a library of numts corresponding to a small segment of 12S rDNA locus has been made by using DNA from a Chinese rhesus macaque. A broad distribution was found with up to 30% sequence variation. Phylogenetic analysis showed that the evolutionary trajectories of numts and bona fide mtDNA haplotypes do not overlap with the signal exception of the host species; mtDNA fragments are continually crossing over into the germ line. In the case of divergent mtDNA sequences from old oral polio vaccine samples [Blancou, P., et al. (2001) Nature (London) 410, 1045-1046], all were closely related to numts in the Chinese macaque library.

Animals↗
PubMed1989

Evolutionary conserved modules associated with zinc fingers in Xenopus laevis.

Many DNA-binding proteins that are involved in the differential regulation of gene expression are composed of multiple discrete modules. Association of the homeobox-encoded helix-turn-helix DNA-binding motif with conserved modules, such as the paired box or the POU domain, has led to the definition of structurally and functionally related subfamilies of regulatory proteins. The zinc finger, which is the second major nucleic acid-binding motif characterized to date, defines large multigene families in higher eukaryotes; we have isolated more than 100 Xenopus finger protein-encoding cDNAs and in this study we show that at least 10 of these clones share extensive sequence homologies in a region of more than 200 amino acids in the N-terminal nonfinger portion of the predicted proteins, which is connected to variable finger clusters. We refer to this element as a finger-associated boxes (FAX) domain. Cross-hybridization with human genomic DNA indicates that the finger-associated boxes domain is evolutionary conserved. Northern blot analysis shows that the corresponding genes are differentially expressed in the course of early Xenopus embryogenesis.

Amino Acid Sequence↗
PubMed1993

Phosducin-like protein: an ethanol-responsive potential modulator of guanine nucleotide-binding protein function.

Acute and chronic exposure to ethanol produces specific changes in several signal transduction cascades. Such alterations in signaling are thought to be a crucial aspect of the central nervous system's adaptive response, which occurs with chronic exposure to ethanol. We have recently identified and isolated several genes whose expression is specifically induced by ethanol in neural cell cultures. The product of one of these genes has extensive sequence homology to phosducin, a phosphoprotein expressed in retina and pineal gland that modulates trimeric guanine nucleotide-binding protein (G protein) function by binding to G-protein beta gamma subunits. We identified from a rat brain cDNA library an isolate encoding the phosducin-like protein (PhLP), which has 41% identity and 65% amino acid homology to phosducin. PhLP cDNA is expressed in all tissues screened by RNA blot-hybridization analysis and shows marked evolutionary conservation on Southern hybridization. We have identified four forms of PhLP cDNA varying only in their 5' ends, probably due to alternative splicing. This 5'-end variation generates two predicted forms of PhLP protein that differ by 79 aa at the NH2 terminus. Treatment of NG108-15 cells for 24 hr with concentrations of ethanol seen in actively drinking alcoholics (25-100 mM) causes up to a 3-fold increase in PhLP mRNA levels. Induction of PhLP by ethanol could account for at least some of the widespread alterations in signal transduction and G-protein function that are known to occur with chronic exposure to ethanol.

Amino Acid Sequence↗
PubMed1993

Evolution of nuclear ribosomal RNAs in kinetoplastid protozoa: perspectives on the age and origins of parasitism.

Molecular evolutionary relationships within the protozoan order Kinetoplastida were deduced from comparisons of the nuclear small and large subunit ribosomal RNA (rRNA) gene sequences. These studies show that relationships among the trypanosomatid protozoans differ from those previously proposed from studies of organismal characteristics or mitochondrial rRNAs. The genera Leishmania, Endotrypanum, Leptomonas, and Crithidia form a closely related group, which shows progressively more distant relationships to Phytomonas and Blastocrithidia, Trypanosoma cruzi, and lastly Trypanosoma brucei. The rooting of the trypanosomatid tree was accomplished by using Bodo caudatus (family Bodonidae) as an outgroup, a status confirmed by molecular comparisons with other eukaryotes. The nuclear rRNA tree agrees well with data obtained from comparisons of other nuclear genes. Differences with the proposed mitochondrial rRNA tree probably reflect the lack of a suitable outgroup for this tree, as the topologies are otherwise similar. Small subunit rRNA divergences within the trypanosomatids are large, approaching those among plants and animals, which underscores the evolutionary antiquity of the group. Analysis of the distribution of different parasitic life-styles of these species in conjunction with a probable timing of evolutionary divergences suggests that vertebrate parasitism arose multiple times in the trypanosomatids.

Animals↗
PubMed1995

Mg-SINE: a short interspersed nuclear element from the rice blast fungus, Magnaporthe grisea.

A short interspersed nuclear element, Mg-SINE, was isolated and characterized from the genome of the rice blast fungus, Magnaporthe grisea. Mg-SINE was isolated as an insertion element within Pot2, an inverted-repeat transposon from M. grisea and shows typical features of a mammalian SINE. Mg-SINE is present as a 0.47-kb interspersed sequence at approximately 100 copies per haploid genome in both rice and non-rice isolates of M. grisea, indicating a common evolutionary origin. Secondary structure analysis of Mg-SINE revealed a tRNA-related region at the 5' end which folds into a cloverleaf structure. Genomic fusions resulting in chimeric Mg-SINEs (Ch-SINEs) composed of a sequence homologous to Mg-SINE at the 3' end and an unrelated sequence at its 5' end were also isolated, indicating that this and other DNA rearrangements mediated by these elements may have a major effect on the genomic architecture of this fungus.

Ascomycota↗
PubMed2000

mtDNA variation in the South African Kung and Khwe-and their genetic relationships to other African populations.

The mtDNA variation of 74 Khoisan-speaking individuals (Kung and Khwe) from Schmidtsdrift, in the Northern Cape Province of South Africa, was examined by high-resolution RFLP analysis and control region (CR) sequencing. The resulting data were combined with published RFLP haplotype and CR sequence data from sub-Saharan African populations and then were subjected to phylogenetic analysis to deduce the evolutionary relationships among them. More than 77% of the Kung and Khwe mtDNA samples were found to belong to the major mtDNA lineage, macrohaplogroup L* (defined by a HpaI site at nucleotide position 3592), which is prevalent in sub-Saharan African populations. Additional sets of RFLPs subdivided macrohaplogroup L* into two extended haplogroups-L1 and L2-both of which appeared in the Kung and Khwe. Besides revealing the significant substructure of macrohaplogroup L* in African populations, these data showed that the Biaka Pygmies have one of the most ancient RFLP sublineages observed in African mtDNA and, thus, that they could represent one of the oldest human populations. In addition, the Kung exhibited a set of related haplotypes that were positioned closest to the root of the human mtDNA phylogeny, suggesting that they, too, represent one of the most ancient African populations. Comparison of Kung and Khwe CR sequences with those from other African populations confirmed the genetic association of the Kung with other Khoisan-speaking peoples, whereas the Khwe were more closely linked to non-Khoisan-speaking (Bantu) populations. Finally, the overall sequence divergence of 214 African RFLP haplotypes defined in both this and an earlier study was 0.364%, giving an estimated age, for all African mtDNAs, of 125,500-165,500 years before the present, a date that is concordant with all previous estimates derived from mtDNA and other genetic data, for the time of origin of modern humans in Africa.

Black People↗
PubMed2006

Using hidden Markov models and observed evolution to annotate viral genomes.

MOTIVATION: ssRNA (single stranded) viral genomes are generally constrained in length and utilize overlapping reading frames to maximally exploit the coding potential within the genome length restrictions. This overlapping coding phenomenon leads to complex evolutionary constraints operating on the genome. In regions which code for more than one protein, silent mutations in one reading frame generally have a protein coding effect in another. To maximize coding flexibility in all reading frames, overlapping regions are often compositionally biased towards amino acids which are 6-fold degenerate with respect to the 64 codon alphabet. Previous methodologies have used this fact in an ad hoc manner to look for overlapping genes by motif matching. In this paper differentiated nucleotide compositional patterns in overlapping regions are incorporated into a probabilistic hidden Markov model (HMM) framework which is used to annotate ssRNA viral genomes. This work focuses on single sequence annotation and applies an HMM framework to ssRNA viral annotation. A description of how the HMM is parameterized, whilst annotating within a missing data framework is given. A Phylogenetic HMM (Phylo-HMM) extension, as applied to 14 aligned HIV2 sequences is also presented. This evolutionary extension serves as an illustration of the potential of the Phylo-HMM framework for ssRNA viral genomic annotation. RESULTS: The single sequence annotation procedure (SSA) is applied to 14 different strains of the HIV2 virus. Further results on alternative ssRNA viral genomes are presented to illustrate more generally the performance of the method. The results of the SSA method are encouraging however there is still room for improvement, and since there is overwhelming evidence to indicate that comparative methods can improve coding sequence (CDS) annotation, the SSA method is extended to a Phylo-HMM to incorporate evolutionary information. The Phylo-HMM extension is applied to the same set of 14 HIV2 sequences which are pre-aligned. The performance improvement that results from including the evolutionary information in the analysis is illustrated.

Algorithms↗
PubMed2003

Dntf-2r, a young Drosophila retroposed gene with specific male expression under positive Darwinian selection.

A direct approach to investigating new gene origination is to examine recently evolved genes. We report a new gene in the Drosophila melanogaster subgroup, Drosophila nuclear transport factor-2-related (Dntf-2r). Its sequence features and phylogenetic distribution indicate that Dntf-2r is a retroposed functional gene and originated in the common ancestor of D. melanogaster, D. simulans, D. sechellia, and D. mauritiana, within the past 3-12 million years (MY). Dntf-2r evolved more rapidly than the parental gene, under positive Darwinian selection as revealed by the McDonald-Kreitman test and other evolutionary analyses. Comparative expression analysis shows that Dntf-2r is male specific whereas the parental gene, Dntf-2, is widely expressed in D. melanogaster. In agreement with its new expression pattern, the Dntf-2r putative promoter sequence is similar to the late testis promoter of beta2-tubulin. We discuss the possibility that the action of positive selection in Dntf-2r is related to its putative male-specific functions.

Animals↗
PubMed2003

Functional antifreeze glycoprotein genes in temperate-water New Zealand nototheniid fish infer an Antarctic evolutionary origin.

The fish fauna of the Antarctic Ocean is dominated by five endemic families of the Perciform suborder Notothenioidei, thought to have arisen in situ within the Antarctic through adaptive radiation of an ancestral stock that evolved antifreeze glycoproteins (AFGPs) enabling survival as the ocean chilled to subzero temperatures. The endemism results from geographic confinement imposed by a massive oceanographic barrier, the Antarctic Circumpolar Current, which also thermally isolated Antarctica over geologic time, leading to its current frigid condition. Despite this voluminous barrier to fish dispersal, a number of species from the Antarctic family Nototheniidae now inhabit the nonfreezing cool temperate coasts of the southern continents. The origin of these temperate-water nototheniids is not completely understood. Since the AFGP gene apparently evolved only once, before the Antarctic notothenioid radiation, the presence of AFGP genes in extant temperate-water nototheniids can be used to infer an Antarctic evolutionary origin. Genomic Southern analysis, PCR amplification of AFGP genes, and sequencing showed that Notothenia angustata and Notothenia microlepidota endemic to southern New Zealand have two to three AFGP genes, structurally the same as those of the Antarctic nototheniids. At least one of these genes is still functional, as AFGP cDNAs were obtained and low levels of mature AFGPs were detected in the blood. A phylogenetic tree based on complete ND2 coding sequences showed monophyly of these two New Zealand nototheniids and their inclusion in the monophyletic Nototheniidae consisted of mostly AFGP-bearing taxa. These analyses support an Antarctic ancestry for the New Zealand nototheniids. A divergence time of approximately 11 Myr was estimated for the two New Zealand nototheniids, approximating the upper Miocene northern advance of the Antarctic Convergence over New Zealand, which might have served as the vicariant event that lead to the northward dispersal of their most recent common ancestor. Similar secondary northward dispersal likely applies to the South American nototheniid Paranotothenia magellanica, which has four AFGP genes in its DNA, but not to the sympatric nototheniid Patagonotothen tessellata, which does not appear to have any AFGP sequences in its genome at all.

Amino Acid Sequence↗
PubMed1995

Insect lysozyme from house fly (Musca domestica) larvae: possible digestive function based on sequence and enzymatic properties.

Lysozyme was purified from the homogenate of the whole body of house fly (Musca domestica) larvae by standard chromatographic techniques. The purified lysozyme was sequenced and its enzymatic properties were examined. This lysozyme was a chicken-type lysozyme composed of 122 amino acids, showing about 75% identity with fruit fly lysozymes and 38% with human lysozyme. This enzyme was inactive towards Micrococcus luteus and under the physiological conditions of PH 7.0 and ionic strength 0.1, but was as active toward glycol chitin as was hen lysozyme. The pH-dependent profile of lytic activity towards M. luteus showed that house fly lysozyme has an acidic pH optimum and shows no enzymatic activity above Ph 7. These features are analogous with those of ruminant stomach lysozymes which have evolved for the digestive function, suggesting that this lysozyme does not function as a self-defense protein, like hen and human lysozyme, but as a digestive enzyme, probably in the gut of the insect body. Although a similar functional conversion to digestive enzyme was reported in fruit fly, phylogenetic tree analysis indicates that the evolutionary change of lysozyme to a digestive enzyme occurred similarly in fruit fly and house fly, but the events are not related and occurred independently in each strain. This observation is in contrast with the case of ruminant stomach lysozymes, which were recruited before the divergence of each species of ruminants.

Amino Acid Sequence↗
PubMed2001

Coevolution of the domains of cytoplasmic tyrosine kinases.

Many signaling molecules are multidomain proteins that have other domains in addition to the catalytic kinase domain. Protein tyrosine kinases almost without exception contain Src homology 2 (SH2) and/or SH3 domains that can interact with other signaling proteins. Here, we studied evolution of the tyrosine kinases containing SH2 and/or SH3 and kinase domains. The three domains seem to have duplicated together, since the phylogenetic analysis using parsimony gave almost identical evolutionary trees for the separate domains and the multidomain complexes. The congruence analysis of the sequences for the separate domains also suggested that the domains have coevolved. There are several reasons for the domains to appear in a cluster. Kinases are regulated in many ways, and the presence of SH2 and SH3 domains at proper positions is crucial. Because all three domains can recognize different parts of ligands and substrates, their evolution has been interconnected. The reasons for the clustering and coevolution of the three domains in protein tyrosine kinases (PTKs) are discussed.

Amino Acid Sequence↗
PubMed2000

Molecular evolution of the Paramyxoviridae and Rhabdoviridae multiple-protein-encoding P gene.

Presented here is an analysis of the molecular evolutionary dynamics of the P gene among 76 representative sequences of the Paramyxoviridae and Rhabdoviridae RNA virus families. In a number of Paramyxoviridae taxa, as well as in vesicular stomatitis viruses of the Rhabdoviridae, the P gene encodes multiple proteins from a single genomic RNA sequence. These products include the phosphoprotein (P), as well as the C and V proteins. The complexity of the P gene makes it an intriguing locus to study from an evolutionary perspective. Amino acid sequence alignments of the proteins encoded at the P and N loci were used in independent phylogenetic reconstructions of the Paramyxoviridae and Rhabdoviridae families. P-gene-coding capacities were mapped onto the Paramyxoviridae phylogeny, and the most parsimonious path of multiple-coding-capacity evolution was determined. Levels of amino acid variation for Paramyxoviridae and Rhabdoviridae P-gene-encoded products were also analyzed. Proteins encoded in overlapping reading frames from the same nucleotides have different levels of amino acid variation. The nucleotide architecture that underlies the amino acid variation was determined in order to evaluate the role of selection in the evolution of the P gene overlapping reading frames. In every case, the evolution of one of the proteins encoded in the overlapping reading frames has been constrained by negative selection while the other has evolved more rapidly. The integrity of the overlapping reading frame that represents a derived state is generally maintained at the expense of the ancestral reading frame encoded by the same nucleotides. The evolution of such multicoding sequences is likely a response by RNA viruses to selective pressure to maximize genomic information content while maintaining small genome size. The ability to evolve such a complex genomic strategy is intimately related to the dynamics of the viral quasispecies, which allow enhanced exploration of the adaptive landscape.

Evolution, Molecular↗
PubMed1986

A comparison of the small ribosomal RNA genes from the mitochondrial DNA of the great apes and humans: sequence, structure, evolution, and phylogenetic implications.

Restriction endonuclease fragments produced by EcoRI/AvaI or KpnI digestion and containing the small (12S) ribosomal RNA (rRNA) genes from the mitochondrial DNAs (mtDNAs) of the common chimpanzee, pygmy chimpanzee, gorilla, and orangutan were inserted into the plasmids pBR322 or pADD1. After species verification the inserted fragments were digested with SauIIIA, subcloned into M13mp7 vectors, and sequenced. The small rRNA gene sequences were compared with each other and with the published human sequence (Anderson et al. 1981). Substitutions were detected at 118 of the 955 nucleotide positions compared. Pairwise, the sequence differences ranged from 1% (between the chimpanzee species) to 9% (comparisons involving the orangutan); the proportion that were transitions ranged from 87% to 100%. Deletions and/or additions were noted at seven locations. With respect to evolutionary sequence lability, kinetic analysis indicated the presence of at least two classes of nucleotide positions; the more labile class occurs in sequences thought to form self-complementary duplexes (stems) in the mature rRNA. The high frequency of compensating substitutions, which maintain base-pairing within these sequences, corroborates their inferred structure. Phylogenetic inferences drawn from the sequence comparisons support the notion of an approximately equidistant relationship among chimpanzees, gorilla, and man, with the orangutan much less closely related. However, inference from a shared deletion suggests that the gorilla and the chimpanzees may be more closely related to one another than they are to man.

Animals↗
PubMed2005

Molecular characterization and origin of novel bipartite cold-regulated ice recrystallization inhibition proteins from cereals.

To understand the molecular basis of freezing tolerance in plants, several low temperature-responsive genes have been identified from wheat. Among these are two genes named TaIRI-1 and TaIRI-2 (Triticum aestivum ice recrystallization inhibition) that are up-regulated during cold acclimation in freezing-tolerant species. Phytohormones involved in pathogen defense pathways (jasmonic acid and ethylene) induce the expression of one of the two genes. The encoded proteins are novel in that they have a bipartite structure that has never been reported for antifreeze proteins. Their N-terminal part shows similarity with the leucine-rich repeat-containing regions present in the receptor domain of receptor-like protein kinases, and their C-terminus is homologous to the ice-binding domain of some antifreeze proteins. The recombinant TaIRI-1 protein inhibits the growth of ice crystals, confirming its function as an ice recrystallization inhibition protein. The TaIRI genes were found only in the species belonging to the Pooideae subfamily of cereals. Comparative genomic analysis suggested that molecular evolutionary events took place in the genome of freezing-tolerant cereals to give rise to these genes with putative novel functions. These apparent adaptive DNA rearrangement events could be part of the molecular mechanisms that ensure the survival of hardy cereals in the harsh freezing environments.

Acclimatization↗
PubMed2002

Sequence analysis of Potato leafroll virus isolates reveals genetic stability, major evolutionary events and differential selection pressure between overlapping reading frame products.

In order to investigate the genetic diversity of Potato leafroll virus (PLRV), seven new complete genomic sequences of isolates collected worldwide were compared with the five sequences available in GenBank. Then, a restricted polymorphic region of the genome was chosen to further analyse new sequences. The sequences of PLRV open reading frames (ORFs) 3 and 4 were also compared with those of two other poleroviruses and the non-synonymous to synonymous substitution ratio distribution was analysed in overlapping and non-overlapping regions of the genome using maximum-likelihood models. Results confirmed that PLRV sequences from around the world are very closely related and showed that the region encoding protein P0 allowed the detection of three groups of isolates. When compared to other poleroviruses, PLRV was the most conserved in both ORFs 3 and 4. However, the results suggest that important events, such as deletion, mutation at a stop codon and intraspecific homologous recombination events, have occurred during the evolution of PLRV. Finally, it was shown that the translation products of ORFs 0 and 3 are significantly more conserved than those of the overlapping ORFs 1 and 4, respectively. All together, the results allow the proposal of new hypotheses to explain the apparent genetic stability of PLRV and its evolution.

Biological Evolution↗
PubMed1991

Cloning and DNA sequence analysis of the serC-aroA operon from Salmonella gallinarum; evolutionary relationships between the prokaryotic and eukaryotic aroA-encoded enzymes.

The serC-aroA operon of Salmonella gallinarum was isolated from a gene library using a labelled oligonucleotide probe and by complementation of an aroA Escherichia coli strain. The nucleotide sequence of a 2.6 kbp fragment was determined. The predicted amino acid sequence of the aroA gene product was compared to the equivalent sequence from ten other organisms. Computer-generated evolutionary trees clearly divide the eleven sequences into four different groups: Gram-negative bacteria, Gram-positive bacteria, fungi and plants. These trees depict a close evolutionary relationship between the sequences from Gram-negative bacteria and higher plants.

3-Phosphoshikimate 1-Carboxyvinyltransferase↗
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↗