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PubMed2003

Nucleotide variation, haplotype structure, and association with end-stage renal disease of the human interleukin-1 gene cluster.

A dense gene-based SNP map was constructed across a 360-kb region containing the interleukin-1 gene cluster (IL1A, IL1B, and IL1RN), focusing on IL1RN. In total, 95 polymorphisms were confirmed or identified primarily by direct sequencing. Polymorphisms were precisely mapped to completed BAC and genomic sequences spanning this region. The polymorphisms were typed in 443 case-control subjects from Caucasian and African American groups. Consecutive pair-wise marker linkage disequilibrium was not strictly correlated with distance and ranged from D'=0.0079 to 1.000 and D'=0.0521 to 1.0000 in Caucasians and African Americans, respectively. Single markers and haplotypes in IL1 cluster genes were evaluated for association with end-stage renal disease (ESRD). Eleven SNPs show some evidence of association with ESRD, with the strongest associations in two IL1A variants, one SNP, rs1516792-3, in intron 5 (p=0.0015) and a 4-bp insertion/deletion within the 3'UTR, rs16347-2 (p=0.0024), among African Americans with non-T2DM-associated ESRD.

Black or African American↗
PubMed2003

Genomic analysis in the sting-2 quantitative trait locus for defensive behavior in the honey bee, Apis mellifera.

We have sequenced an 81-kb genomic region from the honey bee, Apis mellifera, associated with a quantitative trait locus (QTL) sting-2 for aggressive behavior. This sequence represents the first extensive study of the honey-bee genome structure encompassing putative genes in a QTL for a behavioral trait. Expression of 13 putative genes, as well as two transcripts that were present in a honey-bee EST database, was confirmed through reverse transcription analysis of mRNA from the honey-bee head. Whereas most transcripts exhibited little or no variation between European and Africanized honey-bee alleles, one transcript demonstrated significant nonsynonymous substitutions, deletions, and insertions. All 13 putative genes lacked similarity to known invertebrate or vertebrate proteins or transcripts. This observation may be reflective of the processes that determine the genomic evolution of an insect with social behavior and/or haplo-diploidy and are an indication of the unique nature of the honey-bee genome. These results make this sequence an invaluable research tool for the ongoing honey-bee whole-genome sequencing effort.

Animals↗
PubMed1993

African and North American populations of Drosophila melanogaster are very different at the DNA level.

Understanding genetic evolution within species requires an accurate description of variation within and between populations and the ability to distinguish between the potential causes of an observed distribution of variation. In the cosmopolitan species Drosophila melanogaster, previous studies suggested that gene flow within and between continents is extensive and that most of the nuclear gene variation is found within, rather than among, populations. Here we present evidence that a population from Zimbabwe is more than twice as variable as those from the United States of America at the DNA sequence level, that most variants are not shared between the two geographic regions, and that there are nearly fixed differences between the Zimbabwe and USA samples in genomic regions experiencing low recombination rates. It appears that there is an unappreciated degree of population structure in D. melanogaster and that equilibrium models of molecular evolution are inappropriate for this species.

Animals↗
PubMed2006

Application of genome-wide single nucleotide polymorphism typing: simple association and beyond.

The International HapMap Project and the arrival of technologies that type more than 100,000 SNPs in a single experiment have made genome-wide single nucleotide polymorphism (GW-SNP) assay a realistic endeavor. This has sparked considerable debate regarding the promise of GW-SNP typing to identify genetic association in disease. As has already been shown, this approach has the potential to localize common genetic variation underlying disease risk. The data provided from this technology also lends itself to several other lines of investigation; autozygosity mapping in consanguineous families and outbred populations, direct detection of structural variation, admixture analysis, and other population genetic approaches. In this review we will discuss the potential uses and practical application of GW-SNP typing including those above and beyond simple association testing.

Chromosomes, Human↗
PubMed2024

Phased telomere-to-telomere reference genome and pangenome reveal an expansion of resistance genes during apple domestication.

The cultivated apple (Malus domestica Borkh.) is a cross-pollinated perennial fruit tree of great economic importance. Earlier versions of apple reference genomes were unphased, fragmented, and lacked comprehensive insights into the apple's highly heterozygous genome, which impeded advances in genetic studies and breeding programs. In this study, we assembled a haplotype-resolved telomere-to-telomere (T2T) reference genome for the diploid apple cultivar Golden Delicious. Subsequently, we constructed a pangenome based on 12 assemblies from wild and cultivated species to investigate the dynamic changes of functional genes. Our results revealed the gene gain and loss events during apple domestication. Compared with cultivated species, more gene families in wild species were significantly enriched in oxidative phosphorylation, pentose metabolic process, responses to salt, and abscisic acid biosynthesis process. Our analyses also demonstrated a higher prevalence of different types of resistance gene analogs (RGAs) in cultivars than their wild relatives, partially attributed to segmental and tandem duplication events in certain RGAs classes. Structural variations, mainly deletions and insertions, have affected the presence and absence of TIR-NB-ARC-LRR, NB-ARC-LRR, and CC-NB-ARC-LRR genes. Additionally, hybridization/introgression from wild species has also contributed to the expansion of resistance genes in domesticated apples. Our haplotype-resolved T2T genome and pangenome provide important resources for genetic studies of apples, emphasizing the need to study the evolutionary mechanisms of resistance genes in apple breeding.

Malus↗
PubMed2025

The landscape of structural variation in pediatric cancer.

Structural variants (SVs) account for over 60% of the driver variants in pediatric cancer, and in many cases act as the cancer initiating event. To study SVs from a pan-cancer perspective, we analyzed 1,616 pediatric cancer genomes in 16 major cancer types of hematological malignancies (n = 908), brain tumors (n = 183), and solid tumors (n = 525) and compared their profiles to those of 2,203 adult cancers. The SV burden varied ~100-fold across pediatric cancer types and demonstrated an 8- to 16-fold reduction compared to adult brain and solid tumors but was comparable in pediatric versus adult hematological malignancies. Recurrent SV hotspots occurred uniquely in pediatric acute lymphoblastic leukemias (ALLs) in proximity to RAG-mediated recombination signal sequences (RSS) and disrupted multiple immune-related loci as well as 69 genes, which often involved cryptic RSS sites. By contrast, such hotspots affected only immune-related loci but not driver genes in adult lymphoid cancers. Eight SV signatures extracted from the cohort had varying distributions across cancer types, with clustered translocations reflecting templated insertions in osteosarcoma, and medium-sized deletions (10 kb to 1 Mb) enriched in cancers with RAG-mediated deletions. Intra-patient evolutionary analysis in 13 patients with multiple spatiotemporally distinct samples revealed that RAG-mediated recombination in leukemia and complex rearrangements in solid tumors occurred both early in disease initiation and continuously during later diversification, contributing to clonal heterogeneity. Finally, we found that both driver genes and fragile sites were the two genomic regions most frequently disrupted by SVs. The unique and diverse SV landscapes that emerged from this comprehensive analysis expand the scope of RSS-mediated mutagenesis in pediatric ALL and will be a valuable resource for guiding future functional studies and the design of clinical genomic testing in pediatric cancer.

Journal Article↗
PubMedDate not supplied

[Antigenic variability of avian influenza virus A/H13, isolated in the USSR].

The antigenic structure of influenza H13 viruses isolated from wild birds in the USSR in 1976-1985 was studied. Antiserum against the reference A/gull/Maryland/704/77 (H13N6) strain was used to demonstrate the antigenic variations among the viruses. The homology of nucleotide sequences in the region 99-215 for the two A/H13N6 strains, A/gull/Maryland/704/77 and A/great black-headed gull/Astrakhan/227/84, were 75% and 86%, respectively. The 9-base segment deletion in A/grey black-headed gull/Astrakhan/277/84 was observed. Comparison of the predicted amino acid sequences of the strains' hemagglutinin in the appropriate region (amino acids 2-40) revealed 5 replacements (86% homology). Two replacements of arginine by lysine and asparagine by serine in positions 15 and 16, respectively, are the most significant. The latter replacement is accompanied by a change in the glycosylation site and might alter its three-dimensional structure. Further studies of the isolate genome are under way.

Amino Acid Sequence↗
PubMed2003

Evidence for quasispecies distributions in the human hepatitis A virus genome.

Nucleotide sequence analysis of multiple molecular clones of the hepatitis A virus (HAV), generated by reverse transcription-PCR of two capsid-coding regions, revealed a degree of heterogeneity compatible with a quasispecies structure in three clinical samples. Passage of plaque-purified reference strain HAV pHM175 43c in FRhK-4 cells documented the generation of a mutant distribution of HAV genomes. The mutant spectra showed mutation frequencies in the range of 1 x 10(-3) to 1 x 10(-4) substitutions per nucleotide, with a dominance of transition over transversion mutations. While in the VP3-coding region, nonsynonymous mutations were predominant; in the VP1-coding region they were uncommon. Around 50% of the amino acid replacements involved residues located at or near antigenic sites. Most of the detected mutations occurred at or in the vicinity of rare codons, suggesting a dynamics of mutation-selection, predominantly at and around rare codons. The results indicate that despite antigenic conservation, HAV replicates as a complex distribution of mutants, a feature of viral quasispecies.

Amino Acid Sequence↗
PubMed2026

A marine-derived fungal genome of Annulohypoxylon annulatoides reveals AT-rich isochores with putative regulatory functions.

Marine and coastal fungi experience intense environmental variability, yet the genomic features associated with tolerance to such conditions remain unclear. From 56 fungal isolates collected along the Lailai rocky shore in northern Taiwan, we selected the coastal isolate Annulohypoxylon annulatoides RYS0019 for phenotypic and genomic investigation because of its prevalence and distinctive stress-response profile. Compared with 5 bark-derived conspecific strains, RYS0019 showed distinct growth and recovery dynamics under salinity, temperature, and UV-associated stress treatments. We generated a high-quality 41.8 Mb de novo genome assembly with 11,523 predicted proteins and compared it with 15 other Hypoxylaceae genomes. Across Annulohypoxylon genomes, we identified variably sized and dispersed AT-rich isochores that are repeat-enriched and gene-poor. Despite variation in AT content, core gene content and Pfam domain profiles remained broadly conserved. Most AT-rich isochores were embedded within syntenically conserved regions and showed limited positional conservation across species, supporting recurrent, lineage-specific formation or expansion after species divergence. These regions also exhibit several sequence and structural features consistent with scaffold/matrix attachment regions, raising the possibility that they influence higher-order genome organization or context-dependent regulation. Together, our findings identify repeat-rich genome architecture as a dynamic feature of Annulohypoxylon genome evolution and provide a framework for testing how such regions may contribute to fungal environmental flexibility.

Genome, Fungal↗
PubMedDate not supplied

Quantitative trait loci mapping of floral and leaf morphology traits in Arabidopsis thaliana: evidence for modular genetic architecture.

Summary Morphological variation within organisms is integrated and often modular in nature. That is to say, the size and shape of traits tend to vary in a coordinated and structured manner across sets of organs or parts of an organism. The genetic basis of this morphological integration is largely unknown. Here, we report on quantitative trait loci (QTL) analysis of leaf and floral organ size in Arabidopsis thaliana. We evaluate patterns of genetic correlations among traits and perform whole-genome scans using QTL mapping methods. We detected significant genetic variation for the size and shape of each floral and leaf trait in our study. Moreover, we found large positive genetic correlations among sets of either flower or leaf traits, but low and generally nonsignificant genetic correlations between flower and leaf traits. These results support the hypothesis of independent floral and vegetative modules. We consider co-localization of QTL for different traits as support for a pleiotropic basis of morphological integration and modularity. A total of eight QTL affecting flower and three QTL affecting leaf traits were identified. Most QTL affected either floral or leaf traits, providing a general explanation for high correlations within and low correlations between modules. Only two genomic locations affected both flower and leaf growth. These results are discussed in the context of the evolution of modules, pleiotropy, and the putative homologous relationship between leaves and flowers.

Arabidopsis↗
PubMed2006

The genetic structure of human populations studied through short insertion-deletion polymorphisms.

In a landmark study Rosenberg et al. (2002) analyzed human genome diversity with 377 microsatellites in the HGDP-CEPH Genome Diversity Panel and reported that the populations were structured into five geographical regions: America, Sub-Saharan Africa, East Asia, Oceania and a cluster composed of Europe, the Middle East and Central Asia. They also observed that the within-population component accounted for 93-95%, and that the among-regions portion was only 3.6%, of the total genetic variance. We have also studied the HGDP-CEPH Diversity Panel (1,064 individuals from 52 populations) with a set of 40 biallelic slow-evolving short insertion-deletion polymorphisms (indels). We confirmed the partition of worldwide diversity into five genetic clusters that correspond to major geographic regions. Using the indels we have also disclosed an among-regions component of genetic variance considerably larger (12.1%) than had been estimated using microsatellites. Our study demonstrates that a set of 40 well-chosen biallelic markers is sufficient for the characterization of human population structure at the global level.

DNA Transposable Elements↗
PubMed2003

Patterns of polymorphism detected in the chloroplast and nuclear genomes of barley landraces sampled from Syria and Jordan.

In order to examine how molecular polymorphism in barley landraces, sampled from five different ecogeographical regions of Syria and Jordan, is organised and partitioned, genetic variability at 21 nuclear and 10 chloroplast microsatellite loci were examined. Chloroplast polymorphism was detected, with most variation being ascribed to differences between the five regions (Fst 0.45) and to within sites within each region (Fst 0.44). Moreover, the distribution of chloroplast polymorphism is structured and not distributed randomly across the barley landraces sampled. From a total of 125 landrace accessions (five lines from each of five sites from each of five regions) genotyped with 21 SSRs a total of 244 alleles were detected, of which 38 were common to the five regions sampled. Most nuclear variation was detected within sites. Significant differentiation between sites (Fst 0.29) was detected with nuclear SSRs and this partially mirrored polymorphism in the chloroplast genome. Strong statistical associations/interaction was also detected between the chloroplast and nuclear SSRs, together with non-random association (linkage disequilibrium) of alleles at both linked and unlinked SSR loci. These results are discussed in the context of adaptation of landraces to the extreme environment, the concept of 'adapted gene complexes' and the exploitation of landraces in breeding programmes.

Analysis of Variance↗
PubMed1993

Hemagglutination properties and nucleotide sequence analysis of the fiber gene of adenovirus genome types 11p and 11a.

The fiber has been suggested to serve as the ligand between the adenovirus capsid and the host cell receptor. The two genome types, Ad11p and Ad11a, of adenovirus serotype 11 display different tropisms. The fiber amino acid sequences of the two genome types have been deduced from the 975 nucleotides that encoded a fiber polypeptide of 35,500 Da. The fiber consists of a tail, a shaft, and a knob region. The amino acids 44 to 140 form a typical shaft domain of six 15-residue repetitive motifs. Ten amino acids in the Ad11p fiber shaft were substituted in Ad11a. Five unpolar residues have been replaced by four polar and one unpolar amino acid. In the knob region, a total of 14 amino acid mismatches were noted between Ad11p and Ad11a. The amino acid sequence Asn-Asp-Glu at positions 283 to 285 in Ad11p was changed to Arg-Ala-Asp in Ad11a. The sequence Thr-Leu-Trp-Thr from positions 133 to 136 was conserved in all analyzed human and canine adenoviruses. The polypeptide at positions 235 to 244, Phe-Met-Pro-Ser-Thr-Thr-Ala-Tyr-Pro-Phe, probably contains a subgenus epitope, since it is conserved among subgenus B adenoviruses. Ad11p aggregated rhesus and vervet erythrocytes at 37 degrees, 22 degrees, and at 4 degrees, respectively, whereas Ad11a did not display hemagglutination under the same conditions. The complete fibers of Ad11p and Ad11a share an overall amino acid homology of 92.3%. The homology within the shaft and the knob region was 89.7 and 92.4%, respectively. These variable amino acids should be expected to be responsible for the differences in hemagglutination and tropism examplified by the persistent urinary tract infections caused by Ad11p and the acute respiratory tract infections caused by Ad11a.

Adenovirus E3 Proteins↗
PubMed1993

The use of RAPDs for the analysis of parasites.

There is a lack of sequence information concerning polymorphic loci in parasite genomes. Thus, the use of arbitrary PCR primers under low temperature annealing conditions to generate random amplified polymorphic DNAs (RAPDs) represents an important approach to the study of the structure of parasite populations, their genetic variation as well as improved diagnosis of the diseases they cause. Following the examination of all variables and their effect on the reproducibility of the reaction, we have established a protocol for the analysis of RAPDs that involves amplification at two separate DNA concentrations followed by polyacrylamide gel electrophoresis and silver staining. We find the technique to be sensitive, reproducible, simple and relatively cheap. It has already provided insight into the genetic variation in populations of schistosomes and trypanosomes and is being used to study various other endemic infections. We also use specific primers under low stringency conditions in situations where the objective of the amplification is the detection of a particular sequence and where normal high stringency conditions give a positive/negative answer such as sex determination or diagnosis of blood born infections. Under low stringency conditions, specific amplification products persist but products of low stringency priming are also apparent and serve as a perfect internal control for negative samples.

Animals↗
PubMed1999

Highly Variable Microsatellites in the California Market Squid Loligo opalescens.

: Attempts to study the genetic population structure of cephalopods are impeded by the low levels of genetic variation in these species. We have developed polymerase chain reaction (PCR) primers for six hypervariable microsatellite markers in order to analyze the molecular population structure in the Californian market squid Loligo opalescens. Each of these genomic loci has been cloned and fully sequenced. Here we report the sequence and properties of the six PCR primer sets for the amplification of hypervariable microsatellites. Heterozygosity levels in six squid samples from different locations are high for all loci tested.

Journal Article↗
PubMed2006

Testing introgressive hybridization hypotheses using statistical network analysis of nuclear and cytoplasmic haplotypes in the leaf beetle Timarcha goettingensis species complex.

Previous studies of leaf beetles (Chrysomelidae) in the Timarcha goettingensis species complex using mitochondrial (cox2) and nuclear (ITS-2 rRNA) markers revealed two main clades confined to the Iberian Peninsula and the rest of Europe but showing incongruent distributions indicative of gene exchange between both groups. Because of the anastomosing nature of hybridization, which disrupts the cladistic structure of character variation, phylogenetic trees might be inappropriate to represent and study this process. Here we test for evidence of hybridization in the T. goettingensis complex by analyzing the extra homoplasy arising in hybrid genomes from the simultaneous analysis of genetically independent markers. Haplotype networks obtained by Templeton's statistical parsimony analysis were generated for combined (concatenated) cox2 and ITS-2 sequences from 167 individuals of the T. goettingensis complex. Networks were used to detect runs of homoplasious characters physically clustered along a nucleotide sequence, as evidence for recombination between both gene partitions. A hypergeometric tail probability for the chance occurrence of physically clustered character changes on the connections linking networks of genotypes was applied. The test recognized two instances of statistically significant clustering, indicating the presence of cox2-ITS-2 mosaic genotypes and reticulation of both main T. goettingensis clades, supporting the reticulate origin of samples of T. maritima in southwestern France and T. sinuatocollis/T. monserratensis in the eastern Pyrenees. Although the assessment of reticulation in DNA sequences does not provide direct proof for hybridization, the geographical distribution of mosaic genotypes in the vicinity of "pure" genotypes supports the effect of gene flow between the two divergent lineages. The study demonstrates the utility of statistical parsimony networks for the detection of hybrids in the growing number of phylogeographic studies based on multiple gene markers.

Adaptor Proteins, Vesicular Transport↗
PubMed2002

Identification of 779 genetic variations in eight genes encoding members of the ATP-binding cassette, subfamily C (ABCC/MRP/CFTR.

We screened DNAs from 48 Japanese individuals for single-nucleotide polymorphisms (SNPs) in eight genes encoding the ATP-binding cassette, subfamily C (ABCC/ MRP/CFTR), by direct sequencing of their entire genomic regions, except repetitive sequence elements. This approach identified 688 SNPs and 91 insertion/deletion polymorphisms among the eight genes. Of the 688 SNPs, 81 were identified in the ABCC1 gene, 41 in ABCC2, 30 in ABCC3, 230 in ABCC4, 76 in ABCC5, 58 in CFTR, 102 in ABCC8. and 70 in ABCC9. Six SNPs were located in the 5' flanking regions, 617 in introns, 46 in exons, and 19 in the 3' flanking regions. These variants should contribute to studies that investigate possible correlations of genotypes with disease-susceptibility phenotypes and responsiveness or adverse effects to drugs.

ATP-Binding Cassette Transporters↗
PubMed1987

Complete nucleotide sequence of the genome of coxsackievirus B1.

The complete nucleotide sequence of the genome of the coxsackievirus B1, a human enterovirus that belongs to the Picornaviridae, was determined by using molecular cloning and rapid sequence analysis techniques. Sequence analysis of the cloned cDNAs revealed that the virion RNA was 7389 nucleotides long and polyadenylylated at the 3' terminus. Similar to other picornavirus genomes, a single large open reading frame was identified. The translated sequence starts at nucleotide position 742 and ends at 7287 of the genome. Thus, the viral polyprotein should consist of 2182 amino acids. When the predicted amino acid sequence of the viral polyprotein was compared with those of other human enteroviruses such as polioviruses, a striking sequence homology was observed, especially in viral proteins 1B, 2C, and 3D. This allowed us to predict precise map locations of the viral structural and nonstructural proteins on the genome, although two proteolytic processing sites, between 1D and 2A and between 2B and 2C, were obscure. The result presented here implied important information with respect to the genetical variation of human enteroviruses.

Amino Acid Sequence↗