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Jeffrey A Bailey

Publications and source records attributed to Jeffrey A Bailey.

At least 19 recordsLinked to original sources
PubMed2026

Multiple local PfDHFR I164L haplotype expansions drive Plasmodium falciparum antifolate resistance in Uganda.

Mutations in the Plasmodium falciparum genes, pfdhfr and pfdhps, drive antifolate resistance and threaten malaria control in regions where sulfadoxine-pyrimethamine (SP) is the primary chemoprevention strategy. The spatial patterns and evolutionary dynamics of these mutations in high-transmission settings remain incompletely understood. Here we genotyped 11 resistance-associated mutations in pfdhfr and pfdhps in 4,725 P. falciparum isolates collected from 16 Ugandan health facilities as part of annual surveillance between 2016 and 2022. Notably, we show that the frequency of PfDHFR I164L, which confers higher pyrimethamine resistance, increased over time from 19.4% to 32.4%. Using identity-by-descent, haplotype structure, and extended haplotype homozygosity analyses, we show that PfDHFR I164L is present on multiple haplotype backgrounds and undergoes localised expansions, without detectable signatures of recent positive selection at all but one site. Our results suggest that the evolution of antifolate resistance, driven by PfDHFR I164L, is spatially heterogeneous and complex in regions that primarily use SP chemoprevention programmes.

Plasmodium falciparum↗
PubMed2026

Population genomics of Plasmodium malariae from 4 African countries.

BACKGROUNDMalaria caused by Plasmodium malariae is geographically widespread and sometimes associated with prolonged infection, yet little is known about its genomic epidemiology.METHODSWe performed hybrid capture and whole-genome sequencing of 77 isolates collected from Cameroon (n = 7), the Democratic Republic of the Congo (n = 16), Nigeria (n = 4), and Tanzania (n = 50) between 2015 and 2021, analyzing parasite genetic population structure and demography.RESULTSThere is no evidence of geographic population structure. Nucleotide diversity was significantly lower than in colocalized P. falciparum isolates, while linkage disequilibrium was significantly higher. Genome-wide selection scans identified no erythrocyte invasion ligands or antimalarial resistance orthologs as top hits; however, targeted analyses of these loci revealed evidence of selective sweeps around 4 erythrocyte invasion ligands and 6 antimalarial resistance orthologs. Demographic inference modeling suggests that African P. malariae is recovering from a bottleneck.CONCLUSIONP. malariae is genomically atypical among human Plasmodium spp. and lacks strong population structure in Africa. The low diversity has potential impacts on understanding persistent versus new infection through genomic epidemiology.FUNDINGBill & Melinda Gates Foundation (grant 002202), USAID/PMI through Jhpiego and CDC, NIH (T32AI007151, T32AI070114, R01AI107949, R01AI129812, R21 AI148579, R01AI137395, R21AI152260, R01AI132547, and K24AI134990), and the DELTAS Africa initiative (DELGEME grant 107740/Z/15/Z).

Plasmodium malariae↗
PubMed2006

Primate segmental duplications: crucibles of evolution, diversity and disease.

Compared with other mammals, the genomes of humans and other primates show an enrichment of large, interspersed segmental duplications (SDs) with high levels of sequence identity. Recent evidence has begun to shed light on the origin of primate SDs, pointing to a complex interplay of mechanisms and indicating that distinct waves of duplication took place during primate evolution. There is also evidence for a strong association between duplication, genomic instability and large-scale chromosomal rearrangements. Exciting new findings suggest that SDs have not only created novel primate gene families, but might have also influenced current human genic and phenotypic variation on a previously unappreciated scale. A growing number of examples link natural human genetic variation of these regions to susceptibility to common disease.

Animals↗
PubMed2005

Manipulating multiple sequence alignments via MaM and WebMaM.

MaM is a software tool that processes and manipulates multiple alignments of genomic sequence. MaM computes the exact location of common repeat elements, exons and unique regions within aligned genomics sequences using a variety of user identified programs, databases and/or tables. The program can extract subalignments, corresponding to these various regions of DNA to be analyzed independently or in conjunction with other elements of genomic DNA. Graphical displays further allow an assessment of sequence variation throughout these different regions of the aligned sequence, providing separate displays for their repeat, non-repeat and coding portions of genomic DNA. The program should facilitate the phylogenetic analysis and processing of different portions of genomic sequence as part of large-scale sequencing efforts. MaM source code is freely available for non-commercial use at http://compbio.cs.sfu.ca/MAM.htm; and the web interface WebMaM is hosted at http://atgc.lirmm.fr/mam.

Exons↗
PubMed2005

Segmental duplications and copy-number variation in the human genome.

The human genome contains numerous blocks of highly homologous duplicated sequence. This higher-order architecture provides a substrate for recombination and recurrent chromosomal rearrangement associated with genomic disease. However, an assessment of the role of segmental duplications in normal variation has not yet been made. On the basis of the duplication architecture of the human genome, we defined a set of 130 potential rearrangement hotspots and constructed a targeted bacterial artificial chromosome (BAC) microarray (with 2,194 BACs) to assess copy-number variation in these regions by array comparative genomic hybridization. Using our segmental duplication BAC microarray, we screened a panel of 47 normal individuals, who represented populations from four continents, and we identified 119 regions of copy-number polymorphism (CNP), 73 of which were previously unreported. We observed an equal frequency of duplications and deletions, as well as a 4-fold enrichment of CNPs within hotspot regions, compared with control BACs (P < .000001), which suggests that segmental duplications are a major catalyst of large-scale variation in the human genome. Importantly, segmental duplications themselves were also significantly enriched >4-fold within regions of CNP. Almost without exception, CNPs were not confined to a single population, suggesting that these either are recurrent events, having occurred independently in multiple founders, or were present in early human populations. Our study demonstrates that segmental duplications define hotspots of chromosomal rearrangement, likely acting as mediators of normal variation as well as genomic disease, and it suggests that the consideration of genomic architecture can significantly improve the ascertainment of large-scale rearrangements. Our specialized segmental duplication BAC microarray and associated database of structural polymorphisms will provide an important resource for the future characterization of human genomic disorders.

Chromosomes, Artificial, Bacterial↗
PubMed2005

Fine-scale structural variation of the human genome.

Inversions, deletions and insertions are important mediators of disease and disease susceptibility. We systematically compared the human genome reference sequence with a second genome (represented by fosmid paired-end sequences) to detect intermediate-sized structural variants >8 kb in length. We identified 297 sites of structural variation: 139 insertions, 102 deletions and 56 inversion breakpoints. Using combined literature, sequence and experimental analyses, we validated 112 of the structural variants, including several that are of biomedical relevance. These data provide a fine-scale structural variation map of the human genome and the requisite sequence precision for subsequent genetic studies of human disease.

Base Pairing↗
PubMed2004

Genome sequence of the Brown Norway rat yields insights into mammalian evolution.

The laboratory rat (Rattus norvegicus) is an indispensable tool in experimental medicine and drug development, having made inestimable contributions to human health. We report here the genome sequence of the Brown Norway (BN) rat strain. The sequence represents a high-quality 'draft' covering over 90% of the genome. The BN rat sequence is the third complete mammalian genome to be deciphered, and three-way comparisons with the human and mouse genomes resolve details of mammalian evolution. This first comprehensive analysis includes genes and proteins and their relation to human disease, repeated sequences, comparative genome-wide studies of mammalian orthologous chromosomal regions and rearrangement breakpoints, reconstruction of ancestral karyotypes and the events leading to existing species, rates of variation, and lineage-specific and lineage-independent evolutionary events such as expansion of gene families, orthology relations and protein evolution.

Animals↗
PubMed2004

Hotspots of mammalian chromosomal evolution.

BACKGROUND: Chromosomal evolution is thought to occur through a random process of breakage and rearrangement that leads to karyotype differences and disruption of gene order. With the availability of both the human and mouse genomic sequences, detailed analysis of the sequence properties underlying these breakpoints is now possible. RESULTS: We report an abundance of primate-specific segmental duplications at the breakpoints of syntenic blocks in the human genome. Using conservative criteria, we find that 25% (122/461) of all breakpoints contain > or = 10 kb of duplicated sequence. This association is highly significant (p < 0.0001) when compared to a simulated random-breakage model. The significance is robust under a variety of parameters, multiple sets of conserved synteny data, and for orthologous breakpoints between and within chromosomes. A comparison of mouse lineage-specific breakpoints since the divergence of rat and mouse showed a similar association with regions associated with segmental duplications in the primate genome. CONCLUSION: These results indicate that segmental duplications are associated with syntenic rearrangements, even when pericentromeric and subtelomeric regions are excluded. However, segmental duplications are not necessarily the cause of the rearrangements. Rather, our analysis supports a nonrandom model of chromosomal evolution that implicates specific regions within the mammalian genome as having been predisposed to both recurrent small-scale duplication and large-scale evolutionary rearrangements.

Animals↗
PubMed2004

The role of unequal crossover in alpha-satellite DNA evolution: a computational analysis.

Human DNA consists of a large number of tandem repeat sequences. Such sequences are usually called satellites, with the primary example being the centromeric alpha-satellite DNA. The basic repeat unit of the alpha-satellite DNA is a 171 bp monomer. Arbitrary monomer pairs usually have considerable sequence divergence (20-40%). However, with the exception of peripheral alpha-satellite DNA, monomers can be grouped into blocks of k-monomers (4 < or = k < or = 20) between which the divergence rate is much smaller (e.g., 5%). Perhaps the simplest and best understood mechanism for tandem repeat array evolution is unequal crossover. Although it is possible that alpha-satellite sequences developed as a result of subsequent unequal crossovers only, no formal computational framework seems to have been developed to verify this possibility. In this paper, we develop such a framework and report on experiments which imply that pericentromeric alpha-satellite segments (which are devoid of higher order structure) are evolutionarily distinct from the higher order repeat segments. It is likely that the higher order repeats developed independently in distinct regions of the genome and were carried into their current locations through an unknown mechanism of transposition.

Algorithms↗
PubMed2004

Recent segmental duplications in the working draft assembly of the brown Norway rat.

We assessed the content, structure, and distribution of segmental duplications (> or =90% sequence identity, > or =5 kb length) within the published version of the Rattus norvegicus genome assembly (v.3.1). The overall fraction of duplicated sequence within the rat assembly (2.92%) is greater than that of the mouse (1%-1.2%) but significantly less than that of human ( approximately 5%). Duplications were nonuniformly distributed, occurring predominantly as tandem and tightly clustered intrachromosomal duplications. Regions containing extensive interchromosomal duplications were observed, particularly within subtelomeric and pericentromeric regions. We identified 41 discrete genomic regions greater than 1 Mb in size, termed "duplication blocks." These appear to have been the target of extensive duplication over millions of years of evolution. Gene content within duplicated regions ( approximately 1%) was lower than expected based on the genome representation. Interestingly, sequence contigs lacking chromosome assignment ("the unplaced chromosome") showed a marked enrichment for segmental duplication (45% of 75.2 Mb), indicating that segmental duplications have been problematic for sequence and assembly of the rat genome. Further targeted efforts are required to resolve the organization and complexity of these regions.

Animals↗
PubMed2004

Analysis of segmental duplications and genome assembly in the mouse.

Limited comparative studies suggest that the human genome is particularly enriched for recent segmental duplications. The extent of segmental duplications in other mammalian genomes is unknown and confounded by methodological differences in genome assembly. Here, we present a detailed analysis of recent duplication content within the mouse genome using a whole-genome assembly comparison method and a novel assembly independent method, designed to take advantage of the reduced allelic variation of the C57BL/6J strain. We conservatively estimate that approximately 57% of all highly identical segmental duplications (>or=90%) were misassembled or collapsed within the working draft WGS assembly. The WGS approach often leaves duplications fragmented and unassigned to a chromosome when compared with the clone-ordered-based approach. Our preliminary analysis suggests that 1.7%-2.0% of the mouse genome is part of recent large segmental duplications (about half of what is observed for the human genome). We have constructed a mouse segmental duplication database to aid in the characterization of these regions and their integration into the final mouse genome assembly. This work suggests significant biological differences in the architecture of recent segmental duplications between human and mouse. In addition, our unique method provides the means for improving whole-genome shotgun sequence assembly of mouse and future mammalian genomes.

Animals↗
PubMed2003

An Alu transposition model for the origin and expansion of human segmental duplications.

Relative to genomes of other sequenced organisms, the human genome appears particularly enriched for large, highly homologous segmental duplications (> or =90% sequence identity and > or =10 kbp in length). The molecular basis for this enrichment is unknown. We sought to gain insight into the mechanism of origin, by systematically examining sequence features at the junctions of duplications. We analyzed 9,464 junctions within regions of high-quality finished sequence from a genomewide set of 2,366 duplication alignments. We observed a highly significant (P<.0001) enrichment of Alu short interspersed element (SINE) sequences near or within the junction. Twenty-seven percent of all segmental duplications terminated within an Alu repeat. The Alu junction enrichment was most pronounced for interspersed segmental duplications separated by > or =1 Mb of intervening sequence. Alu elements at the junctions showed higher levels of divergence, consistent with Alu-Alu-mediated recombination events. When we classified Alu elements into major subfamilies, younger elements (AluY and AluS) accounted for the enrichment, whereas the oldest primate family (AluJ) showed no enrichment. We propose that the primate-specific burst of Alu retroposition activity (which occurred 35-40 million years ago) sensitized the ancestral human genome for Alu-Alu-mediated recombination events, which, in turn, initiated the expansion of gene-rich segmental duplications and their subsequent role in nonallelic homologous recombination.

Alu Elements↗
PubMed2003

The DNA sequence of human chromosome 7.

Human chromosome 7 has historically received prominent attention in the human genetics community, primarily related to the search for the cystic fibrosis gene and the frequent cytogenetic changes associated with various forms of cancer. Here we present more than 153 million base pairs representing 99.4% of the euchromatic sequence of chromosome 7, the first metacentric chromosome completed so far. The sequence has excellent concordance with previously established physical and genetic maps, and it exhibits an unusual amount of segmentally duplicated sequence (8.2%), with marked differences between the two arms. Our initial analyses have identified 1,150 protein-coding genes, 605 of which have been confirmed by complementary DNA sequences, and an additional 941 pseudogenes. Of genes confirmed by transcript sequences, some are polymorphic for mutations that disrupt the reading frame.

Animals↗
PubMed2003

Genomic sequence and transcriptional profile of the boundary between pericentromeric satellites and genes on human chromosome arm 10p.

Contiguous finished sequence from highly duplicated pericentromeric regions of human chromosomes is needed if we are to understand the role of pericentromeric instability in disease, and in gene and karyotype evolution. Here, we have constructed a BAC contig spanning the transition from pericentromeric satellites to genes on the short arm of human chromosome 10, and used this to generate 1.4 Mb of finished genomic sequence. Combining RT-PCR, in silico gene prediction, and paralogy analysis, we can identify two domains within the sequence. The proximal 600 kb consists of satellite-rich pericentromerically duplicated DNA which is transcript poor, containing only three unspliced transcripts. In contrast, the distal 850 kb contains four known genes (ZNF248, ZNF25, ZNF33A, and ZNF37A) and up to 32 additional transcripts of unknown function. This distal region also contains seven out of the eight intrachromosomal duplications within the sequence, including the p arm copy of the approximately 250-kb duplication which gave rise to ZNF33A and ZNF33B. By sequencing orthologs of the duplicated ZNF33 genes we have established that ZNF33A has diverged significantly at residues critical for DNA binding but ZNF33B has not, indicating that ZNF33B has remained constrained by selection for ancestral gene function. These results provide further evidence of gene formation within intrachromosomal duplications, but indicate that recent interchromosomal duplications at this centromere have involved transcriptionally inert, satellite rich DNA, which is likely to be heterochromatic. This suggests that any novel gene structures formed by these interchromosomal events would require relocation to a more open chromatin environment to be expressed.

Amino Acid Sequence↗
PubMed2003

Analysis of primate genomic variation reveals a repeat-driven expansion of the human genome.

We performed a detailed analysis of both single-nucleotide and large insertion/deletion events based on large-scale comparison of 10.6 Mb of genomic sequence from lemur, baboon, and chimpanzee to human. Using a human genomic reference, optimal global alignments were constructed from large (>50-kb) genomic sequence clones. These alignments were examined for the pattern, frequency, and nature of mutational events. Whereas rates of single-nucleotide substitution remain relatively constant (1-2 x 10(-9) substitutions/site/year), rates of retrotransposition vary radically among different primate lineages. These differences have lead to a 15%-20% expansion of human genome size over the last 50 million years of primate evolution, 90% of it due to new retroposon insertions. Orthologous comparisons with the chimpanzee suggest that the human genome continues to significantly expand due to shifts in retrotransposition activity. Assuming that the primate genome sequence we have sampled is representative, we estimate that human euchromatin has expanded 30 Mb and 550 Mb compared to the primate genomes of chimpanzee and lemur, respectively.

Animals↗
PubMed2002

Recent segmental duplications in the human genome.

Primate-specific segmental duplications are considered important in human disease and evolution. The inability to distinguish between allelic and duplication sequence overlap has hampered their characterization as well as assembly and annotation of our genome. We developed a method whereby each public sequence is analyzed at the clone level for overrepresentation within a whole-genome shotgun sequence. This test has the ability to detect duplications larger than 15 kilobases irrespective of copy number, location, or high sequence similarity. We mapped 169 large regions flanked by highly similar duplications. Twenty-four of these hot spots of genomic instability have been associated with genetic disease. Our analysis indicates a highly nonrandom chromosomal and genic distribution of recent segmental duplications, with a likely role in expanding protein diversity.

Alleles↗