Biomedical subjects

Aleksandar Milosavljevic

Publications and source records attributed to Aleksandar Milosavljevic.

10 recordsLinked to original sources

PubMed2006

A high-resolution map of synteny disruptions in gibbon and human genomes.

Gibbons are part of the same superfamily (Hominoidea) as humans and great apes, but their karyotype has diverged faster from the common hominoid ancestor. At least 24 major chromosome rearrangements are required to convert the presumed ancestral karyotype of gibbons into that of the hominoid ancestor. Up to 28 additional rearrangements distinguish the various living species from the common gibbon ancestor. Using the northern white-cheeked gibbon (2n = 52) (Nomascus leucogenys leucogenys) as a model, we created a high-resolution map of the homologous regions between the gibbon and human. The positions of 100 synteny breakpoints relative to the assembled human genome were determined at a resolution of about 200 kb. Interestingly, 46% of the gibbon-human synteny breakpoints occur in regions that correspond to segmental duplications in the human lineage, indicating a common source of plasticity leading to a different outcome in the two species. Additionally, the full sequences of 11 gibbon BACs spanning evolutionary breakpoints reveal either segmental duplications or interspersed repeats at the exact breakpoint locations. No specific sequence element appears to be common among independent rearrangements. We speculate that the extraordinarily high level of rearrangements seen in gibbons may be due to factors that increase the incidence of chromosome breakage or fixation of the derivative chromosomes in a homozygous state.

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PubMed2006

The genome of the sea urchin Strongylocentrotus purpuratus.

We report the sequence and analysis of the 814-megabase genome of the sea urchin Strongylocentrotus purpuratus, a model for developmental and systems biology. The sequencing strategy combined whole-genome shotgun and bacterial artificial chromosome (BAC) sequences. This use of BAC clones, aided by a pooling strategy, overcame difficulties associated with high heterozygosity of the genome. The genome encodes about 23,300 genes, including many previously thought to be vertebrate innovations or known only outside the deuterostomes. This echinoderm genome provides an evolutionary outgroup for the chordates and yields insights into the evolution of deuterostomes.

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PubMed2006

Designing new microsatellite markers for linkage and population genetic analyses in rhesus macaques and other nonhuman primates.

Identification of polymorphic microsatellite loci in nonhuman primates is useful for various biomedical and evolutionary studies of these species. Prior methods for identifying microsatellites in nonhuman primates are inefficient. We describe a new strategy for marker development that uses the available whole genome sequence for rhesus macaques. Fifty-four novel rhesus-derived microsatellites were genotyped in large pedigrees of rhesus monkeys. Linkage analysis was used to place 51 of these loci into the existing rhesus linkage map. In addition, we find that microsatellites identified this way are polymorphic in other Old World monkeys such as baboons. This approach to marker development is more efficient than previous methods and produces polymorphisms with known locations in the rhesus genome assembly. Finally, we propose a nomenclature system that can be used for rhesus-derived microsatellites genotyped in any species or for novel loci derived from the genome sequence of any nonhuman primate.

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PubMed2006

The DNA sequence, annotation and analysis of human chromosome 3.

After the completion of a draft human genome sequence, the International Human Genome Sequencing Consortium has proceeded to finish and annotate each of the 24 chromosomes comprising the human genome. Here we describe the sequencing and analysis of human chromosome 3, one of the largest human chromosomes. Chromosome 3 comprises just four contigs, one of which currently represents the longest unbroken stretch of finished DNA sequence known so far. The chromosome is remarkable in having the lowest rate of segmental duplication in the genome. It also includes a chemokine receptor gene cluster as well as numerous loci involved in multiple human cancers such as the gene encoding FHIT, which contains the most common constitutive fragile site in the genome, FRA3B. Using genomic sequence from chimpanzee and rhesus macaque, we were able to characterize the breakpoints defining a large pericentric inversion that occurred some time after the split of Homininae from Ponginae, and propose an evolutionary history of the inversion.

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PubMed2006

The finished DNA sequence of human chromosome 12.

Human chromosome 12 contains more than 1,400 coding genes and 487 loci that have been directly implicated in human disease. The q arm of chromosome 12 contains one of the largest blocks of linkage disequilibrium found in the human genome. Here we present the finished sequence of human chromosome 12, which has been finished to high quality and spans approximately 132 megabases, representing approximately 4.5% of the human genome. Alignment of the human chromosome 12 sequence across vertebrates reveals the origin of individual segments in chicken, and a unique history of rearrangement through rodent and primate lineages. The rate of base substitutions in recent evolutionary history shows an overall slowing in hominids compared with primates and rodents.

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PubMed2005

Pooled genomic indexing of rhesus macaque.

Pooled genomic indexing (PGI) is a method for mapping collections of bacterial artificial chromosome (BAC) clones between species by using a combination of clone pooling and DNA sequencing. PGI has been used to map a total of 3858 BAC clones covering approximately 24% of the rhesus macaque (Macaca mulatta) genome onto 4178 homologous loci in the human genome. A number of intrachromosomal rearrangements were detected by mapping multiple segments within the individual rhesus BACs onto multiple disjoined loci in the human genome. Transversal pooling designs involving shuffled BAC arrays were employed for robust mapping even with modest DNA sequence read coverage. A further innovation, short-tag pooled genomic indexing (ST-PGI), was also introduced to further improve the economy of mapping by sequencing multiple, short, mapable tags within a single sequencing reaction.

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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.

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PubMed2004

Pooled Genomic Indexing (PGI): analysis and design of experiments.

Pooled Genomic Indexing (PGI) is a novel method for physical mapping of clones onto known sequences. PGI is carried out by pooling arrayed clones and generating shotgun sequence reads from the pools. The shotgun sequences are compared to a reference sequence. In the simplest case, clones are placed on an array and are pooled by rows and columns. If a shotgun sequence from a row pool and another shotgun sequence from a column pool match the reference sequence at a close distance, they are both assigned to the clone at the intersection of the two pools. Accordingly, the clone is mapped onto the region of the reference sequence between the two matches. A probabilistic model for PGI is developed, and several pooling designs are described and analyzed, including transversal designs and designs from linear codes. The probabilistic model and the pooling schemes are validated in simulated experiments where 625 rat bacterial artificial chromosome (BAC) clones and 207 mouse BAC clones are mapped onto homologous human sequence.

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PubMed2004

Pash: efficient genome-scale sequence anchoring by Positional Hashing.

Pash is a computer program for efficient, parallel, all-against-all comparison of very long DNA sequences. Pash implements Positional Hashing, a novel parallelizable method for sequence comparison based on k-mer representation of sequences. The Positional Hashing method breaks the comparison problem in a unique way that avoids the quadratic penalty encountered with other sensitive methods and confers inherent low-level parallelism. Furthermore, Positional Hashing allows one to readily and predictably trade between sensitivity and speed. In a simulated comparison task, anchoring computationally mutated reads onto a genome, the sensitivity of Pash was equal to or greater than that of BLAST and BLAT, with Pash outperforming these programs as the reads became shorter and less similar to the genome. Using modest computing resources, we employed Pash for two large-scale sequence comparison tasks: comparison of three mammalian genomes, and anchoring millions of chimpanzee whole-genome shotgun sequencing reads onto the human genome. The results of these comparisons by Pash agree with those computed by other methods that use more than an order of magnitude more computing resources. These results confirm the sensitivity of Positional Hashing.

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PubMed2003

Clone-array pooled shotgun mapping and sequencing: design and analysis of experiments.

This paper studies sequencing and mapping methods that rely solely on pooling and shotgun sequencing of clones. First, we scrutinize and improve the recently proposed Clone-Array Pooled Shotgun Sequencing (CAPSS) method, which delivers a BAC-linked assembly of a whole genome sequence. Secondly, we introduce a novel physical mapping method, called Clone-Array Pooled Shotgun Mapping (CAPS-MAP), which computes the physical ordering of BACs in a random library. Both CAPSS and CAPS-MAP construct subclone libraries from pooled genomic BAC clones.

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