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PubMed2005

Generation and annotation of the DNA sequences of human chromosomes 2 and 4.

Human chromosome 2 is unique to the human lineage in being the product of a head-to-head fusion of two intermediate-sized ancestral chromosomes. Chromosome 4 has received attention primarily related to the search for the Huntington's disease gene, but also for genes associated with Wolf-Hirschhorn syndrome, polycystic kidney disease and a form of muscular dystrophy. Here we present approximately 237 million base pairs of sequence for chromosome 2, and 186 million base pairs for chromosome 4, representing more than 99.6% of their euchromatic sequences. Our initial analyses have identified 1,346 protein-coding genes and 1,239 pseudogenes on chromosome 2, and 796 protein-coding genes and 778 pseudogenes on chromosome 4. Extensive analyses confirm the underlying construction of the sequence, and expand our understanding of the structure and evolution of mammalian chromosomes, including gene deserts, segmental duplications and highly variant regions.

Animals↗
PubMed2006

Comparative analysis of the bovine MHC class IIb sequence identifies inversion breakpoints and three unexpected genes.

The bovine major histocompatibility complex (MHC) or BoLA is organized differently from typical mammalian MHCs in that a large portion of the class II region, called class IIb, has been transposed to a position near the centromere on bovine chromosome 23. Gene mapping indicated that the rearrangement resulted from a single inversion, but the boundaries and gene content of the inverted segment have not been fully determined. Here, we report the genomic sequence of BoLA IIb. Comparative sequence analysis with the human MHC revealed that the proximal inversion breakpoint occurred approximately 2.5 kb from the 3' end of the glutamate-cysteine ligase, catalytic subunit (GCLC) locus and that the distal breakpoint occurred about 2 kb from the 5' end from a divergent class IIDRbeta-like sequence designated DSB. Gene content, order and orientation of BoLA IIb are consistent with the single inversion hypothesis when compared with the corresponding region of the human class II MHC (HLA class II). Differences with HLA include the presence of a single histone H2B gene located between the proteasome subunit, beta type, 9 (PSMB9) and DMB loci and a duplicated TAP2 with a variant splice site. BoLA IIb spans approximately 450 kb DNA, with 20 apparently intact genes and no obvious pseudogenes. The region contains 227 simple sequence repeats (SSRs) and approximately 167 kb of retroviral-related repetitive DNA. Nineteen of the 20 genes identified in silico are supported by bovine EST data indicating that the functional gene content of BoLA IIb has not been diminished because it has been transposed from the remainder of BoLA genes.

Animals↗
PubMed2002

Does the rat have an H2-D orthologue next to Bat1?

Unlike all other mammalian species, which have only one class I region, rat and mouse possess a second class I region on the centromeric side of the MHC. The mouse has class Ia genes in both the centromeric H2-K and the telomeric H2-D region, whereas the rat has class Ia genes only in the centromeric RT1.A region. Bat1 is the last gene of the class III region in the mouse, and H2-D was mapped 10 kb telomeric of Bat1. To determine whether the rat possesses an H2-D orthologue, we sequenced a cosmid clone that contains rat Bat1 and an adjacent class I gene, RT1.46 (l). Homology searches suggest a transition in the rat sequence with a proximal stretch containing Nfkbil1, ATP6G, and Bat1, which is homologous to the mouse H2-D region, and a more-distal stretch, which contains the class I gene and has many similarities to mouse H2-Q region sequences. Downstream of Bat1 is a sequence stretch with great similarity to intron 3 of H2-D, which is not present in any of the rat class I genes but is found in mouse H2-K, D-, and - Q region genes. Numerous repetitive elements indicate that the region is prone to repeat-mediated rearrangements. A putative H2-D orthologue may have been present at this location and lost by genomic rearrangements, leaving the short intronic sequence behind. The class I gene RT1.46 (l) has an open reading frame, but it is unlike H2-D due to a unique 5'UTR shared with H2-Q1 and Q2, the absence of the B2 SINE repeat characteristic of H2-D/L, and the apparent lack of surface expression. We conclude that at least the LEW rat (RT1 (l)) does not possess an H2-D orthologue.

Amino Acid Sequence↗
PubMed2001

Short tandem repeat (STR) haplotypes in HLA: an integrated 50-kb STR/linkage disequilibrium/gene map between the RING3 and HLA-B genes and identification of STR haplotype diversification in the class III region.

We present a dense STR/linkage disequilibrium(LD)/gene map between the RING3 and HLA-B loci, reference allelic sizes on the most prevalent HLA haplotypes and their allelic frequencies in pedigree founders. This resource will facilitate LD, evolution and gene mapping studies, including comparisons of HLA and STR haplotypes and identification of HLA recombinants. The map was constructed by testing novel and previously reported STRs using a panel of 885 individuals in 211 families and 60 DNA samples from cell lines and bone marrow donors homozygous in the HLA-A, -B and -DR loci selected from over 15 000 entries into the registry of Swedish bone marrow donors. We have also analysed the variability of STR alleles/haplotypes on the most prevalent HLA haplotypes to identify STRs useful for fine mapping of disease genes in the region previously implicated in susceptibility to many disorders. The analysis of 40 HLA-A*01, B*0801, DRB1*03011, DQB1*0201 haplotypes in homozygous donors showed a surprising stability in 23 STRs between the class II recombination hot spot and HLA-B, with the average of 1.9% (16/838) variant alleles. However, 40% variant alleles were found at the D6S2670 locus in intron 19 of the tenascin-X gene both in the families and homozygous donors. The nucleotide sequence analysis of this STR showed a complex polymorphism consisting of tetra- (CTTT)(8-18) and penta-nucleotide (CTTTT)(1-2) repeats, separated by an intervening non-polymorphic sequence of 42 bp. The HLA-A1, B*0801, DRB1*03011, DQB1*0201 haplotypes had five (CTTT)(14-18)/(CTTTT)(2) variants with a predominant (CTTT)(16) allele, implicating the tetranucleotide component as the source of this ancestral haplotype diversification, which may be due to the location of D6S2670 in the region of the highest GC content in the human MHC.

Centromere↗
PubMed1994

How can the low levels of DNA sequence variation in regions of the drosophila genome with low recombination rates be explained?

Different regions of the Drosophila genome have very different rates of recombination. For example, near centromeres and near the tips of chromosomes, the rates of recombination are much lower than in other regions. Several surveys of polymorphisms in Drosophila have now documented that levels of DNA polymorphism are positively correlated with rates of recombination; i.e., regions with low rates of recombination tend to have low levels of DNA polymorphism within populations of Drosophila. Three hypotheses are reviewed that might account for these observations. The first hypothesis is that regions of low recombination have low neutral mutation rates. Under this hypothesis between-species divergences should also be low in regions of low recombination. In fact, regions of low recombination have diverged at the same rate as other regions of the genome. On this basis, this strictly neutral hypothesis is rejected. The second hypothesis is that the process of fixation of favorable mutations leads to the observed correlation between polymorphism and recombination. This occurs via genetic hitchhiking, in which linked regions of the genome are swept along with the selectively favored mutant as it increases in frequency and eventually fixes in the population. This hitchhiking model with fixation of favorable mutations is compatible with major features of the data. By assuming this model is correct, one can estimate the rate of fixation of favorable mutations. The third hypothesis is that selection against continually arising deleterious mutations results in reduced levels of polymorphism at linked loci. Analysis of this background selection model shows that it can produce some reduction in levels of polymorphism but cannot explain some extreme cases that have been observed. Thus, it appears that hitchhiking of favorable mutations and background selection against deleterious mutations must be considered together to correctly account for the patterns of polymorphism that are observed in Drosophila.

Animals↗
PubMed2003

Two-hybrid search for proteins that interact with Sad1 and Kms1, two membrane-bound components of the spindle pole body in fission yeast.

In interphase cells of fission yeast, the spindle pole body (SPB) is thought to be connected with chromosomal centromeres by an as yet unknown mechanism that spans the nuclear membrane. To elucidate this mechanism, we performed two-hybrid screens for proteins that interact with Kms1 and Sad1, which are constitutive membrane-bound components of the SPB that interact with each other. Seven and 26 genes were identified whose products potentially interact with Kms1 and Sad1, respectively. With the exception of Dlc1 (a homolog of the 14-kDa dynein light chain), all of the Kms1 interactors also interacted with Sad1. Among the genes identified were the previously known genes rhp9+ / crb2+, cut6+, ags1+ / mok1+, gst3+, kms2+, and sid4+. The products of kms2+ and sid4+ localize to the SPB. The novel genes were characterized by constructing disruption mutations and by localization of the gene products. Two of them, putative homologues of budding yeast UFE1 (which encodes a t-SNARE) and SFH1 (an essential component of a chromatin-remodeling complex), were essential for viability. Two further genes, which were only conditionally essential, genetically interact with sad1+. One of these was named sif1+ (for Sad1-interacting factor) and is required for proper septum formation at high temperature. Cells in which this gene was overexpressed displayed a wee -like phenotype. The product of the other gene, apm1+, is very similar to the medium chain of an adaptor protein complex in clathrin-coated vesicles. Apm1 appears to be required for SPB separation and spindle formation, and tended to accumulate at the SPB when it was overproduced. It was functionally distinct from its homologues Apm2 and Apm4. Other novel genes identified in this study included one for a nucleoporin and genes encoding novel membrane-bound proteins that were genetically related to Sad1. We found that none of the newly identified genes tested were necessary for centromere/telomere clustering.

Binding Sites↗
PubMed2001

Segmental duplications: organization and impact within the current human genome project assembly.

Segmental duplications play fundamental roles in both genomic disease and gene evolution. To understand their organization within the human genome, we have developed the computational tools and methods necessary to detect identity between long stretches of genomic sequence despite the presence of high copy repeats and large insertion-deletions. Here we present our analysis of the most recent genome assembly (January 2001) in which we focus on the global organization of these segments and the role they play in the whole-genome assembly process. Initially, we considered only large recent duplication events that fell well-below levels of draft sequencing error (alignments 90%-98% similar and > or =1 kb in length). Duplications (90%-98%; > or =1 kb) comprise 3.6% of all human sequence. These duplications show clustering and up to 10-fold enrichment within pericentromeric and subtelomeric regions. In terms of assembly, duplicated sequences were found to be over-represented in unordered and unassigned contigs indicating that duplicated sequences are difficult to assign to their proper position. To assess coverage of these regions within the genome, we selected BACs containing interchromosomal duplications and characterized their duplication pattern by FISH. Only 47% (106/224) of chromosomes positive by FISH had a corresponding chromosomal position by comparison. We present data that indicate that this is attributable to misassembly, misassignment, and/or decreased sequencing coverage within duplicated regions. Surprisingly, if we consider putative duplications >98% identity, we identify 10.6% (286 Mb) of the current assembly as paralogous. The majority of these alignments, we believe, represent unmerged overlaps within unique regions. Taken together the above data indicate that segmental duplications represent a significant impediment to accurate human genome assembly, requiring the development of specialized techniques to finish these exceptional regions of the genome. The identification and characterization of these highly duplicated regions represents an important step in the complete sequencing of a human reference genome.

Base Sequence↗
PubMed2004

DNA sequence and analysis of human chromosome 9.

Chromosome 9 is highly structurally polymorphic. It contains the largest autosomal block of heterochromatin, which is heteromorphic in 6-8% of humans, whereas pericentric inversions occur in more than 1% of the population. The finished euchromatic sequence of chromosome 9 comprises 109,044,351 base pairs and represents >99.6% of the region. Analysis of the sequence reveals many intra- and interchromosomal duplications, including segmental duplications adjacent to both the centromere and the large heterochromatic block. We have annotated 1,149 genes, including genes implicated in male-to-female sex reversal, cancer and neurodegenerative disease, and 426 pseudogenes. The chromosome contains the largest interferon gene cluster in the human genome. There is also a region of exceptionally high gene and G + C content including genes paralogous to those in the major histocompatibility complex. We have also detected recently duplicated genes that exhibit different rates of sequence divergence, presumably reflecting natural selection.

Base Composition↗