Dr Ireena Dutta
Programme and Strategy
The Programme and Strategy team is led by the Associate Director, Programme and Strategy, Dr Ireena Dutta. Ireena has a PhD in antimicrobial resistance from the University of Cambridge, and extensive experience in knowledge transfer, science communication, and strategy development. She remains an enthusiastic microbiologist.
Knowledge sharing and 'genomic' healthcare.
Nature Biotechnology 2005;23;2;169-70
The DNA sequence of the human X chromosome.
The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence.
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.
The DNA sequence and comparative analysis of human chromosome 10.
The finished sequence of human chromosome 10 comprises a total of 131,666,441 base pairs. It represents 99.4% of the euchromatic DNA and includes one megabase of heterochromatic sequence within the pericentromeric region of the short and long arm of the chromosome. Sequence annotation revealed 1,357 genes, of which 816 are protein coding, and 430 are pseudogenes. We observed widespread occurrence of overlapping coding genes (either strand) and identified 67 antisense transcripts. Our analysis suggests that both inter- and intrachromosomal segmental duplications have impacted on the gene count on chromosome 10. Multispecies comparative analysis indicated that we can readily annotate the protein-coding genes with current resources. We estimate that over 95% of all coding exons were identified in this study. Assessment of single base changes between the human chromosome 10 and chimpanzee sequence revealed nonsense mutations in only 21 coding genes with respect to the human sequence.
The vanC-3 vancomycin resistance gene cluster of Enterococcus flavescens CCM 439.
The Journal of antimicrobial chemotherapy 2003;51;3;703-6
Enterococcus flavescens CCM 439 is phenotypically similar to Enterococcus casseliflavus; it possesses intrinsic low-level resistance to vancomycin and has the VanC phenotype. The complete vanC-3 vancomycin resistance gene cluster was cloned and sequenced, and found to contain five open reading frames. These encoded five proteins that displayed a high degree of amino acid identity to the proteins of the vanC-2 cluster of E. casseliflavus. The serine racemases displayed the lowest degree of identity (97%), whereas the response regulators VanR(C-2) and VanR(C-3) were 100% identical. Long-PCR-RFLP analysis of the vanC-3 and vanC-2 gene clusters distinguished E. flavescens CCM 439 from E. casseliflavus ATCC 25788 due to the absence of a single EcoRV restriction endonuclease site from the E. flavescens gene cluster. However, the lack of nucleotide divergence between the sequences of the vanC-2 and vanC-3 clusters casts doubt on the validity of E. flavescens and E. casseliflavus being classed as distinct species.
Biochemical and genetic characterization of the vanC-2 vancomycin resistance gene cluster of Enterococcus casseliflavus ATCC 25788.
Antimicrobial agents and chemotherapy 2002;46;10;3125-32
The vanC-2 cluster of Enterococcus casseliflavus ATCC 25788 consisted of five genes (vanC-2, vanXY(C-2), vanT(C-2), vanR(C-2), and vanS(C-2)) and shared the same organization as the vanC cluster of E. gallinarum BM4174. The proteins encoded by these genes displayed a high degree of amino acid identity to the proteins encoded within the vanC gene cluster. The putative D,D-dipeptidase-D,D-carboxypeptidase, VanXY(C-2), exhibited 81% amino acid identity to VanXY(C), and VanT(C-2) displayed 65% amino acid identity to the serine racemase, VanT. VanR(C-2) and VanS(C-2) displayed high degrees of identity to VanR(C) and VanS(C), respectively, and contained the conserved residues identified as important to their function as a response regulator and histidine kinase, respectively. Resistance to vancomycin was expressed inducibly in E. casseliflavus ATCC 25788 and required an extended period of induction. Analysis of peptidoglycan precursors revealed that UDP-N-acetylmuramyl-L-Ala-delta-D-Glu-L-Lys-D-Ala-D-Ser could not be detected until several hours after the addition of vancomycin, and its appearance coincided with the resumption of growth. The introduction of additional copies of the vanT(C-2) gene, encoding a putative serine racemase, and the presence of supplementary D-serine in the growth medium both significantly reduced the period before growth resumed after addition of vancomycin. This suggested that the availability of D-serine plays an important role in the induction process.