Cell Biology & Molecular Genetics

Permanent URI for this communityhttp://hdl.handle.net/1903/11811

Browse

Author: search.filters.author.Hannenhalli, Sridhar

Search Results

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Functional divergence of gene duplicates – a domain-centric view
    (Springer Nature, 2012-07-27) Khaladkar, Mugdha; Hannenhalli, Sridhar
    Gene duplicates have been shown to evolve at different rates. Here we further investigate the mechanism and functional underpinning of this phenomenon by assessing asymmetric evolution specifically within functional domains of gene duplicates. Based on duplicate genes in five teleost fishes resulting from a whole genome duplication event, we first show that a Fisher Exact test based approach to detect asymmetry is more sensitive than the previously used Likelihood Ratio test. Using our Fisher Exact test, we found that the evolutionary rate asymmetry in the overall protein is largely explained by the asymmetric evolution within specific protein domains. Moreover, among cases of asymmetrically evolving domains, for the gene copy containing a fast evolving domain, the non-synonymous substitutions often cluster within the fast evolving domain. We found that rare substitutions were preferred within asymmetrically evolving domains suggestive of functional divergence. While overall ~32 % of the domains tested were found to be evolving asymmetrically, certain protein domains such as the Tyrosine and Ser/Thr Kinase domains had a much greater prevalence of asymmetric evolution. Finally, based on the spatial expression of Zebra fish duplicate proteins during development, we found that protein pairs containing asymmetrically evolving domains had a greater divergence in gene expression as compared to the duplicate proteins that did not exhibit asymmetric evolution. Taken together, our results suggest that the previously observed asymmetry in the overall duplicate protein evolution is largely due to divergence of specific domains of the protein, and coincides with divergence in spatial expression domains.
  • Thumbnail Image
    Item
    Derepression of Cancer/Testis Antigens in cancer is associated with distinct patterns of DNA Hypomethylation
    (Springer Nature, 2013-03-22) Kim, Robert; Kulkarni, Prakash; Hannenhalli, Sridhar
    The Cancer/Testis Antigens (CTAs) are a heterogeneous group of proteins whose expression is typically restricted to the testis. However, they are aberrantly expressed in most cancers that have been examined to date. Broadly speaking, the CTAs can be divided into two groups: the CTX antigens that are encoded by the X-linked genes and the non-X CT antigens that are encoded by the autosomes. Unlike the non-X CTAs, the CTX antigens form clusters of closely related gene families and their expression is frequently associated with advanced disease with poorer prognosis. Regardless however, the mechanism(s) underlying their selective derepression and stage-specific expression in cancer remain poorly understood, although promoter DNA demethylation is believed to be the major driver. Here, we report a systematic analysis of DNA methylation profiling data from various tissue types to elucidate the mechanism underlying the derepression of the CTAs in cancer. We analyzed the methylation profiles of 501 samples including sperm, several cancer types, and their corresponding normal somatic tissue types. We found strong evidence for specific DNA hypomethylation of CTA promoters in the testis and cancer cells but not in their normal somatic counterparts. We also found that hypomethylation was clustered on the genome into domains that coincided with nuclear lamina-associated domains (LADs) and that these regions appeared to be insulated by CTCF sites. Interestingly, we did not observe any significant differences in the hypomethylation pattern between the CTAs without CpG islands and the CTAs with CpG islands in the proximal promoter. Our results corroborate that widespread DNA hypomethylation appears to be the driver in the derepression of CTA expression in cancer and furthermore, demonstrate that these hypomethylated domains are associated with the nuclear lamina-associated domains (LADS). Taken together, our results suggest that wide-spread methylation changes in cancer are linked to derepression of germ-line-specific genes that is orchestrated by the three dimensional organization of the cancer genome.
  • Thumbnail Image
    Item
    Conservation in first introns is positively associated with the number of exons within genes and the presence of regulatory epigenetic signals
    (Springer Nature, 2014-06-26) Park, Seung Gu; Hannenhalli, Sridhar; Choi, Sun Shim
    Genomes of higher eukaryotes have surprisingly long first introns and in some cases, the first introns have been shown to have higher conservation relative to other introns. However, the functional relevance of conserved regions in the first introns is poorly understood. Leveraging the recent ENCODE data, here we assess potential regulatory roles of conserved regions in the first intron of human genes. We first show that relative to other downstream introns, the first introns are enriched for blocks of highly conserved sequences. We also found that the first introns are enriched for several chromatin marks indicative of active regulatory regions and this enrichment of regulatory marks is correlated with enrichment of conserved blocks in the first intron; the enrichments of conservation and regulatory marks in first intron are not entirely explained by a general, albeit variable, bias for certain marks toward the 5’ end of introns. Interestingly, conservation as well as proportions of active regulatory chromatin marks in the first intron of a gene correlates positively with the numbers of exons in the gene but the correlation is significantly weakened in second introns and negligible beyond the second intron. The first intron conservation is also positively correlated with the gene’s expression level in several human tissues. Finally, a gene-wise analysis shows significant enrichments of active chromatin marks in conserved regions of first introns, relative to the conserved regions in other introns of the same gene. Taken together, our analyses strongly suggest that first introns are enriched for active transcriptional regulatory signals under purifying selection.