Journal of Genetics and Genomics

Integrated Genomic and Network-Based Analyses of Complex Diseases and Human Disease Network

Olfat Al-Harazi, Sadiq Al Insaif, Monirah A. Al-Ajlan, Namik Kaya, Nduna Dzimiri, Dilek Colak

2016, 43(6): 349-367. doi: 10.1016/j.jgg.2015.11.002

Abstract (57) HTML PDF (2)

Abstract:
A disease phenotype generally reflects various pathobiological processes that interact in a complex network. The highly interconnected nature of the human protein interaction network (interactome) indicates that, at the molecular level, it is difficult to consider diseases as being independent of one another. Recently, genome-wide molecular measurements, data mining and bioinformatics approaches have provided the means to explore human diseases from a molecular basis. The exploration of diseases and a system of disease relationships based on the integration of genome-wide molecular data with the human interactome could offer a powerful perspective for understanding the molecular architecture of diseases. Recently, subnetwork markers have proven to be more robust and reliable than individual biomarker genes selected based on gene expression profiles alone, and achieve higher accuracy in disease classification. We have applied one of these methodologies to idiopathic dilated cardiomyopathy (IDCM) data that we have generated using a microarray and identified significant subnetworks associated with the disease. In this paper, we review the recent endeavours in this direction, and summarize the existing methodologies and computational tools for network-based analysis of complex diseases and molecular relationships among apparently different disorders and human disease network. We also discuss the future research trends and topics of this promising field.

Parkin Somatic Mutations Link Melanoma and Parkinson's Disease

Lotan Levin, Shani Srour, Jared Gartner, Oxana Kapitansky, Nouar Qutob, Shani Dror, Tamar Golan, Roy Dayan, Ronen Brener, Tamar Ziv, Mehdi Khaled, Ora Schueler-Furman, Yardena Samuels, Carmit Levy

2016, 43(6): 369-379. doi: 10.1016/j.jgg.2016.05.005

Abstract (79) HTML PDF (1)

Abstract:
Epidemiological studies suggest a direct link between melanoma and Parkinson's disease (PD); however, the underlying molecular basis is unknown. Since mutations in Parkin are the major driver of early-onset PD and Parkin was recently reported to play a role in cancer development, we hypothesized that Parkin links melanoma and PD. By analyzing whole exome/genome sequencing of Parkin from 246 melanoma patients, we identified five non-synonymous mutations, three synonymous mutations, and one splice region variant in Parkin in 3.6% of the samples. In vitro analysis showed that wild-type Parkin plays a tumor suppressive role in melanoma development resulting in cell-cycle arrest, reduction of metabolic activity, and apoptosis. Using a mass spectrometry-based analysis, we identified potential Parkin substrates in melanoma and generated a functional protein association network. The activity of mutated Parkin was assessed by protein structure modeling and examination of Parkin E3 ligase activity. The Parkin-E28K mutation impairs Parkin ubiquitination activity and abolishes its tumor suppressive effect. Taken together, our analysis of genomic sequence and in vitro data indicate that Parkin is a potential link between melanoma and Parkinson's disease. Our findings suggest new approaches for early diagnosis and treatment against both diseases.

Depletion of BBS Protein LZTFL1 Affects Growth and Causes Retinal Degeneration in Mice

Jiangsong Jiang, Kanyarat Promchan, Hong Jiang, Parirokh Awasthi, Heather Marshall, Adam Harned, Ven Natarajan

2016, 43(6): 381-391. doi: 10.1016/j.jgg.2015.11.006

Abstract (96) HTML PDF (2)

Abstract:
Bardet-Biedl syndrome (BBS) is a heterogeneous disease characterized by deficiencies in various organs that are caused by defects in genes involved in the genesis, structural maintenance, and protein trafficking of cilia. Leucine zipper transcription factor-like 1 (LZTFL1) has been identified as a BBS protein (BBS17), because patients with mutations in this gene exhibit the common BBS phenotypes. In this study, we generated a knockout mouse model to investigate the effects of LZTFL1 depletion. Lztfl1 knockout mice were born with low birth weight, reached similar weight to those of wild-type mice at 10 weeks of age, and later gained more weight than their wild-type counterparts. LZTFL1 was localized to the primary cilium of kidney cells, and the absence of LZTFL1 increased the ciliary localization of BBS9. Moreover, in the retinas of Lztfl1 knockout mice, the photoreceptor outer segment was shortened, the distal axoneme of photoreceptor connecting cilium was significantly enlarged, and rhodopsin was targeted to the outer nuclear layer. TUNEL assay showed that many of these abnormal photoreceptor cells in Lztfl1 knockout mice underwent apoptosis. Interestingly, the absence of LZTFL1 caused an abnormal increase of the adaptor protein complex 1 (AP1) in some photoreceptor cells. Based on these data, we conclude that LZTFL1 is a cilium protein and regulates animal weight and photoreceptor connecting cilium function probably by controlling microtubule assembly and protein trafficking in cilia.

Filamentation of Metabolic Enzymes in Saccharomyces cerevisiae

Qing-Ji Shen, Hakimi Kassim, Yong Huang, Hui Li, Jing Zhang, Guang Li, Peng-Ye Wang, Jun Yan, Fangfu Ye, Ji-Long Liu

2016, 43(6): 393-404. doi: 10.1016/j.jgg.2016.03.008

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Abstract:
Compartmentation via filamentation has recently emerged as a novel mechanism for metabolic regulation. In order to identify filament-forming metabolic enzymes systematically, we performed a genome-wide screening of all strains available from an open reading frame-GFP collection in Saccharomyces cerevisiae. We discovered nine novel filament-forming proteins and also confirmed those identified previously. From the 4159 strains, we found 23 proteins, mostly metabolic enzymes, which are capable of forming filaments in vivo. In silico protein-protein interaction analysis suggests that these filament-forming proteins can be clustered into several groups, including translational initiation machinery and glucose and nitrogen metabolic pathways. Using glutamine-utilising enzymes as examples, we found that the culture conditions affect the occurrence and length of the metabolic filaments. Furthermore, we found that two CTP synthases (Ura7p and Ura8p) and two asparagine synthetases (Asn1p and Asn2p) form filaments both in the cytoplasm and in the nucleus. Live imaging analyses suggest that metabolic filaments undergo sub-diffusion. Taken together, our genome-wide screening identifies additional filament-forming proteins in S. cerevisiae and suggests that filamentation of metabolic enzymes is more general than currently appreciated.

Structure-Based Genetic Analysis of Hel308a in the Hyperthermophilic Archaeon Sulfolobus islandicus

Xueguo Song, Jinfeng Ni, Yulong Shen

2016, 43(6): 405-413. doi: 10.1016/j.jgg.2016.03.003

Abstract (98) HTML PDF (2)

Abstract:
In archaea, the HEL308 homolog Hel308a (or Hjm) is implicated in stalled replication fork repair. The biochemical properties and structures of Hjm homologs are well documented, but in vivo mechanistic information is limited. Herein, a structure-based functional analysis of Hjm was performed in the genetically tractable hyperthermophilic archaeon, Sulfolobus islandicus. Results showed that domain V and residues within it, which affect Hjm activity and regulation, are essential and that the domain V-truncated mutants and site-directed mutants within domain V cannot complement hjm chromosomal deletion. Chromosomal hjm deletion can be complemented by ectopic expression of hjm under the control of its native promoter but not an artificial arabinose promoter. Cellular Hjm levels are kept constant under ultraviolet (UV) and methyl methanesulfonate (MMS) treatment conditions in a strain carrying a plasmid to induce Hjm overexpression. These results suggest that Hjm expression and activity are tightly controlled, probably at the translational level.

Development of japonica Photo-Sensitive Genic Male Sterile Rice Lines by Editing Carbon Starved Anther Using CRISPR/Cas9

Quanlin Li, Dabing Zhang, Mingjiao Chen, Wanqi Liang, Jiaojun Wei, Yiping Qi, Zheng Yuan

2016, 43(6): 415-419. doi: 10.1016/j.jgg.2016.04.011

Abstract (139) HTML PDF (6)

Abstract:

2016 Vol. 43, No. 6