Trends in genetics

Human evolutionary genomics: ethical and interpretive issues.

Publication Date: 2012 Jan 20 PMID: 22265990
Authors: Vitti, J. J. - Cho, M. K. - Tishkoff, S. A. - Sabeti, P. C.
Journal: Trends Genet

Genome-wide computational studies can now identify targets of natural selection. The unique information about humans these studies reveal, and the media attention they attract, indicate the need for caution and precision in communicating results. This need is exacerbated by ways in which evolutionary and genetic considerations have been misapplied to support discriminatory policies, by persistent misconceptions of these fields and by the social sensitivity surrounding discussions of racial ancestry. We discuss the foundations, accomplishments and future directions of human evolutionary genomics, attending to ways in which the interpretation of good science can go awry, and offer suggestions for researchers to prevent misapplication of their work.

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The p53 network: cellular and systemic DNA damage responses in aging and cancer.

Publication Date: 2012 Jan 19 PMID: 22265392
Authors: Reinhardt, H. C. - Schumacher, B.
Journal: Trends Genet

Genome instability contributes to cancer development and accelerates age-related pathologies as evidenced by a variety of congenital cancer susceptibility and progeroid syndromes that are caused by defects in genome maintenance mechanisms. DNA damage response (DDR) pathways that are mediated through the tumor suppressor p53 play an important role in the cell-intrinsic responses to genome instability, including a transient cell cycle arrest, senescence and apoptosis. Both senescence and apoptosis are powerful tumor-suppressive pathways preventing the uncontrolled proliferation of transformed cells. However, both pathways can potentially deplete stem and progenitor cell pools, thus promoting tissue degeneration and organ failure, which are both hallmarks of aging. p53 signaling is also involved in mediating non-cell-autonomous interactions with the innate immune system and in the systemic adjustments during the aging process. The network of p53 target genes thus functions as an important regulator of cancer prevention and aging.

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A complex 'mRNA degradation code' controls gene expression during animal development.

Publication Date: 2012 Feb PMID: 22257633
Authors: Alonso, C. R.
Journal: Trends Genet

Current understanding of the molecular mechanisms underlying mRNA degradation indicates that specific mRNA degradation rates are primarily encoded within the mRNA message itself in the form of cis-regulatory elements bearing particular primary sequences and/or secondary-structures. Such control elements are operated by RNA-binding proteins (RBPs) and/or miRNA-containing complexes. Based on the large number of RBPs and miRNAs encoded in metazoan genomes, their complex developmental expression and that specific RBP and miRNA interactions with mRNAs can lead to distinct degradation rates, I propose that developmental gene expression is shaped by a complex 'mRNA degradation code' with high information capacity. Localised cellular events involving the modification of RBP and/or miRNA target sequences in mRNAs by alternative polyadenylation added to the activation of specific RBP and miRNA activities via cell signalling are predicted to further expand the capacity of the mRNA degradation code by coupling it to dynamic events experienced by cells at specific spatiotemporal coordinates within the developing embryo.

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A model for chromosome condensation based on the interplay between condensin and topoisomerase II.

Publication Date: 2012 Jan 9 PMID: 22236810
Authors: Baxter, J. - Aragon, L.
Journal: Trends Genet

The compaction of chromatin that occurs when cells enter mitosis is probably the most iconic process of dividing cells. Mitotic chromosomal compaction or 'condensation' is functionally linked to resolution of chromosomal intertwines, transcriptional shut-off and complete segregation of chromosomes. At present, understanding of the molecular events required to convert interphase chromatin into mitotic chromosomes is limited. Here, we review recent advances in the field, focusing on potential chromosomal compaction mechanisms and their importance to chromosome segregation. We propose a model of how metaphase chromosomes could be shaped based on the enzymatic activities of condensin and topoisomerase II in overwinding and relaxation of the DNA fiber during mitosis. We suggest that condensin overwinding is an important requirement for intertwine resolution by topoisomerase II and, together with the inhibition of transcription, contributes to cytological mitotic chromosome appearance or 'condensation'.

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Cellular epigenetic stability and cancer.

Publication Date: 2012 Jan 5 PMID: 22226176
Authors: Sarkies, P. - Sale, J. E.
Journal: Trends Genet

When a cell divides, it must not only accurately duplicate its genome, but also restore its previous levels of gene expression. The information determining gene expression is often not directly encoded in the DNA and is hence termed 'epigenetic'. The molecular basis of epigenetic memory remains a subject of intense debate, but is likely to arise from the collaboration of several mechanisms, including histone post-translational modifications, transcription factors, DNA methylation and noncoding RNAs. In this article, we look at how these mechanisms interact to generate robust epigenetic states. We then consider recent observations that mitotic inheritance of stable gene expression can be compromised by interruption of DNA replication. We discuss how these data may provide direct evidence for a central role for histone modifications in transcriptional memory and how they could potentially provide an explanation for the some of the widespread alterations in transcription seen in cancer cells.

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Viral evolution in deep time: lentiviruses and mammals.

Publication Date: 2012 Feb PMID: 22197521
Authors: Gifford, R. J.
Journal: Trends Genet

Lentiviruses are a distinctive genus of retroviruses that cause chronic, persistent infections in mammals, including humans. The emergence of pandemic HIV type-1 (HIV-1) infection during the late 20th century shaped a view of lentiviruses as 'modern' viruses. However, recent research has revealed an entirely different perspective, elucidating aspects of an evolutionary relationship with mammals that extends across many millions of years. Such deep evolutionary history is likely to be typical of many host-virus systems, fundamentally underpinning their interactions in the present day. For this reason, establishing the deep history of virus and host interaction is key to developing a fully informed approach to tackling viral diseases. Here, I use the example of lentiviruses to illustrate how paleovirological, geographic and genetic calibrations allow observations of virus and host interaction across a wide range of temporal and spatial scales to be integrated into a coherent ecological and evolutionary framework.

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mRNP quality control goes regulatory.

Publication Date: 2012 Feb PMID: 22154474
Authors: Muhlemann, O. - Jensen, T. H.
Journal: Trends Genet

The accuracy of eukaryotic gene expression relies on efficient quality control (QC). Most steps in the gene expression pathway en route from transcription to translation are error-prone and QC systems have evolved to utilise many of these biochemical processes as checkpoints to monitor the production or function of mRNA-protein particles (mRNPs). Mechanistically, such evaluation of mRNP fitness is based on competition between the opposing activities of mRNP biogenesis and/or function and mRNP turnover. In fact, quite subtle alteration of any parameter can tip the balance between mRNP persistence and degradation and, therefore, QC checkpoints also comprise perfect opportunities for controlling cellular levels of individual or even entire families of transcripts. From this perspective, QC and gene regulation represent two outcomes of the same molecular process.

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A better prognosis for genetic association studies in mice.

Publication Date: 2012 Feb PMID: 22118772
Authors: Zheng, M. - Dill, D. - Peltz, G.
Journal: Trends Genet

Although inbred mouse strains have been the premier model organism used in biomedical research, multiple studies and analyses have indicated that genome-wide association studies (GWAS) cannot be productively performed using inbred mouse strains. However, there is one type of GWAS in mice that has successfully identified the genetic basis for many biomedical traits of interest: haplotype-based computational genetic mapping (HBCGM). Here, we describe how the methodological basis for a HBCGM study significantly differs from that of a conventional murine GWAS, and how an integrative analysis of its output within the context of other 'omic' information can enable genetic discovery. Consideration of these factors will substantially improve the prognosis for the utility of murine genetic association studies for biomedical discovery.

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The end of gonad-centric sex determination in mammals.

Publication Date: 2012 Feb PMID: 22078126
Authors: Arnold, A. P.
Journal: Trends Genet

The 20th-century theory of mammalian sex determination states that the embryo is sexually indifferent until the differentiation of gonads, after which sex differences in phenotype are caused by the differential effects of gonadal hormones. However, this theory is inadequate because some sex differences precede differentiation of the gonads and/or are determined by non-gonadal effects of the sexual inequality in the number and type of sex chromosomes. In this article, I propose a general theory of sex determination, which recognizes multiple parallel primary sex-determining pathways initiated by genes or factors encoded by the sex chromosomes. The separate sex-specific pathways interact to synergize with or antagonize each other, enhancing or reducing sex differences in phenotype.

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