On the Use of Gene Ontology Annotations to Assess Functional Similarity among Orthologs and Paralogs: A Short Report

On the Use of Gene Ontology Annotations to Assess Functional Similarity among Orthologs and Paralogs: A Short Report:
by Paul D. Thomas, Valerie Wood, Christopher J. Mungall, Suzanna E. Lewis, Judith A. Blake, on behalf of the Gene Ontology Consortium
A recent paper (Nehrt et al., PLoS Comput. Biol. 7:e1002073, 2011) has proposed a metric for the “functional similarity” between two genes that uses only the Gene Ontology (GO) annotations directly derived from published experimental results. Applying this metric, the authors concluded that paralogous genes within the mouse genome or the human genome are more functionally similar on average than orthologous genes between these genomes, an unexpected result with broad implications if true. We suggest, based on both theoretical and empirical considerations, that this proposed metric should not be interpreted as a functional similarity, and therefore cannot be used to support any conclusions about the “ortholog conjecture” (or, more properly, the “ortholog functional conservation hypothesis”). First, we reexamine the case studies presented by Nehrt et al. as examples of orthologs with divergent functions, and come to a very different conclusion: they actually exemplify how GO annotations for orthologous genes provide complementary information about conserved biological functions. We then show that there is a global ascertainment bias in the experiment-based GO annotations for human and mouse genes: particular types of experiments tend to be performed in different model organisms. We conclude that the reported statistical differences in annotations between pairs of orthologous genes do not reflect differences in biological function, but rather complementarity in experimental approaches. Our results underscore two general considerations for researchers proposing novel types of analysis based on the GO: 1) that GO annotations are often incomplete, potentially in a biased manner, and subject to an “open world assumption” (absence of an annotation does not imply absence of a function), and 2) that conclusions drawn from a novel, large-scale GO analysis should whenever possible be supported by careful, in-depth examination of examples, to help ensure the conclusions have a justifiable biological basis.

Contrasting patterns of evolution following whole genome versus tandem duplication events in Populus [RESEARCH]

Contrasting patterns of evolution following whole genome versus tandem duplication events in Populus [RESEARCH]:
Comparative analysis of multiple angiosperm genomes has implicated gene duplication in the expansion and diversification of many gene families. However, empirical data and theory suggest that whole-genome and small-scale duplication events differ with respect to the types of genes preserved as duplicate pairs. We compared gene duplicates resulting from a recent whole genome duplication to a set of tandemly duplicated genes in the model forest tree Populus trichocarpa. We used a combination of microarray expression analyses of a diverse set of tissues and functional annotation to assess factors related to the preservation of duplicate genes of both types. Whole genome duplicates are 700 bp longer and are expressed in 20% more tissues than tandem duplicates. Furthermore, certain functional categories are over-represented in each class of duplicates. In particular, disease resistance genes and receptor-like kinases commonly occur in tandem but are significantly under-retained following whole genome duplication, while whole genome duplicate pairs are enriched for members of signal transduction cascades and transcription factors. The shape of the distribution of expression divergence for duplicated pairs suggests that nearly half of the whole genome duplicates have diverged in expression by a random degeneration process. The remaining pairs have more conserved gene expression than expected by chance, consistent with a role for selection under the constraints of gene balance. We hypothesize that duplicate gene preservation in Populus is driven by a combination of subfunctionalization of duplicate pairs and purifying selection favoring retention of genes encoding proteins with large numbers of interactions.

Células tronco e perspectivas na cura da cegueira

Não minha gente, não foi um pastor nem milagreiro -- Usando células tronco embrionárias, cientistas foram capazes de curar dois pacientes considerados definitivamente cegos em decorrência de doenças degenerativas. Após vários meses, os pacientes não demonstraram qualquer sinal de rejeição ou propensão a formação de tumores.

Embora ainda seja cedo para afirmar que o tratamento servirá para todos imediatamente, mas sem dúvidas apresenta uma esperança para aqueles que sofrem sem poder enxergar o mundo a sua volta.

O artigo completo pode ser encontrado aqui: http://press.thelancet.com/stemcelleyes.pdf

GenomeView: a next-generation genome browser

GenomeView: a next-generation genome browser:
Due to ongoing advances in sequencing technologies, billions of nucleotide sequences are now produced on a daily basis. A major challenge is to visualize these data for further downstream analysis. To this end, we present GenomeView, a stand-alone genome browser specifically designed to visualize and manipulate a multitude of genomics data. GenomeView enables users to dynamically browse high volumes of aligned short-read data, with dynamic navigation and semantic zooming, from the whole genome level to the single nucleotide. At the same time, the tool enables visualization of whole genome alignments of dozens of genomes relative to a reference sequence. GenomeView is unique in its capability to interactively handle huge data sets consisting of tens of aligned genomes, thousands of annotation features and millions of mapped short reads both as viewer and editor. GenomeView is freely available as an open source software package.

A man for our season

Post muito interessante, retirado do blog do Sean Eddy.
Traz uma coleção de artigos que nos faz refletir sobre a realidade da comunidade científica.
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A man for our season:

Peter Lawrence and Michael Locke wrote an essay that made an enormous impression on me (“A Man for Our Season”, Nature, 1997). For a long time a copy hung on the wall of the lab. I was reminded of it last week when I read a recent interview with Lawrence (“The Heart of Research is Sick”, Lab Times, 2011).

When it’s hard to reach me because I’m busy with my own research work; when I have to decline to travel to give seminars; when postdocs in my lab publish their own independent work without my name on their papers; when our papers go to open-access journals that do a good job of delivering substantive content regardless of that journal’s supposed “impact”; when I spend time on the details of a constructive peer review; when I help HHMI recruit and mentor younger scientists — and indeed when I moved to Janelia Farm, to be part of the idealistic culture that we want to build here — it’s principles much like Peter Lawrence’s that I’m aspiring to.

Real lives and white lies in the funding of scientific research
PLoS Biology, 2009

Retiring retirement

Nature, 2008

The mismeasurement of science

Current Biology, 2007

Men, women, and ghosts in science

PLoS Biology, 2006

The politics of publication

Nature, 2003

Rank injustice

Nature, 2002

Science or alchemy?

Nature Reviews Genetics, 2001

A man for our season

Nature, 1997

Parallel bacterial evolution within multiple patients identifies candidate pathogenicity genes.

Parallel bacterial evolution within multiple patients identifies candidate pathogenicity genes.: Parallel bacterial evolution within multiple patients identifies candidate pathogenicity genes.

Nat Genet. 2011 Dec;43(12):1275-80

Authors: Lieberman TD, Michel JB, Aingaran M, Potter-Bynoe G, Roux D, Davis MR, Skurnik D, Leiby N, LiPuma JJ, Goldberg JB, McAdam AJ, Priebe GP, Kishony R

Abstract

Bacterial pathogens evolve during the infection of their human host(1-8), but separating adaptive and neutral mutations remains challenging(9-11). Here we identify bacterial genes under adaptive evolution by tracking recurrent patterns of mutations in the same pathogenic strain during the infection of multiple individuals. We conducted a retrospective study of a Burkholderia dolosa outbreak among subjects with cystic fibrosis, sequencing the genomes of 112 isolates collected from 14 individuals over 16 years. We find that 17 bacterial genes acquired nonsynonymous mutations in multiple individuals, which indicates parallel adaptive evolution. Mutations in these genes affect important pathogenic phenotypes, including antibiotic resistance and bacterial membrane composition and implicate oxygen-dependent regulation as paramount in lung infections. Several genes have not previously been implicated in pathogenesis and may represent new therapeutic targets. The identification of parallel molecular evolution as a pathogen spreads among multiple individuals points to the key selection forces it experiences within human hosts.
PMID: 22081229 [PubMed - indexed for MEDLINE]

Identifying Single Copy Orthologs in Metazoa

Identifying Single Copy Orthologs in Metazoa:

by Christopher J. Creevey, Jean Muller, Tobias Doerks, Julie D. Thompson, Detlev Arendt, Peer Bork

The identification of single copy (1-to-1) orthologs in any group of organisms is important for functional classification and phylogenetic studies. The Metazoa are no exception, but only recently has there been a wide-enough distribution of taxa with sufficiently high quality sequenced genomes to gain confidence in the wide-spread single copy status of a gene.
Here, we present a phylogenetic approach for identifying overlooked single copy orthologs from multigene families and apply it to the Metazoa. Using 18 sequenced metazoan genomes of high quality we identified a robust set of 1,126 orthologous groups that have been retained in single copy since the last common ancestor of Metazoa. We found that the use of the phylogenetic procedure increased the number of single copy orthologs found by over a third more than standard taxon-count approaches. The orthologs represented a wide range of functional categories, expression profiles and levels of divergence.
To demonstrate the value of our set of single copy orthologs, we used them to assess the completeness of 24 currently published metazoan genomes and 62 EST datasets. We found that the annotated genes in published genomes vary in coverage from 79% (Ciona intestinalis) to 99.8% (human) with an average of 92%, suggesting a value for the underlying error rate in genome annotation, and a strategy for identifying single copy orthologs in larger datasets. In contrast, the vast majority of EST datasets with no corresponding genome sequence available are largely under-sampled and probably do not accurately represent the actual genomic complement of the organisms from which they are derived.

Evolutionary biology: A ratchet for protein complexity

Evolutionary biology: A ratchet for protein complexity:

Evolutionary biology: A ratchet for protein complexity

Nature 481, 7381 (2012). doi:10.1038/nature10816
Authors: W. Ford Doolittle

Jogo duro: mecanismos genéticos da cooperação

A existência de comportamentos cooperativos na natureza é uma questão que há séculos desafia a curiosidade de cientistas, pois se apenas o indivíduo mais adaptado (não o mais forte) sobrevive, genes que estejam relacionados com a cooperação deveriam conferir desvantagem, sendo então eliminados da natureza ao longo das gerações. Um grupo do Massachusetts Institute of Technology (MIT), publicou ano passado um artigo importante mostrando bases genéticas que explicam a vantagem evolutiva da cooperação.

O grupo utilizou a levedura Saccharomyces cerevisiae como modelo, dada a facilidade de manipulação genética e crescimento em laboratório. A levedura consome preferencialmente glicose, que pode ser capturada diretamente do ambiente. Na ausência de glicose, sacarose pode ser usada. No entanto, a sacarose não pode ser absorvida diretamente e a levedura precisa secretar uma enzima chamada invertase, que quebra a sacarose em glicose e frutose, que são então absorvidos. Como tal processo ocorre fora da célula, uma levedura mais "esperta" poderia tirar vantagem do processo e absorver glicose sem produzir invertase - uma forma de trapaça que pode conferir vantagens significativas e até mesmo extinguir as leveduras que produzem invertase caso toda a glicose produzida se dilua no ambiente.

Os experimentos iniciais mostraram que os cooperadores têm acesso preferencial a 1% da glicose gerada pelo seu trabalho, sendo o restante diluído no ambiente, podendo ser usado por trapaceiros. A ideia do grupo foi então colocar uma população cooperadora (produzindo invertase) para competir com outra trapaceira (não produtora de invertase). Como esperado, os autores observaram que uma pequena fração de trapaceiros pode invadir a população de cooperadores. Surpreendentemente, o oposto também ocorre, pois aquele 1% de glicose que os cooperadores conseguem garantir lhes confere uma vantagem significativa num meio dominado por trapaceiros. Em resumo, sempre é alcançado um equilíbrio entre trapaceiros e cooperadores. Além disso, tal equilíbrio é independente da fração inicial de cooperadores.

O grupo elaborou mais um experimento elegante, modificando geneticamente os cooperadores de maneira que seu crescimento dependa da absorção do aminoácido histidina. Assim, o custo da cooperação pode ser controlado a partir da quantidade de histidina fornecida. Por exemplo, quanto menos histidina fornecida, mais cara é a cooperação. Os pesquisadores descobriram então que quanto maior o custo da cooperação, menor a fração de cooperadores e menor o crescimento de todos, pois os trapaceiros dependem do trabalho dos cooperadores para obter glicose.



O estudo de tal equilíbrio é muito interessante, pois muita glicose no ambiente repleto de cooperadores favorece fortemente a invasão de trapaceiros. Se a glicose é fornecida de forma constante, os cooperadores podem ser até mesmo levados a extinção. Neste caso em particular, a co-existência entre trapaceiros e cooperadores também parece ocorrer na natureza, onde populações com diferentes números de cópias do gene da invertase podem co-existir. Os resultados podem ser explicados pela teoria dos jogos, ramo da matemática que estuda situações estratégicas onde os jogadores tentam maximizar seu retorno. Mais especificamente, o caso do equilíbrio entre leveduras cooperadoras e trapaceiras é melhor acomodado pelo jogo do monte de neve (snowdrift game), em que dois motoristas estão parados em frente a um monte de neve. Neste jogo, a melhor decisão é sempre a oposta do outro. Se o motorista A limpar a estrada, o melhor que o motorista B pode fazer é ficar no carro. O pior cenário possível é se ninguém sair para retirar a neve.

A levedura é um ótimo modelo para estudar as bases genéticas da cooperação, pois as decisões são tomadas com base na genética em resposta ao ambiente (ao contrário dos humanos, onde decisões são influenciadas decisivamente por pensamentos e emoções). O estudo abre ainda a possibilidade de estudar outras situações que podem envolver o equilíbrio entre trapaceiros e cooperadores, como por exemplo na degradação de amido. Seria ainda interessante buscar modelos que permitam estudos similares em espécies multicelulares.

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Referência e figura:
Gore J, Youk H, van Oudenaarden A. Snowdrift game dynamics and facultative cheating in yeast. Nature. 2009; 459(7244):253-6. PMID: 19349960; PMCID: PMC2888597; doi: 10.1038/nature07921