This blog post is a joint contribution by Joannella Morales, Jane Loveland, Adam Frankish, Fiona Cunningham and Astrid Gall.

We are pleased to introduce the Matched Annotation from the NCBI and EMBL-EBI (MANE) project. This new joint initiative between EMBL-EBI’s Ensembl project and NCBI’s RefSeq project aims to release a genome-wide transcript set that contains one well-supported transcript per protein-coding locus. All transcripts in the MANE set will perfectly align to GRCh38 and will represent 100% identity (5’UTR, coding sequence, 3’UTR) between the RefSeq (NM) and corresponding Ensembl (ENST) transcript.
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Functional genomics data from DANIO-CODE has been released to the public. This international effort, similar to ENCODE in human and mouse, seeks to characterise the functional elements in the zebrafish (Danio rerio) genome. Announced on Saturday at the International Zebrafish Conference, the DANIO-CODE dataset exists as a track hub, which can be viewed in Ensembl.

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From Ensembl 93 onwards, we plan to recommend newer versions of Perl (5.14- 5.26) and BioPerl (1.6.924) when using the Ensembl Perl API. This may affect pipelines which employ the Ensembl Perl API, since we will no longer actively support older versions of Perl and BioPerl.

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I am writing in my capacity as leader of the Ensembl project based at the European Molecular Biology Laboratory’s European Bioinformatics Institute (EMBL-EBI) based near Cambridge, England. Ensembl is one of the world’s leading sources of genome information and a central aggregation point for genomic data.

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Please note that the archive websites for Ensembl releases 71 (April 2013) and 72 (June 2013) will be retired in July when version 85 is released.

This is in accordance with our rolling retirement policy, whereby archives more than three years old are retired unless they include the last instance of the previous assembly from one of our key species (human, mouse and zebrafish).

For more information about how to use archives, please see our previous blog post on the topic; a list of all current archives is available on the main website.

A mysteriously common debilitating genetic disorder. A deadly tropical disease. One of my favourite stories in the history of genetics weaves together these two elements – it’s a good one and it always deserves a re-telling – that of malaria and sickle cell anaemia.

This story captures my attention and inspires me in the power of scientific observation, curiosity and experiment. I’m sure you are all aware of the details of this worn-out tale: it is used as an example in classrooms and lecture theatres every year to explain Mendelian genetics, haploinsufficiency, physiology, disease and protein structure and function to young scientists. To mark the coincidental coinciding of DNA day and Malaria day, we wanted to re-visit this ‘historical’ example of how scientific observation and experimental approaches have led to the understanding of how a disease as debilitating as sickle cell anaemia paradoxically persists in the human population.

Molecular biology and bioinformatics have transformed the face of biological research over the last few decades. The speed that scientists can sequence and analyse DNA means that global collaborations that study thousands of individuals are beginning to shed light on a range of different diseases.

Sickle-cell anaemia is a disease in which red blood cells form an abnormal crescent (or sickle) shape. It is an inherited disorder, and was the first ever to be attributed to a specific genetic variant (rs334, see it here in Ensembl).

rs334_info

In 1949, ‘Sickle Cell Anaemia, a Molecular Disease’, from Pauling et al. identified a difference in the electrophoretic mobility between haemoglobin from healthy individuals and those with sickle-cell anaemia caused by a change in molecular structure of haemoglobin responsible for the sickling process [1]. The genetic variant (A, Reference:T) that causes cell sickling results in the substitution of a conserved glutamic acid residue at position 7 in beta chain of haemoglobin to a valine [2].

You can find this information in the Genes and regulation section for this variant. In the table below, which has been filtered to see only missense variants, the ‘Allele (transcript allele)’ column describes the variant allele (A) and the  transcript allele (T, as the HBB gene is located on the reverse strand). You can also see the nature and location of the variant on the transcript in the ‘Position’, ‘Amino acid’ and ‘Codons’ columns. The SIFT and Polyphen algorithms predict the effect of the amino acid change on protein structure and function. Interestingly, only the SIFT algorithm predicts that the T/A variant would have deleterious effect on haemoglobin structure and function, confirming that predictions can never be as accurate as experimental evidence.

rs334_consequences

Only those individuals that are homozygous for the variant allele develop sickle cell anaemia, although heterozygous individuals do have the much more manageable sickle cell trait. If untreated, individuals with sickle cell anaemia have a shorter than normal life expectancy, experiencing lethargy and breathlessness throughout their lives, with increased risk of stroke and pulmonary hypertension, as well as increased vulnerability to infection. Individuals with the milder sickle cell trait can experience problems in low oxygen or as a result of severe physical exercise, but can mostly be expected to live normal lives.

As such it would be expected that this variant would be rare in human populations. However, observations made in mid-20th century revealed that this variant is, in fact, surprisingly common in African, African American and Caribbean populations (you can see this in the 1000 Genomes allele frequencies available under Population genetics in Ensembl). Coincidentally, these were people descended from those who came from areas where malaria is prevalent [3]. Why was this happening?

rs334_pop_genetics

Individuals carrying just one copy of the variant allele were known not to develop sickle cell anaemia, leading rather normal lives. However, it was found that these same individuals, were in fact highly protected against malaria. It turned out that, quite bizarrely, having alternate alleles at this loci simultaneously prevented infection from the malaria parasite with entirely manageable sickle manifestations! Therefore, individuals with one copy of each allele have a greater chance of survival in geographical areas where malaria is endemic, preserving both alleles in the population.

Understanding this relationship has led to a deeper understanding of the infective lifecycle of the malaria parasite and novel approaches in combating malaria [4-5], but also an appreciation of the genetic factors leading to sickle-cell anaemia.

This story exemplifies how observation, epidemiology and scientific investigation can uncover the mysteries of a human disease and provide important insights for its treatment. Nowadays, this gold standard of studying single genetic disorders has been multiplied and sped up on an unprecedented scale. There are now numerous projects that are aimed at sequencing the DNA of many individuals with different diseases and using the power of bioinformatics to analyse how genetic variation might lay at the foundations for previously poorly understood diseases.

[1] Pauling L. et al. Sickle cell anemia a molecular disease Science, 1949 Nov 25;110(2865):543-8

[2] Ingram VM et al. Abnormal human haemoglobins. III. The chemical difference between normal and sickle cell haemoglobins Biochim Biophys Acta 1959 36: 543–548

[3] Allison AC et al. Protection Afforded by Sickle-cell Trait Against Subtertian Malarial Infection 1954 Br Med J 1 (4857): 290–294

[4] Mounkaila A. et al. Sickle Cell Trait Protects Against Plasmodium falciparum Infection American Journal of Epidemiology, 2012 176 175-185

[5]  Gregory LaMonte et al. Translocation of Sickle Cell Erythrocyte MicroRNAs into Plasmodium falciparum Inhibits Parasite Translation and Contributes to Malaria Resistance Cell Host & Microbe, 2012 12 187-199

 

Please note that the archive website for Ensembl release 68 (Jul 2012) will be retired in September when version 82 is released.

This is in accordance with our rolling retirement policy, whereby archives more than three years old are retired unless they include the last instance of the previous assembly from one of our key species (human, mouse and zebrafish).

For more information about how to use archives, please see our previous blog post on the topic; a list of all current archives is available on the main website.

In line with EMBL-EBI policy, from the end of 2015 Ensembl will be removing support for DAS from our browser. This means that we will no longer provide our annotations over DAS and that we will not visualise third party annotation provided to us via DAS. If you have data with genomic coordinates that you wish to present in Ensembl then we recommend that you do this using TrackHubs. For annotation on other coordinate systems, we are currently working on providing support for this and will announce developments in this area over the course of the coming year. If you need more details then please get in touch with us at helpdesk@ensembl.org.

My recent trip to Malawi as part of a Wellcome Trust Open Door Workshop has really reminded me how privileged I really am. I’m an Outreach Officer, which means that I have the privilege to travel out to institutes around the world to deliver free Ensembl workshops. Most of the time, these workshops are in Europe or the US, at fancy research institutes and universities, and it’s an awesome privilege to facilitate research at these institutes.

An even greater privilege is to be involved in the Open Door Workshops on Working with the Human Genome Sequence, organised by Wellcome Trust Advanced Courses, which head out to more developing countries to teach. They’re called ‘Open Door’ because all the resources we teach in them are free and open on the web, which means anyone, anywhere, with nothing but an internet connection can do it. I teach the Ensembl section of the course, but we also cover other resources from the EBI, Sanger Institute, NCBI and elsewhere.

We hold these courses at Wellcome Trust research centres, for example the Malawi-Liverpool Wellcome Trust I visited recently, which are fantastic investments by the Wellcome Trust in research around the world. Participants travel from all over the continent to attend the course; attendance is free (with selection) and the Wellcome Trust can even fund travel bursaries. It is a great privilege for me to be able to travel to these locations and to teach them all about Ensembl.

Group photograph

The group from the Open Door Workshop at the Malawi-Liverpool Wellcome Trust. Featuring instructors me (seated, second from left), Jane Loveland (Sanger Institute; seated, middle), Rob Finn (EBI; back row, far left), Charlie Steward (Sanger Institute; back row, middle) and Matt Clark (TGAC; back row, second from right). Photo by Heidi Hauser (Wellcome Trust Advanced Courses).

I am proud to present Ensembl to these workshops participants. Partly because I think it’s an amazing resource that can really facilitate research. Partly because we give it away for free, and I know this makes a huge difference to researchers whose labs are not well funded. Even in labs with £1 million grants, money is always tight, but for many of the people who attend our workshops, labs struggle with knackered PCR machines, ghost equipment that they can’t afford to buy the reagents to use and a complete reliance on Open Access publishing as they can’t pay for journal subscriptions, yet they still manage to produce world-class science. If they had to choose between replacing those broken machines and a pay-per-use or subscription-only bioinformatics resource, it would really be a no-brainer. But by giving them a free resource means they don’t have to make that choice. Indeed, it gives them the opportunity to carry out research that doesn’t need any expensive equipment or reagents.

The Wellcome Trust is one of the major funders of Ensembl. We are so grateful to them for allowing us to make our data freely available, so that everybody can make use of it. It really is a privilege.