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Home | Pregnancy Timeline | News Alerts | News Archive July 23, 2013

 

retina

Above: a human iris.





The middle of our eye is filled with a clear gel called
vitreous (vi-tree-us) that is attached to the retina.





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Researchers create a complete description of genes expressed in the human retina

Investigators at Massachusetts Eye and Ear and Harvard Medical School have published the most thorough description of gene expression in the human retina reported to date.

In a study published today in the journal BMC Genomics, Drs. Michael Farkas, Eric Pierce and colleagues in the Ocular Genomics Institute (OGI) at Mass. Eye and Ear reported a complete catalog of the genes expressed in the retina.


The retina is the neural tissue in the back of the eye that initiates vision. It is responsible for receiving light signals and converting them into neurologic signals, and then sending those signals to the brain so that we can see. If one thinks of the eye as a camera, the retina in the "film" in the camera.


For these studies, the investigators used a technique called RNA sequencing (RNA-seq) to identify all of the messenger RNAs (mRNAs) produced in the human retina. The resulting catalog of expressed genes, or transcriptome, demonstrates that the majority of the 20,000+ genes in the human body are expressed in the retina. This in itself is not surprising, because the retina is a complex tissue comprised of 60 cell types.


In a more surprising result, Dr. Farkas and colleagues identified almost 30,000 new exons and over 100 potential new genes that had not been identified previously.

Exons are the portions of the genome that are used to encode proteins or other genetic elements. The investigators validated almost 15,000 of these novel transcript features and found that more than 99 percent of them could be reproducibly detected.

Several thousand of the novel exons appear to be used specifically in the retina. In total, the newly detected mRNA sequence increased the number of exons identified in the human genome by 3 percent.


"While this may not sound like a lot, it shows that there is more to discover about the human genome, and that each tissue may use distinct parts of the genome," said Dr. Pierce, Director of the OGI and the Solman and Libe Friedman Associate Professor of Ophthalmology, Harvard Medical School.

This work is valuable to help scientists understand how the retina works, and how it is affected by disease. For example, Dr. Pierce and colleagues in the OGI study inherited retinal degenerations, which are common causes of vision loss. These diseases are caused by misspellings or mutations in genes that are needed for vision. To date, investigators have identified more than 200 retinal degeneration disease genes, but still can't find the cause of disease for up to ½ of the patients affected by these disorders. Identification of new exons used in the retina may help find the cause of disease in these patients. The transcriptome data can be viewed via the OGI website at http://oculargenomics.meei.harvard.edu/index.php/ret-trans.

Identifying the genetic cause of patients' retinal degeneration has become especially important with the recent success of clinical trials of gene therapy for RPE65 Leber congenital amaurosis (LCA). As a follow-up to these initial proof-of-concept trials, clinical trials of gene therapy for 4 other genetic forms of inherited retinal degeneration are currently in progress. Further, studies in animal models have reported successful gene therapy for multiple additional genetic types of IRD. There is thus an unprecedented opportunity to translate research progress into provide sight preserving and/or restoring treatment to patients with retinal degenerative disorders.

Abstract (provisional)
Background
The retina is a complex tissue comprised of multiple cell types that is affected by a diverse set of diseases that are important causes of vision loss. Characterizing the transcripts, both annotated and novel, that are expressed in a given tissue has become vital for understanding the mechanisms underlying the pathology of disease.

Results
We sequenced RNA prepared from three normal human retinas and characterized the retinal transcriptome at an unprecedented level due to the increased depth of sampling provided by the RNA-seq approach. We used a non-redundant reference transcriptome from all of the empirically-determined human reference tracks to identify annotated and novel sequences expressed in the retina. We detected 79,915 novel alternative splicing events, including 29,887 novel exons, 21,757 3[prime] and 5[prime] alternate splice sites, and 28,271 exon skipping events. We also identified 116 potential novel genes. These data represent a significant addition to the annotated human transcriptome. For example, the novel exons detected increase the number of identified exons by 3%. Using a high-throughput RNA capture approach to validate 14,696 of these novel transcriptome features we found that 99% of the putative novel events can be reproducibly detected. Further, 15-36% of the novel splicing events maintain an open reading frame, suggesting they produce novel protein products.

Conclusions
To our knowledge, this is the first application of RNA capture to perform large-scale validation of novel transcriptome features. In total, these analyses provide extensive detail about a previously uncharacterized level of transcript diversity in the human retina.

About Massachusetts Eye and Ear
Mass. Eye and Ear clinicians and scientists are driven by a mission to find cures for blindness, deafness and diseases of the head and neck. After uniting with Schepens Eye Research Institute in 2011, Mass. Eye and Ear in Boston became the world's largest vision and hearing research center, offering hope and healing to patients everywhere through discovery and innovation. Mass. Eye and Ear is a Harvard Medical School teaching hospital and trains future medical leaders in ophthalmology and otolaryngology, through residency as well as clinical and research fellowships. Internationally acclaimed since its founding in 1824, Mass. Eye and Ear employs full-time, board-certified physicians who offer high-quality and affordable specialty care that ranges from the routine to the very complex. U.S. News & World Report's "Best Hospitals Survey" has consistently ranked the Mass. Eye and Ear Departments of Otolaryngology and Ophthalmology as among the top hospitals in the nation. Mass. Eye and Ear is home to the Ocular Genomics Institute which aims to translate the promise of personalized genomic medicine into clinical care for ophthalmic disorders. For more information about life-changing care and research, or to learn how you can help, please visit MassEyeAndEar.org.

Reference:
Title: Transcriptome analyses of the human retina identify unprecedented transcript diversity and 3.5 Mb of novel transcribed sequence via significant alternative splicing and novel genes

Authors: Farkas H Michael, Grant R Gregory, White A Joseph, Sousa E Maria, Consugar B Mark, Pierce A Eric.

Journal: BMC Genomics

BMC Genomics. 2013, 14:486. DOI: 10.1186/1471-2164-14-486

URL: http://www.biomedcentral.com/1471-2164/14/486

Grant support:

This work was supported by grants from the National Institutes of Health RO1-EY020902 (EAP), RO1-EY012910 (E.A.P.), F32-EY020747 (M.H.F.); the Foundation Fighting Blindness USA; the Penn Genome Frontiers Institute.

Original press release:http://www.eurekalert.org/pub_releases/2013-07/meae-rra071813.php