Analyses of IRD genes in Israeli and Indigenous South Africa population: In colloboration with our colleagues in Israel and South Africa, we performed NGS based analysis (whole exome sequencing, WES) on families with diverse IRD phenotypes. In addition to mutations in known genes (publsihed previously), we also reported unusual findings (Beryozkin et al. 2016). The analysis of 16 South African families have revealed seven different mutations (including six novel) in six distinct families, significantly enhancing the molecular diagnosis of IRD (40%) in South Africa. Novel Genes/Genetic Defects in IRDs: Our WES analyses have led to identification of two novel IRD genes providing insights into retinal pathways and function. (1) We identified mutations in centrosomal-cilia gene CEP78 by WES in patients with cone-rod degeneration and sensorineural hearing loss (Namburi et al. 2016). (2) A combined candidate gene and WES analysis led to discovery of a rare, heterozygous frameshift mutation in FZD5 in autosomal dominant non-syndromic coloboma and implicated WNT-FZD signaling in pathogenesis of coloboma (Liu et al. 2016). Genetics of AMD Common and Rare Variant Analysis As a part of International Age-related Macular Degeneration Genomics Consortium (IAMDGC, we have participated in analysis of 16,144 patients and 17,832 controls using a custom-designed HumanCoreExome Chip. This remarkable study identified 52 independently associated common and rare variants at 34 loci. Presence of very rare coding variants in CFH, CFI and TIMP3 and a splice variant in SLC16A8 suggested their causal roles in AMD (Fritsche et al. 2016). We believe that a similar consortium like approach will be useful in dissecting genetic risk alleles for diabetic retinopathy (Mishra et al. 2016). To discover additional rare variants and characterize the GWAS locus further, we performed whole genome sequencing of 2,394 cases and 2,393 controls and the analysis is in progress. We also generated WES data in 19 large multigenerational AMD families to ascertain high-penetrance causative allele(s). To enhance the power of analysis, we are collaborating with other groups to extract useful information. Functional Genomic Analysis of AMD Current variants/loci can explain 50-60% of AMD heritability, with ARMS2 and CFH accounting for bulk of the effect. Our collaborative studies suggest increased retinal mitochondrial DNA damage in patients with CFH risk alleles (Ferrington et al. 2016). However, causal variants and underlying mechanisms remain largely unknown for majority of the loci. Thus we are now focusing on dissection of relative contributions of variants, genes and pathways to AMD pathology. A Reference Transcriptome of Adult Human Retina:. We have generated a reference transcriptome of the normal human retina by RNA-seq analysis of 128 healthy donor samples (from Dr. D Ferrington) We have characterized both annotated coding regions as well as un-annotated transcripts using de novo assembly,. This dataset would be valuable for the vision community while designing interventions for retinal diseases. Gene and Pathways Associated with AMD Progression: To elucidate genetic underpinnings of progression of AMD phenotypes, AREDS1 data is being examined in collaborative studies. However, lack of longitudinal clinical information in most datasets makes it harder to replicate our findings. Thus we are taking advantage of transcriptomic studies of 390 donor AMD retinas (197 early, 127 intermediate, 66 advanced). We are focusing on AMD-associated and IRD genes, and novel coding and noncoding RNA genes from the region of 34 AMD loci. We are using WGCNA, GO analysis and random forest based approaches for identifying disease pathways and networks that are disrupted during AMD pathogenesis. Contribution to Genomic Data Analysis Our large genotyping data has contributed to generation of genome-wide maps of human variants (1000 Genome Project Consortium, 2015) and development of statistical methods (Fan et al. 2016) and imputation (McCarthy et al. 2016; Das et al. 2016) to analyze human genome data. Mouse Models of Retinal Degeneration We are using mouse models to investigate disease mechanisms and test potential therapies. In one such study we demonstrated that RPGR is glutamylated by TTLL5 and that the Rpgr- and Ttll5-knockout mice show similar phenotypes (Sun et al. 2016). Mitochondrial Dysfunction as a Marker of PR DIstress in Retinal and Macular Degeneration Our transcriptome analyses of aging and degenerating photoreceptors indicated a small yet discrete change in mitochondria-associated genes. To test the impact of aging and disease on mitochondrial function, we are examining mitochondrial metabolism (Rueda et al. 2016) and directly measured oxygen consumption rate (OCR) in acutely isolated, ex vivo mouse retina and demonstrated that healthy adult photoreceptors have low reserve capacity and would therefore be more vulnerable to altered homeostasis (Kooragayala et al. 2015). The retinas of Pde6brd1/rd1, Cep290rd16/rd16 and Rpgrip1-/- mice have dysfunctional or no photoreceptors, and reveal reduced OCR and high mitochondrial reserve capacity. Our studies will help provide physiological bases for photoreceptor dysfunction in retinal diseases.

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van Asten, Freekje; Simmons, Michael; Singhal, Ayush et al. (2018) A Deep Phenotype Association Study Reveals Specific Phenotype Associations with Genetic Variants in Age-related Macular Degeneration: Age-Related Eye Disease Study 2 (AREDS2) Report No. 14. Ophthalmology 125:559-568
Keenan, Tiarnan D; Agrón, Elvira; Domalpally, Amitha et al. (2018) Progression of Geographic Atrophy in Age-related Macular Degeneration: AREDS2 Report Number 16. Ophthalmology 125:1913-1928
Yan, Qi; Ding, Ying; Liu, Yi et al. (2018) Genome-wide analysis of disease progression in age-related macular degeneration. Hum Mol Genet 27:929-940
Zelinger, Lina; Swaroop, Anand (2018) RNA Biology in Retinal Development and Disease. Trends Genet 34:341-351
Adlakha, Yogita K; Swaroop, Anand (2018) Determination of Mitochondrial Oxygen Consumption in the Retina Ex Vivo: Applications for Retinal Disease. Methods Mol Biol 1753:167-177
Corso-Díaz, Ximena; Jaeger, Catherine; Chaitankar, Vijender et al. (2018) Epigenetic control of gene regulation during development and disease: A view from the retina. Prog Retin Eye Res 65:1-27
Pietraszkiewicz, Alexandra; van Asten, Freekje; Kwong, Alan et al. (2018) Association of Rare Predicted Loss-of-Function Variants in Cellular Pathways with Sub-Phenotypes in Age-Related Macular Degeneration. Ophthalmology 125:398-406
Swaroop, Manju; Brooks, Matthew J; Gieser, Linn et al. (2018) Patient iPSC-derived neural stem cells exhibit phenotypes in concordance with the clinical severity of Mucopolysaccharidosis I. Hum Mol Genet :
DiStefano, Tyler; Chen, Holly Yu; Panebianco, Christopher et al. (2018) Accelerated and Improved Differentiation of Retinal Organoids from Pluripotent Stem Cells in Rotating-Wall Vessel Bioreactors. Stem Cell Reports 10:300-313
Veleri, Shobi; Nellissery, Jacob; Mishra, Bibhudatta et al. (2017) REEP6 mediates trafficking of a subset of Clathrin-coated vesicles and is critical for rod photoreceptor function and survival. Hum Mol Genet 26:2218-2230

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