COVID-19 has effectively spread worldwide. As of May 2020, Turkey is 3 among the top ten countries with the most cases. A comprehensive genomic 4 characterization of the virus isolates in Turkey is yet to be carried out. Here, we built a 5 phylogenetic tree with 15,277 severe acute respiratory syndrome coronavirus 2 (SARS-6 CoV-2) genomes. We identified the subtypes based on the phylogenetic clustering in 7 comparison with the previously annotated classifications. We performed a phylogenetic 8 analysis of the first thirty SARS-CoV-2 genomes isolated and sequenced in Turkey. Our 9 results suggest that the first introduction of the virus to the country is earlier than the first 10 reported case of infection. Virus genomes isolated from Turkey are dispersed among most 11 types in the phylogenetic tree. Two of the seventeen sub-clusters were found enriched 12 with the isolates of Turkey, which likely have spread expansively in the country. Finally, 13 we traced virus genomes based on their phylogenetic placements. This analysis suggested 14 multiple independent international introductions of the virus and revealed a hub for the 15 inland transmission. We released a web application to track the global and interprovincial 16 virus spread of the isolates from Turkey in comparison to thousands of genomes 17 worldwide. 18 19 20 24 SARS-CoV genome, the reason behind it's pandemic behaviour is still unclear. Genome 25 sequences around the world were revealed and deposited into public databases such as 26 GISAID (Shu and McCauley 2017). It is crucial to reveal the evolutionary events of 27 SARS-CoV-2 to understand the types of the circulating genomes as well as in which parts 28 of the genome differ across these types. 29 30 The SARS-CoV-2 virus originated from SARS-CoV, and the intermediate versions 31 between two human viruses were found in bats and pangolins (Li, et al. 2020). The virus 32 has been under a strong purifying selection (Li, et al. 2020). With the genomes obtained 33 so far, the sequences of SARS-CoV-2 genomes showed more than 99.9% percent identity 34 suggesting a recent shift to the human species (Tang, et al. 2020). Still, there are clear 35 evolutionary clusters in the genome pool. Various studies use different methods such as 36 SNP based (Tang, et al. 2020) or entropy (Zhao, et al. 2020) based to identify evolving 37 virus strains to reveal genomic regions responsible for transmission and evolution of the 38 virus. Tang et. al identified S and L strains among 103 SARS-CoV-2 genomes based on 39 two SNPs at ORF1ab and ORF8 regions which encode replicase/transcriptase and ATF6, 40 respectively (Tang, et al. 2020). Entropy-based approach generated informative subtype 41 markers from 17 informative positions to cluster evolving virus genomes (Zhao, et al.42 2020). Another study defined a competitive subtype based on D614G mutation at spike 43 59 2.1. Data retrieval, multiple sequence alignment and phylogenomic tree 60 generation 61The entire SARS-CoV-2 genome sequences, along with their metadata were retriev...

COVID-19 has effectively spread worldwide. As of May 2020, Turkey is among the top ten countries with the most cases. A comprehensive genomic characterization of the virus isolates in Turkey is yet to be carried out. Here, we built a phylogenetic tree with globally obtained 15,277 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes. We identified the subtypes based on the phylogenetic clustering in comparison with the previously annotated classifications. We performed a phylogenetic analysis of the first 30 SARS-CoV-2 genomes isolated and sequenced in Turkey. We suggest that the first introduction of the virus to the country is earlier than the first reported case of infection. Virus genomes isolated from Turkey are dispersed among most types in the phylogenetic tree. We find 2 of the seventeen subclusters enriched with the isolates of Turkey, which likely have spread expansively in the country. Finally, we traced virus genomes based on their phylogenetic placements. This analysis suggested multiple independent international introductions of the virus and revealed a hub for the inland transmission. We released a web application to track the global and interprovincial virus spread of the isolates from Turkey in comparison to thousands of genomes worldwide.

Introduction Pathogenic variants in SURF1 , a nuclear-encoded gene encoding a mitochondrial chaperone involved in COX assembly, are one of the most common causes of Leigh syndrome (LS). Material-methods Sixteen patients diagnosed to have SURF1 -related LS between 2012 and 2020 were included in the study. Their clinical, biochemical and molecular findings were recorded. 10/16 patients were diagnosed using whole-exome sequencing (WES), 4/16 by Sanger sequencing of SURF1 , 1/16 via targeted exome sequencing and 1/16 patient with whole-genome sequencing (WGS). The pathogenicity of SURF1 variants was evaluated by phylogenetic studies and modelling on the 3D structure of the SURF1 protein. Results We identified 16 patients from 14 unrelated families who were either homozygous or compound heterozygous for SURF1 pathogenic variants. Nine different SURF1 variants were detected The c.769G > A was the most common variant with an allelic frequency of 42.8% (12/28), c.870dupT [(p.Lys291*); (8/28 28.5%)], c.169delG [(p.Glu57Lysfs*15), (2/24; 7.1%)], c.532 T > A [(p.Tyr178Asn); (2/28, 7.1%)], c.653_654delCT [(p.Pro218Argfs*29); (4/28, 14.2%)] c.595_597delGGA [(p.Gly199del); (1/28, 3.5%)], c.751 + 1G > A (2/28, 4.1%), c.356C > T [(p.Pro119Leu); (2/28, 3.5%)] were the other detected variants. Two pathogenic variants, C.595_597delGGA and c.356C > T, were detected for the first time. The c.769 G > A variant detected in 6 patients from 5 families was evaluated in terms of phenotype-genotype correlation. There was no definite genotype – phenotype correlation. Conclusions To date, more than 120 patients of LS with SURF1 pathogenic variants have been reported. We shared the clinical, molecular data and natural course of 16 new SURF1 defect patients from our country. This study is the first comprehensive research from Turkey that provides information about disease-causing variants in the SURF1 gene. The identification of common variants and phenotype of the SURF1 gene is important for understanding SURF1 related LS. Synopsis SURF1 gene defects are one of the most important causes of LS; patients have a homogeneous clinical and biochemical phenotype.

Evolutionary conservation is a fundamental resource for predicting the substitutability of amino acids and loss of function in proteins. The use of multiple sequence alignment alone—without considering the evolutionary relationships among sequences—results in the redundant counting of evolutionarily related alteration events as if they were independent. Here we propose a new method, PHACT that predicts the pathogenicity of missense mutations directly from the phylogenetic tree of proteins. PHACT travels through the nodes of the phylogenetic tree and evaluates the deleteriousness of a substitution based on the probability differences of ancestral amino acids between neighboring nodes in the tree. Moreover, PHACT assigns weights to each node in the tree based on their distance to the query organism. For each potential amino acid substitution, the algorithm generates a score that is used to calculate the effect of substitution on protein function. To analyze the predictive performance of PHACT, we performed various experiments over the subsets of two datasets that include 3023 proteins and 61662 variants in total. The experiments demonstrated that our method outperformed the widely used pathogenicity prediction tools (i.e., SIFT and PolyPhen-2) and achieved better predictive performance than did other conventional statistical approaches presented in dbNSFP. The PHACT source code is available at https://github.com/CompGenomeLab/PHACT.

The Calcium Sensing Receptor (CaSR) is very important in controlling the levels of calcium in the body by interacting with different types of G-protein. This receptor is highly conserved among other G-protein coupled receptors (GPCRs) and has been linked to disorders affecting the balance of calcium in the body, such as hypercalcemia and hypocalcemia. Although there has been progress in understanding the structure and function of CaSR, there is still a lack of knowledge about which specific residues are important for their function and how it differs from other receptors in the same class. In this study, we used phylogeny-based methods to identify functionally-equivalent orthologs of CaSR, predict the importance of each residue, and calculate specificity-determining position (SDP) scores to uncover the evolutionary basis of its function. Our results showed that the CaSR subfamily is highly conserved, with higher SDP scores than its closest receptor subfamilies. Residues with high SDP scores are likely to be critical in receptor activation and pathogenicity. We applied gradient-boosting trees with evolutionary metrics as inputs to predict the functional consequences of each substitution, and discriminate between gain and loss-of-function mutations those causing hypo- and hypercalcemia, respectively. Our study provides insight into the evolutionary fine-tuning of CaSR, which can help understand its role in calcium balance and related disorders.