Biology subjects

Moldovan, M. A.

Publications and source records attributed to Moldovan, M. A..

6 recordsLinked to original sources

bioRxiv2026

Inference of elevated mutation rates and variant effects using 700k exomes

Genomic sequencing is now widely accessible for genetic diagnostics and is emerging as a component of newborn screening. This technological development generates the need to characterize incoming mutations, create comprehensive datasets of genes causing rare Mendelian disorders, and identify pathogenic variants. Large-scale exome sequencing datasets such as Genome Aggregation Database (gnomAD) have been assembled to help address these challenges. The recent release of gnomAD (v4; n = 730,947) uncovers millions of rare coding variants, many of which have arisen more than once by independent recurrent mutations in the rapidly growing recent human population. Here, we use newly developed theoretical understanding of sampling properties of rare variants to estimate key population genetics parameters of practical importance to human genetics such as demography history, mutation rate, and selection. Solely relying on population data, our method Population Inferred Estimates of Selection (PIES) identifies novel genes with loss-of-function mutational hotspots likely due to selection in spermatogonia. PIES efficiently estimates selection coefficients for heterozygous loss-of-function variants. Combining population genetics inference with variant effect predictors, PIES predicts pathogenic missense mutations and improves variant prioritization for genetic diagnostics and newborn screening.

genetics↗

bioRxiv2024

Joint, multifaceted genomic analysis enables diagnosis of diverse, ultra-rare monogenic presentations

Genomics for rare disease diagnosis has advanced at a rapid pace due to our ability to perform "N-of-1" analyses on individual patients with ultra-rare diseases. The increasing sizes of ultra-rare disease cohorts internationally newly enables cohort-wide analyses for new discoveries, but well-calibrated statistical genetics approaches for jointly analyzing these patients are still under development.1,2 The Undiagnosed Diseases Network (UDN) brings multiple clinical, research and experimental centers under the same umbrella across the United States to facilitate and scale N-of-1 analyses. Here, we present the first joint analysis of whole genome sequencing data of UDN patients across the network. We introduce new, well-calibrated statistical methods for prioritizing disease genes with de novo recurrence and compound heterozygosity. We also detect pathways enriched with candidate and known diagnostic genes. Our computational analysis, coupled with a systematic clinical review, recapitulated known diagnoses and revealed new disease associations. We further release a software package, RaMeDiES, enabling automated cross-analysis of deidentified sequenced cohorts for new diagnostic and research discoveries. Gene-level findings and variant-level information across the cohort are available in a public-facing browser (https://dbmi-bgm.github.io/udn-browser/). These results show that N-of-1 efforts should be supplemented by a joint genomic analysis across cohorts.

genetics↗

bioRxiv2022

Non-triplet genetic code in ciliate Euplotes ciliates is a result of neutral evolution

Although several variants of the standard genetic code are known, its triplet character is universal with an exception in ciliates Euplotes, where stop codons at internal mRNA positions specify ribosomal frameshifting. How did Euplotes spp. evolved and maintained such an unusual genetic code remains a mystery. To investigate these questions, we explored the evolution of frameshifting occurrence in Euplotes genes. We sequenced and analyzed several transcriptomes from different Euplotes spp to characterize the gain-and-loss dynamics of frameshift sites. Surprisingly, we found a sharp asymmetry between frameshift gain and frameshift loss events with the former exceeding the latter by about 10 folds. Further analysis of mutation rates in protein-coding and non-coding regions revealed that this asymmetry is expected based on single nucleotide mutation rates and does not require positive selection for frameshifting. We found that the number of frameshift sites in Euplotes spp is increasing and is far from the steady state. The steady equilibrium state is expected in about 0.1 to 1 billion years leading to about a 10 fold increase in the number of frameshift sites in Euplotes genes.

evolutionary biology↗

bioRxiv2021

A hierarchy in clusters of cephalopod mRNA editing sites

RNA editing in the form of substituting adenine to inosine (A-to-I editing) is the most frequent type of RNA editing, observed in many metazoan species. A-to-I editing sites form clusters in most studied species, and editing at clustered sites depends on editing of the adjacent sites. Although functionally important in some specific cases, A-to-I editing in most considered species is rare, the exception being soft-bodied cephalopods (coleoids), where tens of thousands of potentially important A-to-I editing sites have been identified, making coleoids an ideal object for studying of general properties and evolution of A-to-I editing sites. Here, we apply several diverse techniques to demonstrate a strong tendency of coleoid RNA editing sites to cluster along the transcript. We identify three distinct types of editing site clusters, varying in size, and describe RNA structural features and mechanisms likely underlying formation of these clusters. In particular, these observations may resolve the paradox of sequence conservation at large distances around editing sites.

bioinformatics↗

bioRxiv2020

Phospho-islands and the evolution of phosphorylated amino acids in mammals

BackgroundProtein phosphorylation is the best studied post-translational modification strongly influencing protein function. Phosphorylated amino acids not only differ in physico-chemical properties from non-phosphorylated counterparts, but also exhibit different evolutionary patterns, tending to mutate to and originate from negatively charged amino acids. The distribution of phosphosites along protein sequences is non-uniform, as phosphosites tend to cluster, forming so-called phospho-islands. MethodsHere, we have developed an HMM-based procedure for the identification of phospho-islands and studied the properties of the obtained phosphorylation clusters. To check robustness of evolutionary analysis, we consider different models for the reconstructions of ancestral phosphorylation states. ResultsClustered phosphosites differ from individual phosphosites in several functional and evolutionary aspects including underrepresentation of phosphotyrosines, higher conservation, more frequent mutations to negatively charged amino acids. The spectrum of tissues, frequencies of specific phosphorylation contexts, and mutational patterns observed near clustered sites also are different.

genetics↗

bioRxiv2020

Adaptive evolution at mRNA editing sites in soft-bodied cephalopods

The bulk of variability in mRNA sequence arises due to mutation - change in DNA sequence which is heritable if it occurs in the germline. However, variation in mRNA can also be achieved by post-translational modification including mRNA editing, changes in mRNA nucleotide sequence that mimic the effect of mutations. Such modifications are not inherited directly; however, as the processes affecting them are encoded in the genome, they have a heritable component, and therefore can be shaped by selection. In soft-bodied cephalopods, adenine-to-inosine RNA editing is very frequent, and much of it occurs at nonsynonymous sites, affecting the sequence of the encoded protein. Here, we show that mRNA editing of individual nonsynonymous sites in cephalopods originates in evolution through substitutions at regions adjacent to these sites. As such substitutions mimic the effect of the substitution at the edited site itself, we hypothesize that they are favored by selection if the inosine is selectively advantageous to adenine at the edited position. Consistent with this hypothesis and with observations on Drosophila and human editing sites, we show that edited adenines are more frequently substituted with guanine, an informational analogue of inosine, in the course of evolution than their unedited counterparts, and for heavily edited adenines, these transitions are favored by positive selection. Thus, our study shows that coleoid editing sites may enhance adaptation, which, together with distinct evolutionary features of Drosophila and human editing sites, points at a general role of RNA editing in the molecular evolution of metazoans.

evolutionary biology↗