Multi-modal investigation of the schizophrenia-associated 3q29 genomic interval reveals global genetic diversity with unique haplotypes and segments that increase the risk for non-allelic homologous recombination

Chromosomal rearrangements that alter the copy number of dosage-sensitive genes can result in genomic disorders, such as the 3q29 deletion syndrome. At the 3q29 region, non-allelic homologous recombination (NAHR) between paralogous copies of segmental duplications (SDs) leads to a recurrent ~1.6 Mbp deletion or duplication, causing neurodevelopmental and psychiatric phenotypes. However, risk factors contributing to NAHR at this locus are not well understood. In this study, we used an optical mapping approach to identify structural variations within the 3q29 interval. We identified 18 novel haplotypes among 161 unaffected individuals and used this information to characterize this region in 18 probands with either the 3q29 deletion or 3q29 duplication syndrome. A significant amount of variation in haplotype prevalence was observed between populations. Within probands, we narrowed down the breakpoints to a ~5 kbp segment within the SD blocks in 89% of the 3q29 deletion and duplication cases studied. Furthermore, all 3q29 deletion and duplication cases could be categorized into one of five distinct classes based on their breakpoints. Contrary to previous findings for other recurrent deletion and duplication loci, there was no evidence for inversions in either parent of the probands mediating the deletion or duplication seen in this syndrome.

A Maturity-Onset Diabetes of The Young (MODY) 5 Young Woman With HNF1B Heterozygosity Missing Based On 17q12 Recurrent Deletion Syndrome

Maturity-onset diabetes of the young type 5 (MODY5) is a rare subtype of MODYs. It caused by mutations of the hepatocyte nuclear factor 1 homeobox b gene (HNF1B). A 21-year-old young woman was admitted to our hospital for severe malnutrition and gastrointestinal symptoms. At age 20, she was diagnosed with type 2 diabetes mellitus and was administered with oral antidiabetic drugs. Soon afterwards, the patient discontinued the medication on her own accord, and then went to the hospital again due to diabetic ketoacidosis. After insulin treatment, diabetic ketoacidosis was cured and blood glucose was controlled satisfactorily. But intractable nausea, vomiting and persistent weight loss was stubborn. Further examination revealed that the patient had hypokalemia and hard rectification hypomagnesemia. Genetic testing revealed about 1.85Mb heterozygous fragment deletion on chromosome 17 and deletion of exons 1-9 of HNF1B heterozygosity missing was approved. Finally, the patient was diagnosed MODY 5 with HNF1B heterozygosity missing based on 17q12 recurrent deletion syndrome. Key words: Maturity-onset diabetes of the young 5 (MODY5), Hepatocyte nuclear factor 1 homeobox b gene (HNF1B), 17q12 Recurrent deletion syndrome

Spread of Endemic SARS-CoV-2 Lineages in Russia Before April 2021

In 2021, the COVID-19 pandemic is characterized by global spread of several lineages with evidence for increased transmissibility. Russia is among the countries with the highest number of confirmed COVID-19 cases, making it a potential hotspot for emergence of novel variants. Here, we show that among the globally significant variants of concern, alpha (B.1.1.7), beta (B.1.351) or gamma (P.1), none have been sampled in Russia before January 2021. Instead, between summer 2020 and spring 2021, the epidemic in Russia has been characterized by the spread of two lineages that are rare elsewhere: B.1.1.317 and a sublineage of B.1.1 including B.1.1.397 (hereafter, B.1.1.397+). Their frequency has increased in different parts of Russia. Mutational composition and frequency dynamics suggest that B.1.1.317 and B.1.1.397+ may be more transmissible than the previously predominant B.1.1. On top of these lineages, in January 2021, B.1.1.7 emerged in Russia, reaching the frequency of 17.4% (95% C.I.: 12.0%-24.4%) in March 2021. Additionally, we identify three novel distinct lineages, AT.1, B.1.1.524 and B.1.1.525, that have started to spread, together reaching the frequency of 11.8% (95% C.I.: 7.5%-18.1%) in March 2021. These lineages carry combinations of several notable mutations, including the S:E484K mutation of concern, deletions at a recurrent deletion region of the spike glycoprotein (S:Δ140-142, S:Δ144 or S:Δ136-144), and nsp6:Δ106-108 (also known as ORF1a:Δ3675-3677). Community-based PCR testing indicates that these variants have continued to spread in April 2021, with the frequency of B.1.1.7 reaching 21.7% (95% C.I.: 12.3%-35.6%), and the joint frequency of B.1.1.524 and B.1.1.525, 15.2% (95% C.I.: 7.6%-28.2%). Although these variants have been displaced by the onset of delta variant in May-June 2021, the frequency increase of lineages B.1.1.317, B.1.1.397+, AT.1, B.1.1.524 and B.1.1.525 suggest that the combinations of mutations observed in them could have increased the rate of their spread.

Spread of endemic SARS-CoV-2 lineages in Russia

In 2021, the COVID-19 pandemic is characterized by global spread of several lineages with evidence for increased transmissibility. Russia is among the countries with the highest number of confirmed COVID-19 cases, making it a potential hotspot for emergence of novel variants. Here, we show that among the globally significant variants of concern, B.1.1.7 (501Y.V1), B.1.351 (501Y.V2) or P.1 (501Y.V3), none have been sampled in Russia before January 2021. Instead, since summer 2020, the epidemic in Russia has been characterized by the spread of two lineages that are rare elsewhere: B.1.1.317 and a sublineage of B.1.1 including B.1.1.397 (hereafter, B.1.1.397+). In February-March 2021, these lineages reached frequencies of 26.9% (95% C.I.: 23.1%-31.1%) and 32.8% (95% C.I.28.6%-37.2%) respectively in Russia. Their frequency has increased in different parts of Russia. Together with the fact that these lineages carry several spike mutations of interest, this suggests that B.1.1.317 and B.1.1.397+ may be more transmissible than the previously predominant B.1.1, although there is no direct data on change in transmissibility. Comparison of frequency dynamics of lineages carrying subsets of characteristic mutations of B.1.1.317 and B.1.1.397+ suggests that, if indeed some of these mutations affect transmissibility, the transmission advantage of B.1.1.317 may be conferred by the (S:D138Y+S:S477N+S:A845S) combination; while the advantage of B.1.1.397+ may be conferred by the S:M153T change. On top of these lineages, in January 2021, B.1.1.7 emerged in Russia, reaching the frequency of 17.4% (95% C.I.: 12.0%-24.4%) in March 2021. Additionally, we identify three novel distinct lineages, AT.1, and two lineages prospectively named B.1.1.v1 and B.1.1.v2, that have started to spread, together reaching the frequency of 11.8% (95% C.I.: 7.5%-18.1%) in March 2021. These lineages carry combinations of several notable mutations, including the S:E484K mutation of concern, deletions at a recurrent deletion region of the spike glycoprotein (S:Δ140-142, S:Δ144 or S:Δ136-144), and nsp6:Δ106-108 (also known as ORF1a:Δ3675-3677). Community-based PCR testing indicates that these variants have continued to spread in April 2021, with the frequency of B.1.1.7 reaching 21.7% (95% C.I.: 12.3%-35.6%), and the joint frequency of B.1.1.v1 and B.1.1.v2, 15.2% (95% C.I.: 7.6%-28.2%). The combinations of mutations observed in B.1.1.317, B.1.1.397+, AT.1, B.1.1.v1 and B.1.1.v2 together with frequency increase of these lineages make them candidate variants of interest.

Recurrent deletions in the SARS-CoV-2 spike glycoprotein drive antibody escape

Zoonotic pandemics, such as that caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can follow the spillover of animal viruses into highly susceptible human populations. The descendants of these viruses have adapted to the human host and evolved to evade immune pressure. Coronaviruses acquire substitutions more slowly than other RNA viruses. In the spike glycoprotein, we found that recurrent deletions overcome this slow substitution rate. Deletion variants arise in diverse genetic and geographic backgrounds, transmit efficiently, and are present in novel lineages, including those of current global concern. They frequently occupy recurrent deletion regions (RDRs), which map to defined antibody epitopes. Deletions in RDRs confer resistance to neutralizing antibodies. By altering stretches of amino acids, deletions appear to accelerate SARS-CoV-2 antigenic evolution and may, more generally, drive adaptive evolution.

Craniofacial features of 3q29 deletion syndrome: application of next generation phenotyping technology.

Introduction: 3q29 deletion syndrome (3q29del) is a recurrent deletion syndrome associated with neuropsychiatric disorders and congenital anomalies. Dysmorphic facial features have been described but not systematically characterized. This study aims to detail the 3q29del craniofacial phenotype and use a machine learning approach to categorize individuals with 3q29del through analysis of 2D photos. Methods: Detailed dysmorphology exam and 2D facial photos were ascertained from 31 individuals with 3q29del. Photos were used to train the next generation phenotyping platform Face2Gene (FDNA, Inc, Boston, MA) to distinguish 3q29del cases from controls, using a proprietary algorithm. Area under the curve of receiver operating characteristic curves (AUC-ROC) were used to determine the capacity of Face2Gene to identify 3q29del cases against controls. Results: In this cohort, the most common observed craniofacial features were prominent forehead (48.4%), prominent nose tip (35.5%), and thin upper lip vermillion (25.8%). The FDNA technology showed an ability to distinguish cases from controls with an AUC-ROC value of 0.873 (p = 0.006). Conclusion: This study found a recognizable facial pattern in 3q29del, as observed by trained clinical geneticists and next generation phenotyping technology. These results expand the potential application of automated technology such as FDNA in identifying rare genetic syndromes, even when facial dysmorphology is subtle.

Genomic analysis of sites that present somatic mutations in mice

The recognition that genomes not only contain all the genetic material of a particular organism, but also have their historical information, has increased the range of phylogenetic studies, which provide evolutionary information. The development of complete genome sequencing techniques, in conjunction with the development of bioinformatics has led to a vertiginous growth in the amount of information deposited in the data banks, and in novel tools for analysis. Genomic analyzes allow us to obtain a comprehensive study of the functioning, content, evolution and origin of genomes.  It has been determined that there are dramatic rearrangements in the genomes, thus demonstrating genomic plasticity. It has been concluded that genomic rearrangements can occur as a consequence of events in which sites of small or large regions within the genome can be deleted, moved, exchanged, or inserted. Within these mentioned events are the deletions or deletions that consist in the loss of a DNA fragment of a chromosome, the size includes a range so diverse ranging from a nucleotide to large cytogenetically visible regions. There is a large number of studies that indicate that in various animal groups there are species in which genomic rearrangements occur during development whose functional relevance is still unknown. This project aims to focus on the study of recurrent deletion sites using the mouse as a study model with the main objective of identifying, characterizing and evaluating the presence of these genomic rearrangements in different genomes of mammals using the mouse genome as a study model for determine its possible functional and evolutionary relevance. The results obtained from this proposal will allow us to generate a general overview of the role played by these sequences, their possible correlation with the genome of other mammalian species will allow us to generate phylogenetic reconstructions.