AnFiSA: An open-source computational platform for the analysis of sequencing data for rare genetic disease.

Despite genomic sequencing rapidly transforming from being a bench-side tool to a routine procedure in a hospital, there is a noticeable lack of genomic analysis software that supports both clinical and research workflows as well as crowdsourcing. Furthermore, most existing software packages are not forward-compatible in regards to supporting ever-changing diagnostic rules adopted by the genetics community. Regular updates of genomics databases pose challenges for reproducible and traceable automated genetic diagnostics tools. Lastly, most of the software tools score low on explainability amongst clinicians. We have created a fully open-source variant curation tool, AnFiSA, with the intention to invite and accept contributions from clinicians, researchers, and professional software developers. The design of AnFiSA addresses the aforementioned issues via the following architectural principles: using a multidimensional database management system (DBMS) for genomic data to address reproducibility, curated decision trees adaptable to changing clinical rules, and a crowdsourcing-friendly interface to address difficult-to-diagnose cases. We discuss how we have chosen our technology stack and describe the design and implementation of the software. Finally, we show in detail how selected workflows can be implemented using the current version of AnFiSA by a medical geneticist.

[Polymorphism of trinucleotide CAG-repeats of the first exon of the androgen receptor gene in the Tomsk population]. / Polimorfizm trinukleotidnykh CAG-povtorov pervogo ékzona gena retseptora androgenov v populiatsii g. Tomska.

Polymorphism of the CAG repeat of exon 1 of the androgen receptor (AR) gene was analyzed in the Tomsk population. In total, 12 alleles varying in size from 285 to 318 bp (21-32 CAG units) were revealed. The allele frequency distribution did not differ from the normal one. No difference in allele frequencies was detected between men and women of the same generation. The observed heterozygosity was equal to the expected one (0.88 +/- 0.03). Compared with other populations, the Tomsk population displayed a narrower allele spectrum and a bias of the most common allele to a greater repeat number. The results obtained may reflect specific population genetic processes characteristic of young developing populations.

[X-chromosome inactivation in mammalian ontogeny]. / Inaktivatsiia X-khromosomy v ontogeneze mlekopitaiushchikh.

This review is dedicated to a very interesting problem of developmental genetics: dose compensation of the X-chromosome genes in somatic cells of female mammals. A sequence of events related to X-chromosome inactivation during cell differentiation at the early embryonic stages, association of distributed X-chromosome heterochromatization with developmental pathologies, evolutionary origin of X-inactivation, and its relationship with genomic imprinting are considered.

[The absence of uniparental X-chromosome inheritance in spontaneous abortuses with a 46,XX karyotype]. / Otsutstvie odnoroditel'skogo nasledovaniia X-khromosom u spontannykh abortusov s 46.XX-kariotipom.

The problem of the presence of imprinted regions on the X-chromosome and the possible influence of the imprinted expression of X-linked genes on the embryonic development in man remains largely unsolved. A comparison of the uniparental inheritance of chromosomes or of their regions having different phenotypic manifestations provides an instrument with which to study the phenomenon of genomic imprinting at the chromosomal level. Assuming that the imprinted inactivation of X-chromosomes is functionally significant for embryonic development, we have studied several polymorphic micro- and minisatellite loci of X-chromosomes in 52 fetuses with karyotype 46,XX, which were spontaneously aborted during the first trimester of pregnancy. The purpose was to determine the contribution of uniparental disomy for the X-chromosome in any disturbances of the embryonic development. We found that inheritance of X-chromosomes was biparental in the studied embryos, suggesting the absence of any significant contribution of the parental origin of the X-chromosome to embryonic mortality occurring between 4 and 12 weeks of development.

[Sex ratio in early embryonal mortality in man]. / K voprosu o sootnoshenii polov pri rannei émbrional'noi letal'nosti u cheloveka.

The problem of the functioning specificity of sex chromosomes during the early stages of embryogenesis in man and the associated problem of the sex ratio in spontaneous and induced abortions, as well as in newborns, remains open. We have conducted a cytogenetic examination of 342 spontaneous abortions divided into three clinical groups on the basis of the severity of the developmental disturbances of the embryo: spontaneous abortions sensu stricto with a developed embryo without any significant intrauterine delay of development (n = 100), nondeveloping pregnancies (n = 176), and anembryonic fetuses (n = 66). The frequency of chromosomal mutations in these groups was 22.0, 48.3, and 48.5%, respectively. Statistical analysis has demonstrated significant differences between the studied groups in the frequencies of the normal and abnormal karyotypes: the major contributions to these differences were associated with autosomal trisomy, triploidy, and 46,XY karyotype. The presence of 46,XY may reflect specific genetic mechanisms of prenatal mortality of embryos with normal karyotype, associated with sex and/or with the imprinting of X-chromosomes. The sex ratio in spontaneous abortions with normal karyotype was as follows: 0.77 for spontaneous abortions with well-developed embryos without any significant intrauterine delay of development; 0.60 for non-developing pregnancies; and 0.31 for anembryonic fetuses. An analysis of DNA from the embryos and their parents has demonstrated a low probability of contamination of cell cultures with mother cells as a possible source of prevalence of embryos with 46,XX karyotype among spontaneous abortions. Nondeveloping pregnancies and anembryonic fetuses showed statistically significant differences in the sex ratio (1.11) from the control group consisting of medical abortions. Differences in the sex ratio were due to an increasingly lower proportion of embryos with karyotype 46,XY (relative to the expected one) among the fetuses with an increased severity of developmental disturbances. The statistical "chances ratio" index also provided evidence that embryos with 46,XY karyotype had a higher propensity to produce a well-formed fetus as compared with the female embryos. We propose that the expression of genes of the maternal X-chromosome in XY embryos supports a more stable development during early embryogenesis as compared with XX embryos. In the latter case, normal development is coupled with the operation of an additional mechanism for compensation of the dose of X-linked genes. Operation of this mechanism increases the probability of disturbances in female embryos. A higher viability of XY embryos during the early stages of ontogenesis in man appears to explain their underrepresentation in samples of spontaneously aborted embryos and appears to be the major factor responsible for the deviation of the sex ratio from the theoretically expected value.